Organic & Biomolecular Chemistry Blog

2023 marks twenty years of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

Our next entry to the series comes from Professor Luis R. Domingo at the University of Valencia who first published with OBC in 2003, the journal’s first year. He has continued to support the journal with 27 articles across the years, most recently in 2021.

About Luis

Luis R. Domingo obtained his PhD in Organic Chemistry in 1987. In 2010 he attained his current position as a Full Professor at the Department of Organic Chemistry of the University of Valencia. In 2014 he was admitted as a Fellow of the Royal Society of Chemistry. His research interest is the study of organic chemical reactivity by using quantum chemical procedures based on the analysis of the molecular electron density. He has published more than 370 articles and 8 book chapters, being reviewer of more than 690 articles. Today, he has reached an h index of 61, receiving more than 16,450 citations.

In 2009, Domingo proposed the mechanism of polar Diels-Alder reactions against the ‘pericyclic mechanism’, which is followed by many of the experimental reactions and in 2019 he established the relationship between the structure and reactivity of the three-atom-components participating in [3+2] cycloaddition reactions, proposing four different reaction mechanisms. In 2014, he proposed a new model for the C-C bond formation based on the quantum chemical topology of electron density. He emphasised the significance of the global electron density transfer (GEDT) in the activation energies of polar reactions. After the study of relevant organic reactions classified in 1969 as pericyclic reactions, in 2019 the corresponding mechanism was rejected. He has introduced several concepts widely used today as non-concerted two-stage one-step mechanisms, which involve high asynchronous transition state structures, pseudoradical centres, which participate in many organic reactions involving the formation of new C-C single bonds, and the GEDT which discards the arrow curves used in many textbooks to explain the electronic displacement in polar reactions.

In the present century, Domingo and co-workers have developed several reactivity indices within the Conceptual Density Functional Theory, such as the local electrophilicity ω_k index in 2002, the empirical nucleophilicity N index in 2008, the reactivity difference index in 2012, and the electrophilic and nucleophilic Parr functions in 2013, commonly used nowadays in the study of polar organic reactions.

After 20 years and more than 250 publications in the field of Theoretical Organic Chemistry, in 2016 Domingo proposed a new reactivity theory named Molecular Electron Density Theory (MEDT), which opposes all theories developed in the past century based on analysis of molecular orbitals such as the Frontier Molecular Orbital (FMO) theory. Domingo’s MEDT proposes the study of organic chemical reactivity based on the analysis of electron density changes during a chemical reaction.

First OBC Paper: A. Manuel & L. R. Domingo, Theozyme for antibody aldolases. Characterization of the transition-state analogue, Org. Biomol. Chem., 2003, 1, 637-643, DOI: 10.1039/b209636f

Most recent OBC Paper: M. Ríos-Gutiérrez, P. Pérez, L. R. Domingo & J. Soto-Delgado, The catalytic effects of a thiazolium salt in oxa-Diels-Alder reaction between benzaldehyde and Danishefsky’s diene: A molecular electron density theory study, Org. Biomol. Chem., 2021, 19, 9306-9317, DOI: 10.1039/d1ob01415c

Favourite OBC Paper: L. R. Domingo & J. A. Sáez, Understanding the mechanisms of polar Diels-Alder reactions, Org. Biomol. Chem., 2009, 7, 3576-3583, DOI: 10.1039/b909611f

How has your research developed over the last 20 years?

The development at the end of the last century of quantum chemistry tools capable of performing molecular electron density analysis has made significant advances in the field of Theoretical Organic Chemistry during the last 20 years.

After the proposal in 1999 of Parr’s electrophilicity ω index, which provides a quantitative measure of an important reactivity concept in organic chemistry in 2002, the first electrophilicity ω scale of organic molecules able to explain the reactivity of experimental Diels-Alder reactions was presented¹. The local electrophilicity ω_k index, proposed in 2002, allowed explaining the chemo and regioselectivity in polar cycloaddition reactions². Later in 2008, the empirical nucleophilicity N index was proposed^3,4. Today, the electrophilicity ω and the nucleophilicity N indices allow the quantitative study of polar reactions. Finally, in 2013, the electrophilic and nucleophilic Parr functions were introduced, allowing the understanding of the local reactivity, i.e., the chemo and regioselectivities, in polar reactions⁵.

After numerous theoretical studies of reaction mechanisms in the period 2002-2014 based on the topological analysis of the molecular electron density, a model for the formation of new C-C single bonds experienced by many organic reactions was proposed in 2014⁶. On the other hand, the recognition of the decisive role of the global electron density transfer (GEDT)⁶ in the activation energies of polar organic reactions provided a new vision of relevant reactions such as the polar Diels-Alder reactions⁷, inadequately classified as a pericyclic reaction in 1969.

[3+2] cycloaddition (32CA) reactions are a class of fascinating organic reactions. After 20 years of studying 32CA reactions, an excellent correlation between the electronic structure of the three-atom-components (TACs) and their reactivity was established in 2019. Unlike the 1,2-dipolar structure proposed by Huisgen, four different electronic structures, which experience four different reactivity types, were characterized⁸. Recent studies have shown that although the electronic structure of the TAC can be modified with substitution, the four types of reactivity can be characterized in most 32CA reactions.

After 20 years of working in the field of Theoretical Organic Chemistry, in 2016, Domingo proposed a new reactivity theory named Molecular Electron Density Theory (MEDT)⁹, which establishes that changes in electron density along an organic reaction, and not molecular orbital interactions, are responsible for the chemical reactivity of organic molecules.

Many recent MEDT studies of relevant organic reactions have allowed us to reinterpret the organic reactivity based on electron density analysis. A recent study of the four reactions classified in 1969 by Woodward and Hofmann as pericyclic reactions has proved that this mechanism does not exist since the bonding changes in organic reactions are sequential and non-concerted¹⁰.

How has the field of theoretical organic chemistry changed over the last 2 decades?

The advances carried out in the last 2 decades in the field of theoretical organic chemistry based on the analysis of the molecular electron density, which is the only physical observable, have allowed us to establish new concepts in organic chemistry. This has caused the rejection of models developed in the past such as the FMO theory, the symmetry rules and energy decomposition analyses based on molecular orbitals, all of them proposed in the past century before the possibility to perform any topological analysis of the molecular electron density obtained from Schrödinger’s wavefunction.

On the other hand, the electrophilicity ω and the nucleophilicity N indices, together with the Parr functions have become easy and powerful tools in studying local reactivity in polar reactions for experimental organic chemists.

Finally, the recent topological analysis of the ELF of the reagents in relevant organic reactions such as 32CA reactions has established a good correlation between the electronic structure and chemical reactivity.

Where do you see the challenges being for this field over the next 20 years?

The establishment of Schrödinger’s equation in 1926 was one of the more relevant advances in the field of theoretical organic chemistry as it provides the molecular electron density distribution, which determines the structure and reactivity of organic molecules. Still unfortunately, it cannot be resolved even for the simplest organic molecules. In 1932, the molecular orbital theory was established as a mathematical approach to the wavefunction, but inappropriately molecular orbitals were taken as a reality, proposing in 1931 the Hückel’s p-bonds in unsaturated compounds and 1956 Fukui’s FMO theory to explain organic chemical reactivity. Many concepts, such as pericyclic reactions or concerted reactions are still used today in many organic chemistry textbooks.

Extensive work developed in the present century, based on the analysis of the molecular electron density, has allowed the understanding of many organic reactions, rejecting those concepts based on molecular orbital analyses. Unfortunately, there is still strong influence by research groups that continue working with molecular orbital theories to study reaction mechanisms. But in the last two decades, they have not introduced any advances in chemical understanding.

MEDT proposed in 2016, suggests that the analysis of the molecular electron density, which is the only physical observable, is accurate for understanding organic molecules’ electronic structure and reactivity. Today, theoretical and experimental organic chemists have a great variety of quantum chemical tools able to perform a rigorous analysis of the molecular electron density obtained by any computational level, thus rejecting any obsolete molecular orbital analysis. Note that molecular orbitals were defined to approach the wavefunction, the square of which provides the molecular electron density.

The relationship of HOMO and LUMO energies with the ionization potential and the electron affinity used in Conceptual Density Functional Theory to attain the reactivity indices and that between molecular orbital coefficients and the Fukui functions used to study the local reactivity allows explaining the good correlations found between experimental data and FMO analyses, but non HUMO-LUMO interactions, but rather nucleophilic/electrophilic interactions between molecules of different electronegativity are responsible for the chemical reactivity in polar reactions.

These similitudes make it that unfortunately, many people continue using models based on the updated FMO theory, but it is essential to remember that Schrödinger’s wavefunction was proposed only to describe the electron distribution in a molecule and that electronic interactions between particles constituting a molecule, i.e., nuclei and electrons are responsible for electronic energies.

Check out the other entries in our blog series here!