Pergamon Tetrahedron 55 (1999) 561-568 TETRAHEDRON Application of Pertubation Theory to Free-radical Benzylic and Allylic Oxidation of Unconjugated n-Systems Gadi Rothenberg and Yoel Sasson ** Casali Institute of AppliedChemistry,HebrewUniversityof Jerusalem, Jerusalem91904, Israel. Received 8 September 1998; revised 20 October 1998; accepted 5 November 1998 Abstract: Pertubationinteractions between FrontierMolecularOrbitalsare utilized to predeterminethe regioselectivity of allylic and benzylic oxidation reactions. Thus, it is shown that in unsaturated compounds containing two nonconjugatedand nonequivalentn-systems,one system contributesmainly to the HOMO and the other to the HOMO-I. Analysis of four representativeexamples corroborates empiricalevidence with previouslypublishedstudies. © 1998 ElsevierScienceLtd. All fights reserved. INTRODUCTION Selective oxidation is still one of the most sought after goals in organic and bioorganic synthesis. Many common organic compounds contain more than one oxidizable site, a situation which often leads to non-selective reactions. Part of this product diversity results from different reaction paths (e. g. epoxidation vs. ailylic oxidation), and can be circumvented by altering the reaction conditions) The problem is more serious when the same substrate has several available sites for the same type of reaction. (R)-Limonene la, for example, has more than one reactive site for allylic oxidation. In this case, regioselective oxidation carries much industrial benefit. Enone lb is an important precursor for the synthesis of food and aroma chemicals, while alcohol ld is practically worthless. 2 The low product selectivity normally obtained in autoxidations of such substrates forces the use of expensive, and often environmentally unacceptable, reagents. l a RI=R2=R3=R4=R5=H R2""] "1 ~. R 3 l b R1,R2=O;R3=R4=R5=H 1¢ RI=OH; R2=R3=R4=RS=H R 4 l d RI=R2=RS=R4=H;RS=OH .,~ R 5 This example demonstrates the importance of free-radical hydrogen abstraction (HA) processes. HA is a key step in autoxidations that controls (barring allylic rearrangements) the oxygenation site on the substrate, due to the fast subsequent reaction between the alkyl radical and molecular oxygen (k=10s-109). 3 Accumulated experimental findings indicate the following order of reactivity: acyclic position activated by a single 7t-system < cyclic activated by a single ~t-system < acyclic activated by two n-systems < cyclic activated by two ~-systerns: However, extrapolation of these rules to substrates combining two inequivalent and unconjugated 7t-systerns is problematic: t E-marl: ysasson@vms.huji.ac.il 0040-4020/99/$ - see front matter © 1998 Elsevier Science Ltd. All fights reserved. PII: S0040-4020(98)01054-0