Substitution Effects in Aryl Halides and Amides into the Reaction Mechanism of Ullmann-Type Coupling Reactions.

In this article, we present a comprehensive computational investigation into the reaction mechanism of N-arylation of substituted aryl halides through Ullmann-type coupling reactions. Our computational findings, obtained through DFT ωB97X-D/6-311G(d,p) and ωB97X-D/LanL2DZ calculations, reveal a direct relation between the previously reported experimental reaction yields and the activation energy of haloarene activation, which constitutes the rate-limiting step in the overall coupling process. A detailed analysis of the reaction mechanism employing the Activation Strain Model indicates that the strain in the substituted iodoanilines is the primary contributor to the energy barrier, representing an average of 80% of the total strain energy. Additional analysis based on conceptual Density Functional Theory (DFT) suggests that the nucleophilicity of the nitrogen in the lactam is directly linked to the activation energies. These results provide valuable insights into the factors influencing energetic barriers and, consequently, reaction yields. These insights enable the rational modification of reactants to optimize the N-arylation process.

Basis Electronic Activity of Molecular Systems. A Theory of Bond Reactivity.

In this paper, we present a new finding, the basis electronic activity (BEA) of molecular systems; it corresponds to the significant, although nonreactive, vibrationally induced electronic activity that takes place in any molecular system. Although the molecule's BEA is composed of an equal number of local contributions as the vibrational degrees of freedom, our results indicate that only stretching modes contribute to it. To account for this electronic activity, a new descriptor, the bond electronic flux (BEF), is introduced. The BEF combined with the force constant of the potential well hosting the electronic activity gives rise to the effective bond reactivity index (EBR), which turns out to be the first density functional theory-based descriptor that simultaneously accounts for structural and electronic effects. Besides quantifying the bond reactivity, EBR provides a basis to compare the reactivities of bonds inserted in different chemical environments and paves the way for the exertion of selective control to enhance or inhibit their reactivities. The new concepts formulated in this paper and the associated computational tools are illustrated with characterization of the BEA of a set of representative molecules. In all cases, the BEFs follow the same linear pattern, whose slopes indicate the intensity of the electronic activity and quantify the reactivity of chemical bonds.

Antioxidant Capacity of Free and Peptide Tryptophan Residues Determined by the ORAC (Oxygen Radical Absorbance Capacity) Assay Is Modulated by Radical-Radical Reactions and Oxidation Products.

The ORAC (Oxygen Radical Absorbance Capacity) assay is commonly employed for determining the antioxidant capacity of bioactive peptides. To gain insights into the meaning of this index for peptides containing a single Trp, we studied the consumption of this residue and fluorescein (FLH, the probe of ORAC method), induced by radicals generated by AAPH (2,2'-Azo-bis(2-amidinopropane) dihydrochloride) thermolysis. ORAC values were rationalized from kinetics and computational calculations of bond dissociation energies (BDE) of the N-H bond (indole ring of Trp). Free Trp, di- and tri- peptides, and three larger peptides were studied. Solutions containing 70 nM FLH, 1-5 µM free Trp or peptides, and 10 mM AAPH were incubated at 37 °C in phosphate buffer. Kinetic studies showed that FLH minimally affected Trp consumption. However, a clear protection of FLH, characterized by pseudo-lag times, was evidenced, reflecting radical-radical reactions and FLH repairing. Peptides showed similar ORAC values (~1.9-2.8 Trolox equivalents), while BDE varied between 91.9 and 103.5 kcal. These results, added to the protection of FLH observed after total consumption of Trp, indicate a lack of discrimination of the assay for the chemical structure of peptides and the contribution of oxidation products to the index.

A surface functionalized with per-(6-amino-6-deoxy)-ß-cyclodextrin for potential organic pollutant removal from water.

In this work, we present a solid silicon substrate functionalized with modified ß-cyclodextrin monolayers as an optimal surface for organic contaminant uptake. The inclusion and capture of three potential pollutants, 4-chlorophenoxyacetic acid, 4-aminobenzoic acid and phenylethylamine, were studied. 1H-NMR and ROESY studies revealed the complete inclusion and details of the conformational orientation of the three guests in the per-(6-amino-6-deoxy)-ß-cyclodextrin matrix, forming three new inclusion complexes that have not yet been reported. Capture assays for the guests were carried out by immersing the substrates in an aqueous pollutant solution and by measuring the UV-vis spectra. This substrate showed a high sorption capacity at equilibrium, between 2.5 × 10-5 and 6.0 × 10-5 mmol/substrate, for the studied pollutants. In addition, this surface can be reused four times with an efficiency equal to the initial use. Therefore, it could be a versatile platform that could be applied for the capture of other organic pollutants from water.

On the nature of the interaction of copper hydride and halide with substituted ethylene and acetylene.

The association of Cu-X (X = -H, -Cl, and -F) with H2CCHCHmYn and HCCCHmYn (Y = -Cl, -F, -OH, -CH3) has been studied at a high level of theory. The density functional theory (DFT) at B3LYP/6-311G(d,p)//B3LYP/6-311 + G(3df,2p) level has been chosen to calculate the structure and the relative stability of 24 different complexes. The interaction of Cu-F with the derivatives of ethylene and acetylene was found very strong, with interaction energies close to those of conventional covalent bonds. In all complexes, the most stable structure was found when Cu-X is positioned on the unsaturated CC bond, forming a three-membered ring that leads to longer CC bond distances. Both ethylene and acetylene complexes show similar trends of interaction energies with respect to the same moiety. All electronic indexes analyzed by means of the QTAIM, ELF, and NBO formalisms indicate that the strength of the interaction should increase with the number of withdrawing substituents in both series of compounds. Graphical abstractThe p-Interaction of ethylene and acetylene derivative with fluoride copper. The ELF graphs and its 2D projection show the disynaptic basins of the electrostatic binding.

Theoretical Study of the Mechanism of Catalytic Enanteoselective N-H and O-H Insertion Reactions.

Theoretical density functional theory (DFT) calculations were carried out to study bond insertion reactions using a copper(I)-Box-carbenoid as a bond activator. In order to understand the reaction mechanism where N-H and O-H bonds actively participate, the reaction force (RF) and activation strain model (ASM) were used. Results indicate that the first step of the reaction is barrierless for both bond insertions (N-H and O-H), and the second step of the insertion reaction in the phenol (O-H bond) is favored kinetically and thermodynamically with regard to the aniline substrate (N-H bond). The enantioselectivity is driven by the ligand of the catalyst by steric repulsion, favoring the formation of the R isomer. The analysis of the reaction force and ASM exhibited that the higher energy barrier in aniline is mainly due to a higher W2 contribution together with repulsive interactions, which hinders the insertion process.

Mechanistic Insight toward Understanding the Role of Charge in Thiourea Organocatalysis.

Pyranylation and glycosylation are pivotal for accessing a myriad of natural products, pharmaceuticals, and drug candidates. Catalytic approaches for enabling these transformations are of utmost importance and integral to advancing this area of synthesis. In exploring this chemical space, a combined experimental and computational mechanistic study of pyranylation and 2-deoxygalactosylation catalyzed by a cationic thiourea organocatalyst is reported. To this end, a thiourea-cyclopropenium organocatalyst was employed as a model system in combination with an arsenal of mechanistic techniques, including 13C kinetic isotope effect experiments, deuterated labeling studies, variable-temperature 1H NMR spectroscopy, and density functional theory calculations. From these studies, two distinct reaction pathways were identified for this transformation corresponding to either dual hydrogen bond (H-bond) activation or Brønsted acid catalysis. The former involving thiourea orchestrated bifurcated hydrogen bonding proceeded in an asynchronous concerted fashion. In contrast, the latter stepwise mechanism involving Brønsted acid catalysis hinged upon the formation of an oxocarbenium intermediate accompanied by subsequent alcohol addition.

Reaction Mechanism of Li and Mg Carbenoid Cyclopropanations: Metal-π and σ Interactions.

The mechanism of the reaction of lithium and magnesium carbenoids with ethylene to give cyclopropane has been explained in detail in all the steps at the G4 level of theory. We explored the lithium and magnesium interaction toward πC=C and σC-C bonds in the reactants and the products. We have also investigated the reaction path by means of the force profile formalism in order to highlight the electronic and the structural rearrangements along the potential energy surface of the cyclopropanation. The results indicate that all of the reactions are stepwise, exoenergetic, with low barriers. All our findings were confirmed by dynamic simulations for chlorometal carbenoids. Furthermore, from the intrinsic reaction coordinate procedure, we were able to find out the intermediates that can take place when the reaction is descending from the transition state to the products or reactants. The reaction force analysis at B3LYP/6-311G(d,p) indicates that the energy barriers are mostly due to structural rearrangements which are produced by the approach of the carbenoid to ethylene. Quantum theory of atoms in molecules and electron localization function analyses indicate that products, reactants, and intermediates form complexes stabilized by attractive forces between Li/Mg and single/double bonds.

Theoretical study of C-arylations with aryl halides to determine the reaction mechanism, the effect of substituents and heteroatoms.

Carbon arylations are very important in the pharmaceutical industry. New synthesis routes are often studied with the objective of trying to insert new bonds and substituents into an organic framework. Ullman reactions have been very useful in this context. In light of this, a wB97XD/6-311g set of Ullman-like reactions among substituted amide arylations with iodoaniline were theoretically studied in order to understand their intrinsic reactivity and their reaction mechanisms. The studied systems included unsubstituted (C), sulphur (S), synthesized by the authors in a previous experimental work. In this study, amino (NH) and butyloxycarbonyl (NBoc) amides were added. IRC calculations on catalyzed species showed that the catalyst lowers the reaction barrier, and changes the reactivity in order to lower the nitrogen charge. The reaction mechanism proceeds by binding the CuI catalyst and N,N-dimethylethylenediamine (DMEN) to the N lactam, in a barrierless reaction, thereby activating the nitrogen to bond with the aryl iodine through a nucleophilic substitution, and thus recovering the catalyst.

An extension of the Marcus equation: the Marcus potential energy function.

An analytic potential function consistent with the Marcus equation for activation energy is formulated and used to reveal new insights into the activation process in chemical reactions. As for the Marcus equation, the new potential function depends only on two parameters, the reaction energy and the activation energy (or the so-called Marcus intrinsic activation energy). Combination of the Marcus potential with the reaction force analysis provides two-parameter analytic expressions for the reaction force, reaction force constant, and reaction works. Moreover, since the parameters necessary to define the Marcus potential energy function can be obtained experimentally, the present model may produce experimental analytic potentials allowing for new and interesting applications, thus emerging as a powerful tool to characterize activation processes in chemical reactions.

Reaction Electronic Flux Perspective on the Mechanism of the Zimmerman Di-π-methane Rearrangement.

The reaction electronic flux (REF) offers a powerful tool in the analysis of reaction mechanisms. Noteworthy, the relationship between aromaticity and REF can eventually reveal subtle electronic events associated with reactivity in aromatic systems. In this work, this relationship was studied for the triplet Zimmerman di-π-methane rearrangement. The aromaticity loss and gain taking place during the reaction is well acquainted by the REF, thus shedding light on the electronic nature of reactions involving dibenzobarrelenes.

Study of antiradical mechanisms with dihydroxybenzenes using reaction force and reaction electronic flux.

Phenolic compounds represent an important category of antioxidants because they help inhibit the oxidation process of organic compounds, while also acting as antiradicals in many biological processes. In this work, we analyze the transfer mechanisms for a set of catechols and resorcinols of a single electron, proton and hydrogen, with the radical peroxyl (˙OOH) and with different electron withdrawing and donating groups as substituents. By using the M05-2X exchange correlation functional within the Density Functional Theory framework combined with the 6-311++G(d,p) basis set, we were able to compute the Gibbs free energies for all mechanisms and compounds. According to the thermodynamic results, the hydrogen atom transfer mechanism was the most favorable. Therefore, this mechanism with substituents -CH3 and -COH in catechol and resorcinol was analyzed, using the reaction force and reaction electronic flux to characterize the structural and electronic changes that take place during the reaction. Our results show that electron donating groups favor electronic changes along the reaction path, increasing the spontaneity of the hydrogen atom transfer mechanism.

Reaction electronic flux and its role in DNA intramolecular proton transfers.

Proton transfer reactions present a key step in many biological and chemical processes. Here, we focused on the electronic changes in the proton transfer reactions of the four DNA bases. In combination with the previous structural analysis the reaction electronic flux together with local descriptors as the Hirshfeld-I charges allow us to identify chemical events and rationalize the underlying reaction mechanism. Our results show that imine-enamine in adenine and citosyne, and keto-enol tautomerizations in thymine and guanine have different reaction mechanisms. The former involve net structural rearrangements driven by favoured electrostatic interactions between the proton and the acceptor atom whereas the keto-enol tautomerizations require electronic changes reflected in the reaction electronic flux and changes in the NBO bond orders which favour the proton transfer reaction.

Atomic decomposition of conceptual DFT descriptors: application to proton transfer reactions.

In this study, we present an atomic decomposition, in principle exact, at any point on a given reaction path, of the molecular energy, reaction force and reaction flux, which is based on Bader's atoms-in-molecules theory and on Pendás' interacting quantum atoms scheme. This decomposition enables the assessment of the importance and the contribution of each atom or molecular group to these global properties, and may cast the light on the physical factors governing bond formation or bond breaking. The potential use of this partition is finally illustrated by proton transfers in model biological systems.

The mechanism of chemisorption of hydrogen atom on graphene: insights from the reaction force and reaction electronic flux.

At the PBE-D3/cc-pVDZ level of theory, the hydrogen chemisorption on graphene was analyzed using the reaction force and reaction electronic flux (REF) theories in combination with electron population analysis. It was found that chemisorption energy barrier is mainly dominated by structural work (∼73%) associated to the substrate reconstruction whereas the electronic work is the greatest contribution of the reverse energy barrier (∼67%) in the desorption process. Moreover, REF shows that hydrogen chemisorption is driven by charge transfer processes through four electronic events taking place as H approaches the adsorbent surface: (a) intramolecular charge transfer in the adsorbent surface; (b) surface reconstruction; (c) substrate magnetization and adsorbent carbon atom develops a sp(3) hybridization to form the σC-H bond; and (d) spontaneous intermolecular charge transfer to reach the final chemisorbed state.

The mechanism of Menshutkin reaction in gas and solvent phases from the perspective of reaction electronic flux.

The mechanism of Menshutkin reaction, NH(3) + CH(3)Cl = [CH(3)-NH(3)]+ + Cl-, has been thoroughly studied in both gas and solvent (H(2)O and cyclohexane) phase. It has been found that solvents favor the reaction, both thermodynamically and kinetically. The electronic activity that drives the mechanism of the reaction was identified, fully characterized, and associated to specific chemical events, bond forming/breaking processes, by means of the reaction electronic flux. This led to a complete picture of the reaction mechanism that was independently confirmed by natural bond-order analysis and the dual descriptor for chemical reactivity and selectivity along the reaction path.

Using the reaction force and the reaction electronic flux on the proton transfer of formamide derived systems.

In this work, we present a theoretical study of the mechanism of double proton transfer in formamide, formamide-thioformamide and thioformamide dimers. The reaction mechanisms were analyzed in terms of the energy profile and novel concepts such as the reaction force profile and reaction electronic flux, along with local electronic properties such as NBO analysis. All systems were characterized computationally using DFT/B3LYP 6-311G** on Gaussian09. These results show that the electronic processes take place mostly in the transition state for all the systems; in the formamide and thioformamide dimers, electron transfer has a synchronic nature, while the electron transfer is asynchronic in the formamide-thioformamide dimer.

Efficacy of Acetic Acid against Listeria monocytogenes Attached to Poultry Skin during Refrigerated Storage.

This work evaluates the effect of acetic acid dipping on the growth of L. monocytogenes on poultry legs stored at 4 °C for eight days. Fresh inoculated chicken legs were dipped into either a 1% or 2% acetic acid solution (v/v) or distilled water (control). Changes in mesophiles, psychrotrophs, Enterobacteriaceae counts and sensorial characteristics (odor, color, texture and overall appearance) were also evaluated. The shelf life of the samples washed with acetic acid was extended by at least two days over the control samples washed with distilled water. L. monocytogenes counts before decontamination were 5.57 log UFC/g, and after treatment with 2% acetic acid (Day 0), L. monocytogenes counts were 4.47 log UFC/g. Legs washed with 2% acetic acid showed a significant (p < 0.05) inhibitory effect on L. monocytogenes compared to control legs, with a decrease of about 1.31 log units after eight days of storage. Sensory quality was not adversely affected by acetic acid. This study demonstrates that while acetic acid did reduce populations of L. monocytogenes on meat, it did not completely inactivate the pathogen. The application of acetic acid may be used as an additional hurdle contributing to extend the shelf life of raw poultry and reducing populations of L. monocytogenes.

Influence of the monoclinic and tetragonal zirconia phases on the water gas shift reaction. A theoretical study.

We present a theoretical study of the water gas shift reaction taking place on zirconia surfaces modeled by monoclinic and tetragonal clusters. In order to understand the charge transfer between the active species, in this work we analyze the influence of the geometry of monoclinic and tetragonal zirconia using reactivity descriptors such as electronic chemical potential (µ), charge transfer (ΔN) and molecular hardness (η). We have found that the most preferred surface is tetragonal zirconia (tZrO2) indicating also that low charge transfer systems will generate less stable intermediates, that will allow to facilitate desorption process.

Selective nanodecoration of modified cyclodextrin crystals with gold nanorods.

Gold nanorods (AuNRs) stabilized by cetyltrimethylammonium bromide (CTAB) were deposited onto crystals of α-cyclodextrin (α-CD) inclusion compounds (ICs) that contained octanethiol (OT) as guest molecules. The nanodecoration was produced specifically at the {001} crystal planes through interaction between the -SH groups of the ICs and the AuNRs.