Enhanced clickability of doubly sterically-hindered aryl azides

Abstract

Steric character is one of the most fundamental factors to determine the reactivity of the substrate in organic synthesis. In bimolecular reaction, the sterically-bulky group situated close to the reactive center generally prevents the approach of the reaction partner retarding the bond formation. This report describes, to the contrary, significantly enhanced reactivity of 2,6-disubstituted phenyl azides observed in catalyst-free 1,3-dipolar cycloaddition with alkynes, unexpectedly reacting faster than unsubstituted phenyl azide and even more faster than unhindered alkyl azide, despite the steric hindrance adjacent to the reactive azido group. Experimental and computational studies have indicated that the steric hindrance eliciting the inhibition of resonance between azido group and the aromatic ring is the primary cause of this apparently-paradoxical phenomenon. This is the first type of steric acceleration, indicating a possibility of designing a highly reactive functional group by strategically locating it in the sterically-congested environment.

Highly accelerated inverse electron-demand cycloaddition of electron-deficient azides with aliphatic cyclooctynes

“…For example, Hosoya et al noted a 3.9 Â increase in reaction rate for p-MeOC 6 H 4 N 3 (I) versus PhN 3 in reaction with 7 (ref. 20). A positive effect on reactivity (1.6 Â faster) upon cyclooctyne fluorination, as in DIFO 8 or BARAC 25 , or upon DIBAC halogenation (up to 2.2 Â faster) 26 further supports this notion.…”

“…Stimulated by this finding, we were curious to investigate whether cycloaddition of BCN with 2,6-diisopropylphenyl azide (E) would be further accelerated, as reported for Sondheimer diyne 7 (ref. 20). However, in this case, only a modest effect was observed (1.5 Â faster than unsubstituted phenyl azide, D), while DIBAC, a dibenzoannulated cyclooctyne, like Sondheimer diyne, showed a large increase in reaction rate (23 Â faster).…”

“…It must be noted, however, that the absolute rate constants as measured by this protocol are about twofold lower than those reported earlier in other solvent systems 1 . One sensible explanation lies in the fact that 1,3-dipolar cycloadditions generally proceed faster in a more polar environment (for example, 50% aqueous CH 3 CN) 23 , as for example was also demonstrated by us for strain-promoted nitrone cycloadditions 24 19,20 , reaction with BCN unexpectedly proceeded 2.9 Â faster in comparison with benzyl azide (A, entry 1). Thus, in a side-by-side comparison, reaction of phenyl azide with BCN is in fact 6 Â faster than with DIBAC, quite opposite to aliphatic azides.…”

“…The reason to generally avoid aromatic azides for SPAAC presumably lies in the reported sevenfold reduced reactivity of phenyl azide in comparison with an aliphatic azide, at least in conjunction with DIBAC 19 . The observation that reaction rates of aromatic azides are hardly influenced by changing the electronic nature of substituents (as determined for p-methoxy and p-CF 3 -phenyl azide) 20 , has provided further ground to avoid aromatic azides for SPAAC. However, because an in-depth structure-reactivity relationship of azides with cyclooctynes is lacking to date, we designed a comparative study of aliphatic and aromatic azides in their reactivity with an aliphatic cyclooctyne (BCN) and a dibenzoannulated cyclooctyne (DIBAC).…”

“…Our investigations on the structure-reactivity relationship of azides in strain-promoted cycloadditions were stimulated by the fact that much effort has been devoted to the development of more reactive cyclooctynes 8,[10][11][12][13][14][15] , but only scant information is available on the influence of the azide structure on SPAAC rates 19,20 . In addition, it struck us that SPAAC reaction rate constants are nearly always determined with an aliphatic azide (typically benzyl azide), but rarely with an aromatic azide.…”