The formal [2sigma + 2sigma + 2pi] cycloaddition of quadricyclane, 1, with dimethyl azodicarboxylate, 2, in water has been studied using DFT methods at the B3LYP/6-31G** and MPWB1K/6-31G** levels. In the gas phase, the reaction of 1 with 2 has a two-stage mechanism with a large polar character and an activation barrier of 23.2 kcal/mol. Inclusion of water through a combined discrete-continuum model changes the mechanism to a two-step model where the first nucleophilic attack of 1 to 2 is the rate-limiting step with an activation barrier of 14.7 kcal/mol. Analysis of the electronic structure of the transition state structures points out the large zwitterionic character of these species. A DFT analysis of the global electrophilicity and nucleophilicity of the reagents provides a sound explanation about the participation of 1 as a nucleophile in these cycloadditions. This behavior is reinforced by a further study of the reaction of 1 with 1,1-dicyanoethylene.

The molecular mechanisms for the inverse-electron-demand Diels−Alder reactions between nitroethene and three substituted ethenes (propene, methyl vinyl ether, and dimethylvinylamine) to give the corresponding nitroso cycloadducts have been characterized with density functional theory methods using the B3LYP/6-31G* calculational level. On the basis of stability arguments and molecular orbital analysis relative rates, regioselectivity, and stereoselectivity, the presence of Lewis acid catalyst modeled by the BH3 system and the inclusion of solvent effects as a function of the nature of substituent in the dienophile fragment are analyzed and discussed. The ortho attack mode presents transition structures more stable than the meta one. For the former, reactivity, endo selectivity, and asynchronicity are enhanced with the increase of the electron-releasing character of the substituent on dienophile fragment. The reaction between nitroethene and propene has dissymmetric concerted transition structures associated with a pericyclic process, while the reaction between nitroethene and dimethylvinylamine takes place along an asynchronous transition structure corresponding to a nucleophilic attack to nitroethene, with concomitant ring closure and without participation of zwitterionic intermediates. For the most unfavorable meta attack modes, the reactions have synchronous mechanisms that are not sensible to the substitution on the dienophile system. For the ortho channels, the inclusion of Lewis acid catalyst and solvent effects contributes to the charge-transfer process from the substituted ethenes to nitroethene and rate acceleration, as well as a significant increase of the endo stereoselectivity.

The mechanism of the N-heterocyclic carbene (NHC)-catalyzed intramolecular Stetter reaction of salicylaldehyde 1 to yield chromanone 3 has been theoretically studied at the B3LYP/6-31G** level. This NHC-catalyzed reaction takes place through six elementary steps, which involve: (i) formation of the Breslow intermediate IN2; (ii) an intramolecular Michael-Type addition in IN2 to form the new C-C σ bond; and (iii) extrusion of the NHC catalyst from the Michael adduct to yield chromanone 3. Analysis of the relative free energies in toluene indicates that while formation of Breslow intermediate IN2 involves the rate-determining step of the catalytic process, the intramolecular Michael-type addition is the stereoselectivity determining step responsible for the configuration of the stereogenic carbon α to the carbonyl of chromanone 3. An ELF analysis at TSs and intermediates involved in the Michael-type addition allows for the characterization of the electronic changes along the C-C bond-formation.

A series of synthetic spongiane-type diterpenes have been tested in vitro for their potential antitumor and antiherpetic activity. Although the antiviral activity of these compounds against herpes simplex virus type 2 (HSV-2) was very weak, some compounds exhibited relevant cytotoxicity in the human tumor cell lines HeLa and HEp-2. The biological activity of formyl spongianes is reported for the first time. With the present study, some structure−activity trends are suggested for the cytotoxic activity of these sponge-derived natural products.

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The NHC catalysed nucleophilic additions of enols to α,β-unsaturated acyl-azolium intermediates have been investigated using DFT methods at the MPWB1K/6-31G** computational level. In the direct and the conjugate additions, formation of a hydrogen bond (HB) with the carboxyl oxygen is not sufficient to favour the C-C bond formation as a consequence of the low nucleophilic character of enols. Interestingly, when enols form a HB with the chloride counterion, the activation energies associated with the conjugate addition decrease as a consequence of the increased nucleophilic character of enols and the increased electrophilic character of the 'acyl-azolium + Cl' ion pair. Analysis of the DFT reactivity indices allows establishing a base catalysed C-C bond-formation step promoted by the chloride counterion.

The molecular mechanisms for the cycloaddition reactions of four low activated 1,3-butadiene systems (1,3-butadiene, (E)-1,3-pentadiene, (Z)-1,3-pentadiene, and 4-methyl-1,3-pentadiene) with dimethyl acetylenedicarboxylate (DMAD) have been studied using density functional theory methods. For these cycloadditions, two competitive mechanisms have been characterized:  the first one corresponds to a concerted C−C bond-formation where the asynchronicity depends on the methyl substitution. The second one corresponds to a stepwise process with a larger polar character where first a C−C bond is formed along the nucleophilic attack of 1,3-butadiene system to a conjugate position of the electron-poor substituted acetylene. Although the nonactivated 1,3-butadiene prefers the concerted process, substitution of hydrogen atoms by electron-releasing methyl groups favors the stepwise mechanism along with an increase of the charge-transfer process. A conformational analysis for DMAD reveals that both planar and perpendicular arrangements of the two-carboxylate groups have a decisive role on the dienophile/electrophile nature of this acetylene derivative. Thus, although the planar arrangement is preferred along the concerted process, the perpendicular favors the polar one along an increase of the electrophilicity of DMAD. The global and local electrophilicity power of these 1,3-butadienes and DMAD have been evaluated in order to rationalize these results. The study is completed with an analysis of the electrophilic/nucleophilic site activation, by probing the variations in local properties of DMAD perturbed by a model nucleophile with reference to a model transition structure. Inclusion of solvent effects, by means of a polarizable continuum model, does not modify these gas-phase results.

The N-heterocyclic carbene (NHC) catalyzed addition of enals to enones to yield trans-cyclopentenes has been investigated using DFT methods at B3LYP/6-31G** computational level. This NHC catalyzed reaction comprises several steps. The first one is the formation of a Breslow intermediate, which nucleophilically attacks to the conjugated position of the enone to yield an enol-enolate. This second step is responsible for the trans relationship at the final cyclopentene. An intramolecular aldolic condensation allows for the formation of the alkoxy cyclopentane intermediate, that by intramolecular nucleophilic attack on the carbonyl group yields a bicyclic ether. The extrusion of the NHC catalyst affords a bicyclic lactone, yielding by CO(2) elimination, the final trans-cyclopentene.