Hyperconjugative Interactions of the Carbon–Halogen Bond that Influence the Geometry of Cyclic α-Haloacetals

Abstract

The analysis of the structures of low-energy conformers of different α-haloacetals reveals changes in bond lengths and geometries that correspond to stabilizing orbital interactions that contribute to the ground-state structures of these systems. Several factors, including the electron-donating and electron-accepting abilities of the substituents on the ring, affect the degree of the electronic interactions in these carbohydrate-like systems. The presence of an α-halogen atom that can participate in hyperconjugation has been shown to contribute to the structural characteristics of the low-energy conformer. The experimental evidence is supported by natural bond order (NBO) analysis to identify the types of interactions and to assess their relative importance.

Halogen Atom Participation in Guiding the Stereochemical Outcomes of Acetal Substitution Reactions

“…The faster hydrolysis rates of the five-membered rings compared to the six-membered rings align with the generally higher reactivity of furan acetals over pyran acetals. [22,38] The larger influence of halogen atoms in the five-membered-ring acetals compared to the six-membered-ring acetals is consistent with the computational studies (Figure 3) that show a generally larger preference for the axial conformers in five-membered rings, likely because of better overlap between σ C-X and π* C-O + .…”

“…Differences in selectivities between the C‐2‐Cl and C‐2‐Br substrates were observed with oxygen nucleophiles, however: additions of strongly nucleophilic alcohols to chlorinated acetal 17 were unselective, whereas additions to brominated acetal 18 were trans ‐selective (Table 5). Decreasing the nucleophilicity of the alcohol restored the high 1,2‐ trans selectivity (entries 3–5) [22] …”

“…The stereochemical outcomes of substitutions of fluorinated pyran 1 a with oxygen nucleophiles showed a different pattern (Table 4). Substitutions initiated with Me 3 SiOTf using strong O ‐nucleophiles occurred with moderate trans ‐selectivity, while the addition of a weak nucleophile, hexafluoroisopropanol, was low‐yielding and unselective [22] . The stereochemistry of the substitution reactions differed from the reaction using allyltrimethylsilane (Table 1, entry 1).…”

“…using strong O-nucleophiles occurred with moderate transselectivity, while the addition of a weak nucleophile, hexafluoroisopropanol, was low-yielding and unselective. [22] The stereochemistry of the substitution reactions differed from the reaction using allyltrimethylsilane (Table 1, entry 1). Slight differences in stereoselectivities were observed using BF 3 • OEt 2 compared to Me 3 SiOTf, but not enough to justify that a covalent triflate [20,23] was responsible for the selectivities in those reactions.…”

“…Analysis of the rates of hydrolysis of the individual stereoisomers of halogenated pyrans 1 b and 1 c indicate the importance of the orientation of the C-2 halogen atom on the ionization of the leaving group, which, in accordance with the Hammond postulate, [37] should reflect the degree of stabilization of the oxocarbenium ion intermediate. The four acetals all adopted conformations that place the leaving group in an axial orientation, as inferred from analysis of 1 H NMR spectra (Scheme 3), so the orientation of the leaving group to the most electron-donating group, the endocyclic oxygen atom, [22] are similar. The acetals differ only in the halogen atom and whether it adopts an axial or equatorial orientation.…”