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

Abstract

Acetal substitution reactions of α-halogenated five- and six-membered rings can be highly stereoselective. Erosion of stereoselectivity occurs as nucleophilicity increases, which is consistent with additions to a halogen-stabilized oxocarbenium ion, not a three-membered-ring halonium ion. Computational investigations confirmed that the open-form oxocarbenium ions are the reactive intermediates involved. Kinetic studies suggest that hyperconjugative effects and through-space electrostatic interactions can both contribute to the stabilization of halogen-substituted oxocarbenium ions.

Keywords: Diastereoselectivity; Glycosylation; Halonium Ion; Hyperconjugation; Oxocarbenium Ion.

Scheme 1

Substitutions of halofurans 11 and 13 with allyltrimethylsilane.

Figure 1

Nucleophilic additions to halonium ion intermediates.

Figure 2

Nucleophilic additions to α‐halogenated oxocarbenium ion intermediates.

Figure 3

Conformational energy landscape (CEL) maps of halopyranyl and ‐furanyl oxocarbenium ions in which the local minima identified are shown with their respective energy. Energies of all conformations in the CEL are computed at SMD(dichloromethane)‐revDSD‐PBEP86‐D4‐DKH‐def2TZVPP//PCM(dichloromethane)‐B3LYP‐D3BJ‐DKH‐def2TZVP and expressed as Gibbs free energy (T=195.15 K) in kcal mol⁻¹, and between parentheses reference Gibbs free energies (T=195.15 K) for that specific conformation are given in SMD(dichloromethane)‐CCSD(T)‐DKH‐def2TZVPP//PCM(dichloromethane)‐B3LYP‐D3BJ‐DKH‐def2TZVP. Oxocarbenium ion CEL maps for: a) 2‐F‐pyranyl, b) 2‐Cl‐pyranyl, c) 2‐Br‐pyranyl, d) 2‐I‐pyranyl, e) 2‐F‐furanyl, f) 2‐Cl‐furanyl, g) 2‐Br‐furanyl, h) 2‐I‐furanyl.

Scheme 2

Rates of hydrolysis of haloacetals.

Scheme 3

Rates of hydrolysis of halopyran stereoisomers.