Selective Transition State Stabilization via Hyperconjugative and Conjugative Assistance: Stereoelectronic Concept for Copper-Free Click Chemistry

Abstract

Dissection of stereoelectronic effects in the transition states (TSs) for noncatalyzed azide-alkyne cycloadditions suggests two approaches to selective transition state stabilization in this reaction. First, the formation of both 1,4- and 1,5-isomers is facilitated via hyperconjugative assistance to alkyne bending and C···N bond formation provided by antiperiplanar σ-acceptors at the propargylic carbons. In addition, the 1,5-TS can be stabilized via attractive C-H···F interactions. Although the two effects cannot stabilize the same transition state for the cycloaddition to α,α-difluorocyclooctyne (DIFO), they can act in a complementary, rather than competing, fashion in acyclic alkynes where B3LYP calculations predict up to ∼1 million-fold rate increase relative to 2-butyne. This analysis of stereoelectronic effects is complemented by the distortion analysis, which provides another clear evidence of selective TS stabilization. Changes in electrostatic potential along the reaction path revealed that azide polarization may create unfavorable electrostatic interactions (i.e., for the 1,5-regioisomer formation from 1-fluoro-2-butyne and methyl azide). This observation suggests that more reactive azides can be designed via manipulation of charge distribution in the azide moiety. Combination of these effects with the other activation strategies should lead to the rational design of robust acyclic and cyclic alkyne reagents for fast and tunable "click chemistry". Further computational and experimental studies confirmed the generality of the above accelerating effects and compared them with the conjugative TS stabilization by π-acceptors.

Reactivity of Biarylazacyclooctynones in Copper-Free Click Chemistry

“…Alabugin and co-workers have shown that the observed acceleration results from hyperconjugative stabilization of the cycloaddition transition state via electron donation from the in-plane alkyne π-orbital to the σ* C–F -orbital. 9 …”

ChemInform Abstract: Synthesis of α,α‐Difluoromethylene Alkynes by Palladium‐Catalyzed gem‐Difluoropropargylation of Aryl and Alkenyl Boron Reagents.

“…On the basis of this strategy, a series of carbon-substituted internal alkynes with a CF 2 Ar substituent could be efficiently prepared, offering a complementary method to the approach illustrated in Table 2 (3 r-u). [19] In view of its good reactivity, simple synthesis, and stability, we believe that terminal alkyne 11 and its derivatives may have applications in drug development and chemical biology. [17a] To our delight, the [3+2] cycloaddition product 12 was obtained in high yield (93 %, as a mixture of regioisomers: 12 a, 70%; 12 b, 23%) when terminal alkyne 11 was treated with the dansyl fluorophore 13 in the absence of copper in phosphate buffered saline (PBS; pH 7.4) at 37 8C.…”

“…[b] Determined by19 F NMR spectroscopy using fluorobenzene as an internal standard; the value in brackets denotes the yield of isolated product. [c] K 2 CO 3 (3.0 equiv).…”

Practical, Asymmetric Route to Sitagliptin and Derivatives: Development and Origin of Diastereoselectivity

“…Although CH···F interactions have been observed in crystal structures (CH-F distance 2.26 Å), they are rarely invoked in influencing selectivities and reactivities. 30 …”