Rate Determination of Azide Click Reactions onto Alkyne Polymer Brush Scaffolds: A Comparison of Conventional and Catalyst-Free Cycloadditions for Tunable Surface Modification

Abstract

The postpolymerization functionalization of poly(N-hydroxysuccinimide 4-vinylbenzoate) brushes with reactive alkynes that differ in relative rates of activity of alkyne-azide cycloaddition reactions is described. The alkyne-derived polymer brushes undergo "click"-type cycloadditions with azido-containing compounds by two mechanisms: a strain-promoted alkyne-azide cycloaddition (SPAAC) with dibenzocyclooctyne (DIBO) and azadibenzocyclooctyne (ADIBO) or a copper-catalyzed alkyne-azide cycloaddition (CuAAC) to a propargyl group (PPG). Using a pseudo-first-order limited rate equation, rate constants for DIBO, ADIBO, and PPG-derivatized polymer brushes functionalized with an azide-functionalized dye were calculated as 7.7 × 10(-4), 4.4 × 10(-3), and 2.0 × 10(-2) s(-1), respectively. The SPAAC click reactions of the surface bound layers were determined to be slower than the equivalent reactions in solution, but the relative ratio of the reaction rates for the DIBO and ADIBO SPAAC reactions was consistent between solution and the polymer layer. The rate of functionalization was not influenced by the diffusion of azide into the polymer scaffold as long as the concentration of azide in solution was sufficiently high. The PPG functionalization by CuAAC had an extremely fast rate, which was comparable to other surface click reaction rates. Preliminary studies of dilute solution azide functionalization indicate that the diffusion-limited regime of brush functionalization impacts a 50 nm polymer brush layer and decreases the pseudo-first-order rate by a constant diffusion-limited factor of 0.233.

Site‐Specific In Vivo Bioorthogonal Ligation via Chemical Modulation

“…The reaction rate constant of original azide-alkyne click chemistry has been reported to be about 10-100 M -1 s -1 ( k obs ) per 10-100 μM Cu(I) catalyst (Table 1). [25] Strained alkynes without copper showed about 1,000-fold slower click reaction (1-140 × 10 -3 M -1 s -1 ), [26] while the Tz-TCO reaction has been reported as fast as 6×10 3 M -1 s -1 , [27] which is one of the fastest copper-free click reactions reported in literature. However, considering the association rate constant of biological ligands to their receptors (e.g., Nimotuzumab and epidermal growth factor receptor, k on = 5.2 × 10 4 M -1 s -1 ), [28] click chemistry is still slower than other biological binding processes.…”

Rapid and Complete Surface Modification with Strain‐Promoted Oxidation‐Controlled Cyclooctyne‐1,2‐Quinone Cycloaddition (SPOCQ)

“…Based on this model, the rate constant for SPOCQ was found to be (10.1±0.3)×10 −3  s −1 (Figure 4 B, inset), two‐fold faster than the interfacial SPAAC of BCN with azides and about 15‐fold faster than other reported surface‐SPAAC reactions 17d. This finding differs dramatically from the 1000‐fold larger difference in magnitude observed for SPOCQ and SPAAC in protic solutions (methanol/water 1:1) 5…”

Sequential “Click” – “Photo-Click” Cross-Linker for Catalyst-Free Ligation of Azide-Tagged Substrates

“…We have chosen azadibenzocyclooctyne (ADIBO, Scheme 1) 21 as the first SPAAC moiety, as this cyclooctyne combines high reactivity toward azides with excellent aqueous stability and long shelf life. 22 PhotoDIBO (Scheme 1), on the other hand, does not react with azides in the dark and possesses excellent thermal stability. 23 Exposure of photoDIBO moiety to a low intensity 350 nm light results in the efficient decarbonylation and the formation of azide-reactive dibenzocyclooctyne (DIBO).…”