Letters in Organic Chemistry - Volume 8, Issue 2, 2011

The Diels-Alder (DA) reaction is arguably one of the most powerful reactions in the arsenal of the synthetic organic chemist. From the establishment of the DA reaction in the 1920s by Otto Diels and Kurt Alder, a tremendous amount of experimental and theoretical work has been devoted to the study of the mechanism and the selectivity of these cycloaddition reactions. Several theories and rules have been proposed in the literature for the study of the reactivity and selectivity of DA reactions, namely the transition state theory (TST) and the frontier molecular orbital (FMO) theory. For many years, I have studied the molecular mechanism of DA reactions. An exhaustive study of DA reactions involving different substitutions at the diene and dienophile has allowed for a rationalization of the main factor responsible for the activation energy of DA reactions. A good correlation between the activation energy and the polar character of the DA reaction measured as the charge transfer (CT) at the transition state structure (TS) has been found (Org. Biomol. Chem. 2009, 7, 3576). This finding allowed for the establishment of the polar mechanism, which is characterized by electrophilic/nucleophilic interactions in the TS, instead of frontier molecular orbital interactions as proposed by the FMO theory. Several years ago, a series of studies devoted to the application of the reactivity indices defined within the conceptual density functional theory (DFT) for the study of polar cycloadditions were performed in collaboration with Contreras and Perez. The initial goal was to correlate the global electrophilicity index proposed by Parr, ω, with the activation barriers of the DA reactions previously studied in our laboratory. Thus, the common dienes and dienophiles involved in DA reactions were classified in a unique electrophilicity scale for the first time. The Δω of the diene/dienophile pairs was proposed as a measure of the polar character of the reactions. Since it does not apply to complex molecules having electrophilic/nucleophilic behaviors, we have recently introduced a simple empirical nucleophilicity index, N. On the other hand, the use of the local electrophilicity, ωk, and nucleophilicity, Nk, which also were proposed by us, allow for the understanding of the regio- and chemoselectivity in polar DA reactions. Although, the actual correlation between the experimental and the polar theoretical model is found between the reaction rate constants and the CT at the TSs, it is difficult for the experimental organic chemists to characterize the TSs for a series of DA reactions using the TST. Our studies have stated that the use of the global reactivity indices is a semiquantitative approach to estimate the polar character of DA reactions. However, it has to be noted that for complex molecules a local reactivity can not be accounted for adequately by global indices. Finally, I would like to emphasize that although some experimental/theoretical papers have appeared in the literature, in which the electrophilicity of the reagents is discussed within the electrophilicity scale, they do not make any sense if these analyses are not presented within the polar DA reaction model, since they are merely an approximation of the CT analysis that will take place at the TSs of the polar DA reactions. In this Special Issue, several studies based on the analysis of the DFT reactivity indices of different reagents involved in DA reactions are presented, thus reflecting the broad range of application of DFT indices in the study of reactivity and regioselectivity of polar DA reactions.

The dienophilic behavior of electron-deficient substituted five-membered aromatic heterocyclices in polar cycloaddition reactions is studied from a theoretical point of view employing the global electrophilicity index to estimate the electrophilic character of the dienophiles and to compare them with the available experimental information. The type of substitution on the heteroatomic ring is also discussed. Complementary some new reactions of these substrates are described.

The non-polar character of Diels-Alder (DA) reactions using 1- and 2-substituted butadienes and ethylene is discussed. Linear correlations between variations in the energy barrier and the electrophilicity index have been obtained. The charge transfer (CT) process in the cycloaddition reactions depends on the substitution pattern on almost all ethylene reagents. The current work stresses that a polar DA reaction will occur when only the ethylene is substituted by electronwithdrawing (EW) groups increasing its electrophilicity or when both DA reagents are being activated by EW and electron-releasing (ER) groups, enhancing their electrophilic and nucleophilic nature.

The analysis of the global electrophilicity indexes of some substituted thiophene-1,1- dioxides shows that these species act as potential electrophiles in polar Diels-Alder reactions with diene systems. The chemo- and regioselectivity of these cycloadditions are rationalized using local electrophilicity and local nucleophilicity indexes recently proposed by Domingo's group [Domingo, L. R.; Aurell, M. J.; Perez, P.; Contreras, R. Quantitative Characterization of the Local Electrophilicity of Organic Molecules. Understanding the Regioselectivity on Diels Alder Reactions. J. Phys. Chem. A., 2002, 106(29), 6871-6875; Perez, P.; Domingo, L. R.; Duque-Norena, M.; Chamorro, E. A Condensed-to-Atom Nucleophilicity Index. An Application to the Director Effects on the Electrophilic Aromatic Substitutions. J. Mol. Struct. THEOCHEM, 2009, 895, 86-91]. The cyclization modes, predicted using these static DFT-based reactivity indexes, are in good agreement with experimental outcomes.

The global electrophilicity index, defined within the conceptual density functional theory (DFT), was used to classify the dienes and dienophiles currently used in Diels-Alder reactions on a unique scale of electrophilicity. The index, obtained within the Kohn-Sham scheme, is based on the HOMO and LUMO energies. A systematic study of the global reactivity indexes of the reagents involved in formal [4 + 2+] Diels-Alder cycloaddition reactions of nitrilium and immonium ions with isoprene is presented.

A close relationship between the superelectrophilic reactivity of a large set of nitrobenzofuroxans and related 10Π-heteroaromatics (nitrobenzofurazans, nitrobenzotriazoles, nitrotetrazolopyridines..) and the high propensity of these compounds to contribute to a variety of Diels-Alder processes has been experimentally established. This relationship suggests that most of the corresponding cycloadditions must be strongly polar processes. In this paper, it is shown that this important mechanistic outcome is fully supported by an analysis of the reactions on the basis of the reactivity descriptors defined by Parr within the DFT theory, namely the global electrophilicity parameter ω (and the related ΔNmax parameter) and the local electrophilicity parameter (ωk).

Reactivity and regioselectivity for the experimentally studied Diels-Alder reactions between the 2,3,4,4a-tetrahydroquinoline 1 and some electrophilically activated dienophiles 2 [E.V. Nikitina, V.N. Khrustalev, D.G. Grudinin, F.A.A. Toze, V.V. Kouznetsov, F.I. Zubkov, Tetrahedron, 2010, 66, 15, 2889] have been analysed within the framework of reactivity parameters derived from DFT in global and local sense at B3LYP/6-31G(d) level of theory.

Three different intramolecular Diels-Alder (IMDA) reactions associated with the formation of fused and bridged tricyclodecane skeletons have been studied at the B3LYP/6-31G(d) computational level. While substitution on the diene and dienophile fragments modulates the polar character of the reaction, the strain effect produced by the methylene tether affects the activation energy, and its torsion controls the different regioisomeric channels of the IMDA process. Analysis of the reactivity indices recently proposed [J. Soto-Delgado et al., Org. Biomol. Chem., 2010, 8, 3678] within the conceptual density functional theory allows for the characterization of the mechanism including the charge transfer within the reagents involved in these IMDA reactions as well as for the direction of the electronic flux in the intramolecular processes.

The Diels-Alder reaction of methyl 2-(4-methylphenyl)-2H-azirine-3-carboxylate (dienophile), with four dienes namely 1-methoxy-1,3-butadiene D-1, cyclopentadiene D-2, penta-1,3-diene D-3, and 1-acetoxy-1,3-butadiene D-4 has been studied using DFT method at B3LYP/6-31G* level of theory. A novel approach of using global and local electrophilicity patterns was evoked to interpret the electrophilic/nucleophilic behavior of dienes and dienophile in polar hetero-Diels-Alder cycloaddition. Moreover, regional nucleophilicity has been evaluated using local nucleophilicity descriptor Nk, whereas regional electrophilicity at the active sites of the interactive species involved in hetero-Diels-Alder processes has been quantitatively interpreted using local electrophilicity index ωk.

Bezocyclobutenes are useful compounds as precursors to o-quinodimethanes, which are highly reactive dienes. However, the thermal isomerization temperatures(IT) of substituted benzocyclobutenes to o-quinodimethanes have not been predictable based on the simple substituent effect. In this paper, we provide a simple method to predict the IT of benzocyclobutenes by calculation of the activation energies using a semi-empirical molecular orbital calculation. ITs of the various substituted benzocyclobutenes were estimated by this method.

Novel synthesis of putaminoxin, stagonolide-F and aspinolide-A have been achieved by utilizing (S) and (R)- malic acid. The key feature of the synthetic strategy includes Horner-Wittig olefination, double bond reduction and Steglich esterification. Olefinic acid for putaminoxin and stagonolide-F was prepared from (S)-malic acid whereas olefinic acid for aspinolide-A was prepared from (R)-malic acid and olefinic alcohols for putaminoxin, stagonolide-F and aspinolide-A were prepared by using Brown's asymmetric allylboration.

An efficient method for the three- or pseudo five-component synthesis of mono- and bis-2-amino-4H-pyrans in excellent yields using Alum (KAl(SO4)2.12H2O) as recyclable catalyst is described. The present methodology offers several advantages such as excellent yields, simple procedures, shorter reaction times, milder conditions and the catalysts exhibited remarkable reusable activity.