Correlation between the reactivities and the computed conformational and electronic properties of N,S,O-mixed-donor crown ethers

Abstract

The nucleophilic coupling of the secondary nitrogen atoms of the mixed-donor crown ethers [16]aneS₄N, [15]aneS₄N, [15]aneO₄N, [15]aneO₂S₂N and [12]aneS₃N to an epoxide proceeds in an unexpected manner. The degree of coupling appears to be inversely related to the number of thioethers in the crown ether. Two possible explanations were considered: (i) steric factors affecting the accessibility of the lone pair on the secondary nitrogen and (ii) electronic factors affecting the nucleophilicity of the nitrogen. In order to discriminate between these possibilities, molecular modeling was applied. Firstly, suitable conformers of the mixed-donor crown ethers were generated by a conformational search on a molecular mechanics level (MM3). Next, these conformers underwent a (semi-empirical) PM3 geometry optimisation to obtain information on the electronic properties. Results of the molecular-modeling study indicate that both steric and electronic factors work hand-in-hand, rendering a plausible explanation for the observed phenomena: with an increasing number of thioethers in the crown ether, the orientation of the nitrogen lone pair becomes directed more towards the inside of the macrocycle so that the accessibility for reaction is decreased. Apart from this, the nucleophilicity of the secondary nitrogen is also reduced seriously with increasing number of thioethers, as can be deduced from the location, size and level of the HOMOs. These are located mainly on the sulfur atoms in the (oxa)azathia crown ethers, thereby lowering the reactivity of the nitrogen atom. In the case of [15]aneO₄N, the HOMO is located on the nitrogen lone pair only, which provides an explanation for the observed higher reactivity of this macrocycle.