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Deep eutectic solvents (DESs) have been considered "the organic reaction medium of the century" because they can be used as solvents and active catalysts in chemical reactions. However, experimental and theoretical studies are still needed to provide information on the structures of DESs, the kinetics and thermodynamics properties, the interactions between the DESs and the substrates, the effect of water on the DES supramolecular network and its physicochemical properties, and so forth. This information is very useful to understand the essence of the processes that take place in the catalysis of chemical reactions and, therefore, to help in the design of a DES for a specific reaction and sample. This article shows a systematic study of the impact of DES choline chloride/p-toluenesulfonic acid and DES choline chloride/p-toluenesulfonic acid-water in the aza-Michael addition of arylamines to maleimide to obtain aminopyrrolidine-2,5-dione derivatives. The derivatives are obtained under very mild reaction conditions with good yield. The global reaction is exothermic, spontaneous, permitted by enthalpy, and prohibited for entropy. The calculated potential energy surface shows a reaction mechanism of six steps controlled by enthalpy (except the last step that is controlled by entropy). The water incorporated in the supramolecular DES complex stabilizes the transition states and favors the enthalpy-driven binding. A set of H/D exchange NMR experiments validates the transition state existing in the fourth stage of the mechanism.

The chemical synthesis of C60 fullerene in the laboratory is still a challenge. In order to achieve this goal, we propose a synthetic route based on the dimerization between two pentacyclopentacorannulene (C30H10) fragments employing the Diels–Alder cycloaddition reaction. Density functional calculations indicate that a step wise non-concerted dimerization mechanism of C30H10 is favored over a one stage dimerization. The step wise dimerization implies the sequential formation of 2, 4, 6, and 10 new C–C bonds between the two fragments. This leads to the formation of the Diels–Alder cycloadduct C60H20. The results then suggest the synthesis of C60H20 as a precursor for C60. The synthesis of the analogue C60F20 has already been reported.

The local and condensed Fukui functions as well as the principle of hard and soft acids and bases were used to study the addition of free radicals to the exocyclic and endocyclic double bonds of seven monocyclic monoterpenes of formula C10H16. The results obtained showed that, in general, the most reactive double bond was the one with the most substituents on the double-bonded carbon atoms, and that the reaction of a double bond with an electrophile is a soft-soft interaction. The effects of substituents on the double-bonded carbon atoms and the stabilization of the monoterpenes were interpreted by invoking hyperconjugated structures, which led us to propose a simple rule: the larger the value of the Fukui function for the double bond, the greater the hyperconjugative stabilization and the susceptibility of the double bond to electrophilic attack. In general, our results are in good accordance with relevant experimental and theoretical results published in the literature. Graphical abstract The specific electrophilic addition to monocyclic monoterpenes.

Chemical reactivity descriptors of indol-4-ones obtained via density functional theory (DFT) and hard–soft acid–base (HSAB) principle were calculated to prove their contribution in antifungal activity. Simple linear regression was made for global and local reactivity indexes. Results with global descriptors showed a strong relationship between antifungal activity vs. softness (S) (r = 0.98) for series I (6, 7a–g), and for series II (8a–g) vs. chemical potential (µ), electronegativity (χ) and electrophilicity (ω) (r = 0.86), p < 0.05. Condensed reactivity descriptors sk+, ωk− for different fragments had strong relationships for series I and II (r = 0.98 and r = 0.92). Multiple linear regression was statistically significant for S (r = 0.98), η (r = 0.91), and µ/ω (r = 0.91) in series I. Molecular electrostatic potential maps (MEP) showed negative charge accumulation around oxygen of carbonyl group and positive accumulation around nitrogen. Fukui function isosurfaces showed that carbons around nitrogen are susceptible to electrophilic attack, whereas the carbon atoms of the carbonyl and phenyl groups are susceptible to nucleophilic attack for both series. The above suggest that global softness in conjunction with softness and electrophilicity of molecular fragments in enaminone systems and pyrrole rings contribute to antifungal activity of indol-4-ones.

The simultaneous contributions of proton and electron transfer to the Brønsted-Lowry and Lewis acid-base properties of a set of p-substituted phenols are reported in this work. As a result of the analysis, a novel protophilicity index considered as the second-order energy change of a Brønsted-Lowry base as it is saturated with protons, a combined Brønsted-Lowry-Lewis acidity index (with a corresponding basicity index), and a protofelicity equalization principle (a parallel of the electronegativity equalization principle) are presented.

A theoretical study was undertaken regarding the regioselective Lewis acid-promoted intramolecular cyclization of novel enaminones 1-3 leading to the corresponding benzofurans 4-5 and indoles 6. The density functional theory (DFT) and hard and soft acids and bases (HSAB) principle provided data to describe the electronic effects of the substituents in the reactivity of the benzene ring and the enaminone moiety. The condensed and local Fukui functions for nucleophilic and electrophilic attacks of the reactants accounted for the experimentally observed preference, in regard to precursors 1-3, of the cyclization between the C6' carbon (rather than the C2' carbon) of the benzene ring and the C3 center of the enaminone moiety.

The silicon atom may increase its coordination number to values greater than four, to form pentacoordinated compounds. It has been observed experimentally that, in general, pentacoordinated compounds show greater reactivity than tetracoordinated compounds. In this work, density functional theory is used to calculate the global softness and the condensed softness of the silicon atom for SiH n F4−n and SiH n F 5− 1− . The values obtained show that the global and condensed softness are greater in the pentacoordinated compounds than in the tetracoordinated compounds, a result that explains the enhanced reactivity. If the results are analysed through a local version of the hard and soft acids and bases principle, it is possible to suggest that in nucleophilic substitution reactions, soft nucleophiles preferably react with SiH n F 5− 1− , and hard nucleophiles with SiH n F4−n .

The electronic structures of sixteen carbenes and four alkenes calculated at the B3LYP/6-31G* level were used to carry out a hard−soft acid−base investigation of carbene singlet−triplet gaps and of the addition of carbenes to alkenes. The carbenes chosen include examples where the ground state varies from triplet to singlet state and examples that have been characterized as nucleophilic, electrophilic, or ambiphilic based on their reactivity with alkenes having varying electron demands. We confirmed that singlet−triplet gaps calculated by DFT methods with the B3LYP functional correlate well with experimentally known values of carbenes spanning over 70 kcal/mol. Correlations between electron-density-based parameters and singlet−triplet gaps, or with carbene−alkene reactivity, were analyzed to gain insight into the electronic structure of the carbenes and their acid−base tendencies. A good correlation was found between the singlet−triplet energy gap and the condensed softness for electrophilic attack at the...

The hard and soft acids and bases principle is used together with the condensed fukui function to analyze the regioselectivity and reactivity of two model 1,3-dipolar cycloaddition reactions. Results obtained for benzonitrile oxide with vinyl p-nitrobenzoate or 1-acetyl vinyl p-nitrobenzoate illustrate the value of these concepts to describe their inherent reactivity. The calculations of the interaction energy by density functional theory using a perturbative, orbital independent method suggest the specific direction of the electronic process at each of the reaction sites. The electrophilic nature of the 1,3-dipole and the nucleophilic nature of the two dipolarophiles was determined by this model. The partitioning of the interaction energy in a term resulting from the chemical potential equalization principle at constant external potential and a term resulting from the maximum hardness principle at constant chemical potential show that the former term, arising from the charge-transfer process, contributes...

As part of our continuing interest in the connection between chemical reactivity and the HSAB principle, both globally and locally, we explored via 3-21 G calculations on local and global softness the statement made by Gazquez and Mendez. Their statement, claiming that two chemical species should react through atoms showing equal softness, has been precised to rationalize the regioselectivity of Normal Electron Demand Diels−Alder reactions between terminally monosubstituted 1,3-butadienes and monosubstituted ethenes. In the presence of this substitution pattern, a head-to-head mode of cyclization is largely experimentally observed, also known as “ortho rule”. The closest values of the condensed local softness were found for the unsubstituted termini, thereby suggesting that these cycloadditions would proceed through an asynchronous pathway, as supported by transition state geometries reported by Houk et al.

The Lewis structures that contribute to the imidazolium protonated cation resonance hybrid can be explained in a unified way in terms of the Fukui function (density functional descriptor) and the local hard and soft acids and bases principle. The results obtained open the possibility of analyzing the resonance contributors and the resonance hybrid in terms of the electronic density. [structure--see text]

The principle of hard and soft acids and bases is interpreted as the result of two opposing tendencies, one related to the charge transfer process (chemical potential equalization principle), and the other one related to the reshuffling of the electronic density (maximum hardness or minimum softness principle). A local version of the principle is elucidated by assuming that these tendencies are dominated by the local properties rather than by the global properties of the molecule. This principle is used together with the Fukui function of the atoms in the molecule to characterize the reactive sites. The results presented for the nucleophilic addition to the pyridinium ion, and for the electrophilic substitution on pyridine oxide show the usefulness of these concepts in describing the inherent reactivity of chemical species.

The electronic structures of sixteen carbenes and four alkenes calculated at the B3LYP/6-31G* level were used to carry out a hard−soft acid−base investigation of carbene singlet−triplet gaps and of the addition of carbenes to alkenes. The carbenes chosen include examples where the ground state varies from triplet to singlet state and examples that have been characterized as nucleophilic, electrophilic, or ambiphilic based on their reactivity with alkenes having varying electron demands. We confirmed that singlet−triplet gaps calculated by DFT methods with the B3LYP functional correlate well with experimentally known values of carbenes spanning over 70 kcal/mol. Correlations between electron-density-based parameters and singlet−triplet gaps, or with carbene−alkene reactivity, were analyzed to gain insight into the electronic structure of the carbenes and their acid−base tendencies. A good correlation was found between the singlet−triplet energy gap and the condensed softness for electrophilic attack at the...

The influence of basicity in a set of para-substituted phenolates on the elimination-substitution ratio obtained upon reaction with p-nitrophenethyl bromide has been studied. A correlation between experimental equilibrium data (pK(a)) and reactivity indices obtained from density functional theory (DFT) was looked for in order to show that the hard and soft acids and bases principle (HSAB) is well suited to describe the basicity properties of the para-substituted phenolates. When the basicity of para-substituted phenolates increases, their global hardness and their condensed softness at the oxygen atom increase; the negative net charge, condensed nucleophilic fukui function, and condensed nucleophilic softness of the oxygen atom increase. The proposal that the alkyl halide substrate possesses a hard beta-hydrogen atom and a soft alpha-carbon was studied for p-nitrophenethyl bromide; it turns out that the beta-hydrogen atom is soft, even softer than the carbon atom. The experimental results for the elimination-substitution ratio for p-nitrophenethyl bromide can be explained from a local-local HSAB viewpoint for the para-substituted phenolates and p-nitrophenethyl bromide and not from a global-local level viewpoint as suggested before. The results suggest that para-substituted phenolates with higher basicity (harder), less delocalized negative charge into the fragment R-C(6)H(4), and a more polarizable oxygen atom (softer) do have a lower (relative) attraction toward an alkyl carbon atom (soft) than toward a hydrogen atom (softer) from p-nitrophenethyl bromide. The beta-hydrogen and alpha-carbon atoms can be considered to act as a Lewis acid toward the para-substituted phenolate nucleophile considered as a base.

Captodative olefins 1-acetylvinyl carboxylates proved to be highly regioselective dipolarophiles in 1,3-dipolar cycloadditon to propionitrile oxide, arylphenylnitrile imines, diazoalkanes, and nitrones to yield the corresponding 5-substituted heterocycles. The addition of the latter was also stereoselective, being slightly susceptible to steric demand of the carboxylate substituent in the olefin. All atempts to cleave the isoxazolidine N−O bond under reductive conditions failed, providing diverse products with side-group reduction. FMO theory was unsuccessful to explain the regioselectivity observed with nitrones, since the opposite orientation was predicted. The recently formulated DFT/HSAB theoretical model was able to rationalize this regioselectivity, identifying the nucleophilic and electrophilic atoms involved in the process via calculation of interaction energies, suggesting the specific direction of the electronic process at each of the reaction sites.

The calculation of the XC6H4O−H bond dissociation energy (BDE) in a set of p-substituted phenols using the local hard and soft acids and basis principle (HSAB) is described. The expression for the interaction energy (ΔEint) in terms of the chemical potentials of the reagents (μXC6H4O, μH) and the atomic hardness fragments (ηO, ηH) provides good gas-phase BDE values.

The reactivity of maleic anhydride with respect to nucleophiles is studied by using some concepts defined within density functional theory formalism. It is shown that the hard and soft acids and bases principle in a local approach, is useful for distinguish the reactivity of the two type of carbon atoms in the molecule.