This is a collection of my work as a theoretical and computational chemist, organized by theme and year: For each theme, the most recent works are listed on top. At the moment, most of my works fit into one of the following categories:
There are also some Other Works, which originated from different collaborations. These are collected at the end of the page.
Transition Metal-Catalysed Epoxidations
This is the main theme on my PhD dissertation. The main purpose of this work was to evaluate the consequences of immobilization in transition metal complexes. In particular, immobilization techniques in which the procedure directly affects the coordination sphere of the metal center received considerable attention. Moreover, this work focuses on the chemistry of Mn(salen) complexes and VO(acac)2 towards the epoxidation of alkenes and allylic alcohols, respectively. The energetics of the immobilized complexes and their most significant intermediates are investigated using DFT calculations at the X3LYP/triple-ζ level of theory, and the properties of each system at their equilibrium geometries are rationalized using different computational approaches. A summarized state-of-the-art (as of 2017, was recently published as a review/perspective on Catalysts.
Strengths, Weaknesses, Opportunities and Threats: Computational Studies of Mn- and Fe-Catalyzed Epoxidations
Abstract: The importance of epoxides as synthetic intermediates in a number of highly added-value chemicals, as well as the search for novel and more sustainable chemical processes have brought considerable attention to the catalytic activity of manganese and iron complexes towards the epoxidation of alkenes using non-toxic terminal oxidants. Particular attention has been given to Mn(salen) and Fe(porphyrin) catalysts. While the former attain remarkable enantioselectivity towards the epoxidation of cis-alkenes, the latter also serve as an important model for the behavior of cytochrome P450, thus allowing the exploration of complex biological processes. In this review, a systematic survey of the bibliographical data for the theoretical studies on Mn- and Fe-catalyzed epoxidations is presented. The most interesting patterns and trends are reported and finally analyzed using an evaluation framework similar to the SWOT (Strengths, Weaknesses, Opportunities and Threats) analysis performed in enterprise media, with the ultimate aim to provide an overview of current trends and areas for future exploration.
Personal Note: The application of a SWOT framework to a review was heavily criticized during the peer-review process, leading to a “toned down” text to be published. The main argument against applying this kind of analysis is the fact that this technique comes from the soft sciences (marketing, business administration, etc), and it is subjective. On the other hand, the SWOT is an excellent way to divide the information about the state-of-the-art in a systematic manner. Applying this framework to the state-of-the-art would probably help direct research to more pressing areas of development.
Driving Forces in the Sharpless Epoxidation Reaction: A Coupled AIMD/QTAIM Study
Abstract: In order to better understand the epoxide-formation step of the Sharpless epoxidation process, a set of 263 oxygen-transfer reactions reflecting the complexity of the Sharpless epoxidation process were studied using density functional theory (DFT) and Bader’s quantum theory of atoms in molecules (QTAIM). The diversity within these reactions reflects the different ligands in the coordination sphere of vanadium and also different substrates (alkene and an allylic alcohol both free and in the form of an alcoxo ligand). The transition states for 76 of these reactions were also characterized using DFT and QTAIM, allowing for an estimation of the impact of the different ligands and substrates on the activation barriers. A smaller subset of the latter was further subjected to an ab initio molecular dynamics (AIMD) simulation coupled to QTAIM analysis. The results show that the type of active catalyst plays an important role in the thermodynamic outcome of these reactions, with vanadium(V) tert-butylhydroperoxide adducts being responsible for the most exoenergetic reactions. On the other hand, the different ligands tested play only a limited role in modulating the thermodynamics and kinetics of these reactions. Moreover, no evidence was found to support a thermodynamic or kinetic preference for the epoxidation of an allylic alcohol over that of an unfunctionalized alkene. However, the results suggest that the reaction path is strongly influenced by the orientation of the substrate upon approximation to the active catalyst, confirming the well-known regioselectivity of the Sharpless epoxidation process.
Roots of Acetate-Vanadium Linkage Isomerism: A QTAIM Study
Abstract: The possibility of linkage isomerism in a number of vanadium(IV) and vanadium(V) complexes with acetate was surveyed using Density Functional Theory (DFT) and Bader’s Quantum Theory of Atoms in Molecules (QTAIM). The results show that vanadium-acetate linkages may be classified as bidentate symmetrical, bidentate asymmetrical, or monodentate, the latter being observed in about 40% of the cases. These latter ones correspond to situations where the two oxygen atoms of the acetate moiety are not equivalent. They are associated with an energy penalty of about 263 kJ·mol–1, as determined by the distribution of the scaled kinetic energy of the atomic basins forming the acetate ligand. In the presence of bidentate symmetrical vanadium-acetate linkages, the inner valence-shell charge concentrations on the vanadium atom deviate from the traditional VSEPR-derived arrangement, with an energy penalty of about 780 kJ·mol–1. A compromise situation is partially accomplished in the case of bidentate asymmetrical linkages, which allow a Gillespiean-like arrangement of the inner valence-shell charge concentrations. In this case, one of these local charge concentrations lies close to a V–OAcO bond, which slightly disrupts the equivalence between the two oxygen atoms in the acetate ligand.
Personal Note: This is actually a very interesting work I stumbled upon while inspecting the topology of ∇²ρ(r) in the vanadium complexes that Vandichel et al. (J. Catal., 2012, 294, 1-18) used when modeling the Sharpless epoxidation of cyclohexene. While this work has little to do with the catalytic behaviour of these complexes per se, it rekindled the exploration of the factors driving the geometry of Transition Metal complexes, first pioneered by Prof. Gillespie in the 1990’s.
Effects of Axial Coordination on Immobilized Mn(salen) Catalysts
Abstract: The consequences of anchoring Mn(salen) catalysts onto a supporting material using one of the vacant positions of the metal center are tackled by studying several Mn(salen) complexes with different axial ligands attached. This is accomplished using Density Functional Theory at the X3LYP/Triple-ζ level of theory and the Atom In Molecules formalism. The results suggest that both Mn(salen) complexes and their oxo derivatives should lie in a triplet ground state. Also, the choice of the axial ligand bears a moderate effect on the energy involved in the oxidation of the former to oxo-Mn(salen) complexes, as well as in the stability of such complexes toward ligand removal by HCl. AIM analysis further suggests that the salen ligand acts as a “charge reservoir” for the metal center, with strong correlations being obtained between the charge of salen and the electron population donated by the axial ligand to the metal center. Moreover, the results suggest that the Mn atom in Mn(salen) complexes holds different hybridization of its valence orbitals depending on the type of axial ligand present in the system.
Principal Component Analysis of Mn(salen) Catalysts
Abstract: The theoretical study of Mn(salen) catalysts has been traditionally performed under the assumption that Mn(acacen′) (acacen′ = 3,3′-(ethane-1,2-diylbis(azanylylidene))bis(prop-1-en-olate)) is an appropriate surrogate for the larger Mn(salen) complexes. In this work, the geometry and the electronic structure of several Mn(salen) and Mn(acacen′) model complexes were studied using Density Functional Theory (DFT) at diverse levels of approximation, with the aim of understanding the effects of truncation, metal oxidation, axial coordination, substitution on the aromatic rings of the salen ligand and chirality of the diimine bridge, as well as the choice of the density functional and basis set. To achieve this goal, geometric and structural data, obtained from these calculations, were subjected to Principal Component Analysis (PCA) and PCA with orthogonal rotation of the components (rPCA). The results show the choice of basis set to be of paramount importance, accounting for up to 30% of the variance in the data, while the differences between salen and acacen′ complexes account for about 9% of the variance in the data, and are mostly related to the conformation of the salen/acacen′ ligand around the metal centre. Variations in the spin state and oxidation state of the metal centre also account for large fractions of the total variance (up to 10% and 9%, respectively). Other effects, such as the nature of the diimine bridge or the presence of an alkyl substituent in the 3,3 and 5,5 positions of the aldehyde moiety, were found to be less important in terms of explaining the variance within the data set. A matrix of discriminants was compiled using the loadings of the principal and rotated components that best performed in the classification of the entries in the data. The scores obtained from its application to the data set were used as independent variables for devising linear models of different properties, with satisfactory prediction capabilities.
Charge Distribution in Mn(salen) Complexes
Abstract: The charge and spin distribution in manganese-salen complexes were analyzed using different basis sets and density functionals. Five population analysis methods [Mulliken, Löwdin, Natural population analysis (NPA), atoms in molecules (AIM), and CHelpG] were used to characterize the charge distribution. Results show that NPA and AIM were the only methods capable of giving charges with the correct sign for all cases under study. According to the analysis of the natural charge and spin distributions, the salen ligand shows a complex behavior, counteracting the effect of the chloro and oxo- ligands on the metal center. Furthermore, the presence of a chloride counter ion increases the oxo-radical character of Oxo-Mn(salen) complexes, which may play an important role in the rationalization of the catalytic properties of Mn(salen) complexes.
Calibration sets and the accuracy of vibrational scaling factors: A case study with the X3LYP hybrid functional
Abstract: A linear least-squares methodology was used to determine the vibrational scaling factors for the X3LYP density functional. Uncertainties for these scaling factors were calculated according to the method devised by Irikura et al. J. Phys. Chem. A 109, 8430 (2005). The calibration set was systematically partitioned according to several of its descriptors and the scaling factors for X3LYP were recalculated for each subset. The results show that the scaling factors are only significant up to the second digit, irrespective of the calibration set used. Furthermore, multivariate statistical analysis allowed us to conclude that the scaling factors and the associated uncertainties are independent of the size of the calibration set and strongly suggest the practical impossibility of obtaining vibrational scaling factors with more than two significant digits.
Personal Notes: This was one of my first works to be published, and it is still one of the most cites. Ironically, most citations use this paper as a source for vibrational scaling factors for the X3LYP functional. This work also generated some comments and remarks from other researchers, leading to a reply published a year later in the same journal. Unfortunately, I was not yet able to do a follow up on this matter, although I keep the needed calculations in the back of the oven ;)
I started working on Aza-Diels-Alder reactions back in 2009, when I started to work towards my PhD. Despite being unappealing and un-original by today’s standards, these works really allowed me to understand the process of doing research in Theoretical Chemistry, and develop my skill as a computational chemist, as well as a statistician at a latter stage.
Simple descriptors for assessing the outcome of aza-Diels-Alder reactions
Abstract: The iminium aza-Diels–Alder (iADA) reaction of cyclopentadiene with 16 protonated alkyl alkylimineglyoxilates was studied using density functional theory (DFT) in order to elucidate how different substitution patterns in the dienophile may affect the reaction’s outcome. Additionally, the application of the polarisable continuum model (PCM) together with the evaluation of the thermodynamic properties at different temperatures further allowed the surveying of the importance of such factors. These effects were combined into linear models which use the temperature, Taft’s constants and characteristics of the solvent as descriptors for modelling and predicting the activation enthalpy and enthalpic balance of the iADA reactions under study. This model performs in a satisfactory manner, providing a cross-validation of the DFT framework traditionally used for predicting the outcome of these reactions and also uncovering novel insights into how the substitution patterns in the dienophile, the solvent and the temperature interact in order to give the characteristic regio- and stereoselectivity of the iADA reaction. Moreover, the results show that Taft’s polar and steric substituent constants are important descriptors for assessing the outcome of iADA reactions.
Aza-Diels-Alder addition of cyclopentadiene to propynyliminoglyoxylates
Abstract: The aza-Diels-Alder reaction of cyclopentadiene with protonated propynylimine of methyl (Me) and tert-butyl (t-Bu) carboxylate was studied, using density functional theory (DFT) at the X3LYP/6-31G (d) level, in order to elucidate the role of the ester group of the dienophile. Four independent reaction pathways were found for each diene/dienophile pair, all of them proceeding through a concerted, highly asynchronous, mechanism. Both systems exhibit a clear tendency for the formation of exo adducts and show the same overall behavior, despite steric hindrances. The exo cycloadducts are always favored relative to the endo analogs, both by kinetic and thermodynamic reasons. Gas-phase results showed that the exo/endo rate would be mostly controlled by the relative thermodynamic stability of the final products. However, the application of the polarizable continuum model (PCM) preferentially lowered the activation enthalpy of the reaction exo channels, stressing the importance of the kinetic over the thermodynamic aspects of the proposed mechanism. This resulted in a reaction model that satisfies the experimental evidence.
Stereoselectivity of the aza-Diels-Alder reaction between cyclopentadiene and protonated phenylethylimine derived from glyoxylates. A density functional theory study.
Abstract: The aza-Diels–Alder reaction of cyclopentadiene with protonated (S)-phenylethylimine of methyl carboxilate was studied using density functional theory (DFT) at the B3LYP/6-31G(d) level to elucidate the reported stereoselectivity of this reaction. Four independent reaction pathways were found, all of them proceeding through a concerted, asynchronous, mechanism. Inclusion of solvent effects revealed a high exo/endo stereoselectivity that decreases with increasing temperature, in good accordance with the experimental reports.
Other Works & Collaborations
- Voroshylova, I. V.; Teixeira, F.; Costa, R.; Pereira, C. M. & Cordeiro, M. N. D. S., Interactions in the ionic liquid [EMIM][FAP]: a coupled experimental and computational analysis, Phys. Chem. Chem. Phys., 2016, 18, 2617-2628 [link][top]
- Fajín, J. L.; Teixeira, F.; Gomes, J. R. & Cordeiro, M. D. Effect of van der Waals interactions in the DFT description of self-assembled monolayers of thiols on gold Theor. Chem. Acc., 2015, 134, 67 [link][top]
- Gaspar, A.; Teixeira, F.; Uriarte, E.; Milhazes, N.; Melo, A.; Cordeiro, M. N. D. S.; Ortuso, F.; Alcaro, S. & Borges, F., Towards the Discovery of a Novel Class of Monoamine Oxidase Inhibitors: Structure-Property-Activity and Docking Studies on Chromone Amides, ChemMedChem, 2011, 6, 628-632 [link][top]
- Peixoto, A.; Fernandes, E.; Gaiteiro, C.; Lima, L.; Azevedo, R.; Soares, J.; Cotton, S.; Parreira, B.; Neves, M.; Amaro, T.; Tavares, A.; Teixeira, F.; Palmeira, C.; Rangel, M.; Silva, A. M. N.; Reis, C. A.; Santos, L. L.; Oliveira, M. J. & Ferreira1, J. A. Hypoxia enhances the malignant nature of bladder cancer cells and concomitantly antagonizes protein O-glycosylation extension, Oncotarget, 2016, 7, 63138-63157 [Open Access Link][top]
- Almeida, A.; Ferreira, J. A.; Teixeira, F.; Gomes, C.; Cordeiro, M. N. D. S.; Osório, H.; Santos, L. L.; Reis, C. A.; Vitorino, R. & Amado, F. Challenging the limits of detection of sialylated Thomsen–Friedenreich antigens by in-gel deglycosylation and nano-LC-MALDI-TOF-MS, Electrophoresis, 2013, 34, 2337-2341 [link][top]