Editing Diels–Alder reaction (section)

===Regioselectivity===
Frontier molecular orbital theory has also been used to explain the regioselectivity patterns observed in Diels–Alder reactions of substituted systems. Calculation of the energy and orbital coefficients of the components' frontier orbitals<ref name="AshbyChao1973">{{cite journal |last1=Ashby |first1=E. C. |last2=Chao |first2=L.-C. |last3=Neumann |first3=H. M. |year=1973 |title=Organometallic reaction mechanisms. XII. Mechanism of methylmagnesium bromide addition to benzonitrile |journal=Journal of the American Chemical Society |volume=95 |issue=15 |pages=4896–4904 |doi=10.1021/ja00796a022}}</ref> provides a picture that is in good accord with the more straightforward analysis of the substituents' resonance effects, as illustrated below.

[[File:Resonance of diene and dienophile.png|500x500px|center|Resonance structures of normal-demand dienes and dienophiles|alt=]]

In general, the regioselectivity found for both normal and inverse electron-demand Diels–Alder reaction follows the '''ortho-para rule''', so named, because the cyclohexene product bears substituents in positions that are analogous to the ''ortho'' and ''para'' positions of disubstituted arenes.  For example, in a normal-demand scenario, a diene bearing an electron-donating group (EDG) at C1 has its largest HOMO coefficient at C4, while the dienophile with an electron withdrawing group (EWG) at C1 has the largest LUMO coefficient at C2. Pairing these two coefficients gives the "ortho" product as seen in case 1 in the figure below. A diene substituted at C2 as in case 2 below has the largest HOMO coefficient at C1, giving rise to the "para" product. Similar analyses for the corresponding inverse-demand scenarios gives rise to the analogous products as seen in cases 3 and 4. Examining the canonical mesomeric forms above, it is easy to verify that these results are in accord with expectations based on consideration of electron density and polarization.

[[File:Diels-Alder regiochemistry.png|600x600px|center|Regioselectivity in normal (1 and 2) and inverse (3 and 4) electron demand Diels-Alder reactions|alt=]]

In general, with respect to the energetically most well-matched HOMO-LUMO pair, maximizing the interaction energy by forming bonds between centers with the largest frontier orbital coefficients allows the prediction of the main regioisomer that will result from a given diene-dienophile combination.<ref name="ca836" /> In a more sophisticated treatment, three types of substituents ('''Z''' ''withdrawing'': HOMO and LUMO lowering (CF<sub>3</sub>, NO<sub>2</sub>, CN, C(O)CH<sub>3</sub>), '''X''' ''donating'': HOMO and LUMO raising (Me, OMe, NMe<sub>2</sub>), '''C''' ''conjugating'': HOMO raising and LUMO lowering (Ph, vinyl)) are considered, resulting in a total of 18 possible combinations. The maximization of orbital interaction correctly predicts the product in all cases for which experimental data is available. For instance, in uncommon combinations involving '''X''' groups on both diene and dienophile, a 1,3-substitution pattern may be favored, an outcome not accounted for by a simplistic resonance structure argument.<ref>{{Cite book|title=Frontier Orbital and Organic Chemical Reactions|last=Fleming|first=I.|publisher=Wiley|year=1990|isbn=978-0471018193|location=Chichester, UK}}</ref> However, cases where the resonance argument and the matching of largest orbital coefficients disagree are rare.