Quantum mechanical study on the facial selectivity of dioxa and trioxa cage molecules

High facial selectivity (>99%) of nucleophilic addition to the carbonyl groups of the title compounds (1 and 2) has been achieved for the novel trioxa cage 2, but not for the dioxa 1. Similar experimental observations were made for the carbene addition to the double bonds of cage compounds, 3 and 4. Calculations were carried out for the cage compounds and their reaction transition structures, with LiH as a nucleophile and :CCl(2) as an attacking carbene. The calculated facial preference for nucleophilic and carbene addition agreed well with experimental results. The origins of facial selectivity are examined from the viewpoints of structure, frontier orbitals, and molecular electrostatic potential of the reactants, as well as strain, electrostatic, and hyperconjugation effects in the transition state. For dioxa cages, the structural facial difference around the reaction center is minor, but the electronic difference of syn and anti faces generated by the two remote oxygen atoms is clearly demonstrated via frontier orbital and MEP analyses. For trioxa cages, the close proximity of the third ether oxygen (O(s)) to the reaction center brings large structural and electronic changes around the reaction center. The calculated electrostatic and strain energy differences of syn and anti transition structures are significantly larger for trioxa cages than for the dioxa cages. Therefore, they both contribute to the enhanced facial selectivity of trioxa compounds. Finally, analysis of hyperconjugative stabilization in transition structures reveals the danger of relying solely on Cieplak or Anh models in rationalization of facial selectivity, especially when nonequivalent steric and electrostatic effects as those present in the trioxa systems are involved.