FULL PAPER The Source of the endo Rule in the DielsAlder Reaction: Are Secondary Orbital Interactions Really Necessary? Jose ´ Ignacio Garcı ´a, [a] Jose ´ Antonio Mayoral, [a] and Luis Salvatella* [a] Keywords: Cycloaddition / Noncovalent interactions / Pi interactions / Through-space interactions The endo preference in Diels-Alder reactions is usually attri- buted to the occurrence of attractive Secondary Orbital Inter- actions (SOI), whereas other interaction mechanisms (pri- mary interactions, closed-shell repulsions, electrostatics) are assumed to be identical for both endo and exo approaches. However, analysis of the parallel approximation between s- trans butadiene and fumaronitrile shows that SOI is over- come by closed-shell repulsions. Furthermore, the study of several reactions (cyclopentadiene + maleic anhydride, cy- Introduction It is well known that most Diels-Alder reactions be- tween simple reactants lead preferentially to the endo ad- duct. [1] However, the reason for such behavior has become the subject of great debate in recent years. The most com- monly used explanation is based on the existence of a stabil- izing overlap (called a Secondary Orbital Interaction, SOI) between the frontier molecular orbitals of the reactants at centers that do not participate in the formation of σ bonds in the endo approach. [2] However, this hypothesis has been called into question by our research, which has shown that the main arguments suggesting the existence of SOI are in- conclusive. [3] A method to quantify the SOI has been proposed by Cossı ´o and co-workers. [4] The application of this method- ology to the cyclopentadiene + maleic anhydride cycload- dition shows significant stabilization of the endo transition state (TS) attributed to SOI. The authors concluded from these results that ‘‘SOI do exist and are responsible for at least an important part of the observed stereocontrol’’. [4] However, analysis of the methodology used in the study outlined above raises questions about the validity of several quite wide-ranging approximations applied to the Klopman-Salem equation. Firstly, the magnitudes of the primary interactions (i.e., those leading to the formation of new σ bonds) are assumed to be equal in both endo and [a] Departamento de Quı ´mica Orga ´nica, ICMA and IUCH, Universidad de Zaragoza - C.S.I.C., Pedro Cerbuna 12, 50009 Zaragoza, Spain Fax: + 34-976-762-077 E-mail: lsalvate@unizar.es Supporting information for this article is available on the WWW under http://www.eurjoc.org or from the author. Eur. J. Org. Chem. 2005, 85-90 DOI: 10.1002/ejoc.200400424 © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 85 clobutadiene + cyclobutenedione, cyclobutadiene + norborna- diene) indicates the absence of a net attraction for the atom pairs involved in SOI. As a conclusion, the endo preference is not due to the occurrence of an attractive interaction bet- ween the atom pairs involved in SOI and so this concept is unnecessary. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) exo approaches. More interestingly, the role of electrostatic and closed-shell interactions are neglected in spite of the known influence of these interactions on the endo/exo selec- tivity of some Diels-Alder reactions (e.g. furan + cyclo- propenone [5] or cyclopentadiene + cyclopentene [6] ). Finally, a numerical bias derived from the assumption of a strictly parallel approach between the two reactants and the use of the AM1 method (a method that wrongly predicts an in- crease in the activation barrier of Diels-Alder reactions when the number of electron-withdrawing groups in the di- enophile is increased) [7,8] may also be possible. Given these circumstances, the conclusions drawn by Cossı ´o must be open to question. For example, the energy analysis is focused on the interaction that exists between occupied and vacant frontier molecular orbitals (MOs) for the approximation between the secondary centers. It is therefore not surprising to find a certain stabilization en- ergy in the approach between the reactants, since the Per- turbation Molecular Orbital (PMO) theory predicts a nega- tive interaction energy for any occupied-vacant MO pair (unless a long distance is involved or particular symmetry requirements are met). From this perspective, the statement ‘‘SOI do exist’’ is self-evident and numerical studies are unnecessary to prove it. However, the restriction of the analysis to the occupied-vacant MO interactions would lead to the para- doxical conclusion that the approximation between any pair of molecular fragments leads to a stabilization in all cases (including, for example, two colliding tert-butyl groups). In contrast, it is our opinion that such a discussion should include all the possible mechanism interactions between the atom pairs involved. In this paper we wish to revisit the role of SOI in the Diels-Alder reaction by considering the net