A combined quantum mechanical and experimental approach towards chiral diketopiperazine hydroperoxides

In order to improve hydroperoxide formation from heterocyclic compounds relating to the formation rate and to allow a suitable choice of starting materials for autoxidation, theoretical studies on a set of different amino acid‐derived diketopiperazines and pyrazinoquinazolines were carried out. To estimate their reactivity towards hydroperoxide formation, bond dissociation enthalpies (BDEs) of tertiary α‐C? H bonds as well as reaction enthalpies to the corresponding hydroperoxides were calculated at the B3LYP/TZVP and RMP2/aug‐cc‐pVTZ level of theory. The Evans–Polanyi relation was then used to correlate substrate reactivity with calculated BDEs. Thermal and zero point vibrational energy (ZPE) corrections were determined in the classical harmonic oscillator‐rigid rotor‐particle in a box model. While for the investigated set of diketopiperazines BDEs of 318.8–327.0 kJ mol^?1 were found, BDEs for pyrazinoquinazolines spread between 248.4 and 368.4 kJ mol^?1 at the B3LYP/TZVP level of theory. A selected subset of heterocycles was converted to the corresponding hydroperoxides and the diketopiperazines were obtained in up to 39% yield after 5–7 days, whereas the pyrazinoquinazoline hydroperoxides were isolated in up to 67% yield after 24 h. Thus, replacing an amido moiety in an N‐aryl‐imino moiety when using pyrazinoquinazolines instead of diketopiperazines leads indeed to an improved captodative stabilization of the radical intermediate. Furthermore the theoretical calculations allowed a distinctive forecast of the preferred regioisomeric hydroperoxide. Copyright © 2010 John Wiley & Sons, Ltd.