The effect of cyclochirality of rccc‐2,8,14,20‐tetra‐n‐decyl‐4,10,16,22‐tetra‐O‐methylresorcin[4]arene (C) on the enantiodiscrimination of a number of chiral bidentate and tridentate aromatic and aliphatic biomolecules (G) has been investigated by nano‐electrospray ionization (nano‐ESI)‐Fourier transform ion cyclotron resonance mass spectrometry. The experimental approach is based on the formation of diastereomeric proton‐bound [C·H·G]+ complexes by nano‐ESI of solutions containing an equimolar amount of quasi‐enantiomers (C) together with the chiral guest (G) and the subsequent measurement of the rate of the G substitution by the attack of several achiral and chiral amines. In general, the heterochiral complexes react faster than the homochiral ones, except when G is an aminoalcoholic neurotransmitter whose complexes, beyond that, exhibit the highest enantioselectivity. The kinetic results were further supported by both collision‐induced dissociation experiments on some of the relevant [C2·H·G]+ three‐body species and Density functional theory (DFT) calculations performed on the most selective systems. Copyright © 2012 John Wiley & Sons, Ltd.