A new tool to guide halofunctionalization reactions: the halenium affinity (HalA) scale

Abstract

We introduce a previously unexplored parameter-halenium affinity (HalA)- as a quantitative descriptor of the bond strengths of various functional groups to halenium ions. The HalA scale ranks potential halenium ion acceptors based on their ability to stabilize a "free halenium ion". Alkenes in particular but other Lewis bases as well, such as amines, amides, carbonyls, and ether oxygen atoms, etc., have been classified on the HalA scale. This indirect approach enables a rapid and straightforward prediction of chemoselectivity for systems involved in halofunctionalization reactions that have multiple nucleophilic sites. The influences of subtle electronic and steric variations, as well as the less predictable anchimeric and stereoelectronic effects, are intrinsically accounted for by HalA computations, providing quantitative assessments beyond simple "chemical intuition". This combined theoretical-experimental approach offers an expeditious means of predicting and identifying unprecedented reactions.

Figure 1

Geometry minimized structures of (E)- and (Z)-β-methylstyrene upon treatment with different halenium ions. B3LYP/6-31G* for HalA (F, Cl, and Br). B3LYP/6-31G*/LANL2DZ for HalA (I).

Figure 2

Theoretically estimated relativeHalA values for pyridine 1a in comparison to the counterions of commonly employed chlorenium sources (B3LYP/6-31G*/SM8 acetone).

Figure 3

Overlay of ¹H NMR (500 MHz, acetone-d₆) spectra (a–f). Spectrum a represents a section of ¹H NMR displaying the C3-H of 1a, whereas overlay of spectra b–f shows the effects of treatment of 1a with different chlorenium sources: NCS (N-chlorosuccinimide), DCDMH (1,3-dichloro-5,5-dimethylhydantoin), NCP (N-chlorophthalimide), TCCA (trichloroisocyanuric acid), CDSC (chlorodiethylsulfonium antimony(VI) chloride).

Figure 4

Spectra a–f depicts ¹H NMR data for titration of 1a with CDSC. The plot below shows change in chemical shift of C3-H of 1a upon titration with different halenium sources. CDSC (chlorodiethylsulfonium antimony(VI) chloride), BDSB (bromodiethylsulfonium antimony(VI) halide), IDSI (iododiethylsulfonium antimony(VI) halide), XtF (Xtalfluor-E).

Figure 5

(a) Partial chlorination of 1c using 0.5 equiv of CDSC leads to distinctly observable species 1c and 1c-Cl at −30 °C by ¹H NMR (500 MHz). (b) Competition study between 1b and 1c in acetone-d₆ at −90 °C as quantified by ¹H NMR.

Figure 6

Comparison of ΔHalA (Cl) (B3LYP/6-31G*/SM8) with experimental results of equilibrium studies between 1c-Cl (prepared in situ using 1.0 equiv of CDSC) in the presence of 1.0 equiv of pyridines 1b–g. The sigmoidal curve fit (R² = 0.974) is derived from the Henderson–Hasselbalch equation.

Figure 7

(a) Example of two reactions under identical conditions with different chemoselectivity. (b) HalA (Cl) values (B3LYP/6-31G*) for the reactive components of 2 and 4.

Figure 8

(a) Chlorocyclization of diene 9 to 10 is predicted by the higher HalA (Cl) of the 1,1-disubstituted olefin. Intermediate 11 is the computationally assessed outcome upon geometry minimization of 9 with chlorenium ion (B3LYP/6-31G*). (b) HalA (Cl) values for the reactive components in the cyclization of 9, illustrating the effect of N-Ms substitution. (c) Anchimeric assistance of the sulfonyl group toward stabilization of the chlorocarbenium ion 15-Cl and 16-Cl as predicted by HalA calculations.

Figure 9

HalA (Cl) scale based on theoretical estimates of over 500 chlorenium ion acceptors evaluated at the B3LYP/6-31G* (gas phase) level of theory.