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Extending the Molecular Electron Density Theory

Periodic Reporting for period 2 - Extending MEDT (Extending the Molecular Electron Density Theory)

Período documentado: 2021-06-17 hasta 2022-06-16

The central idea of Molecular Electron Density Theory (MEDT) is that chemical reactions can be classified, understood, and predicted by directly studying changes in electron density. However, even though physical/computational chemists have repeatedly demonstrated its utility, it is not widely used by organic chemists, who prefer to use classic resonance structures and Frontier Molecular Orbital (FMO) theory. The foundations of three of the main pillars of organic chemistry have already been shaken by MEDT, which emphasizes that the way that organic chemists conceive chemical reactions demands a contemporary revision consistent with the analysis of the changes of electron density along a chemical reaction.

To date, MEDT has only used few reactivity indicators and quantum-chemical tools. To obtain a more complete picture of chemical reactivity it is useful to extend MEDT to different tools. In addition, all previous applications of MEDT have relied on methods that are known to fail in some reactions. In this sense, it would be desirable to explore whether MEDT is sensitive to how accurately the electron-density descriptors it uses are computed.

Finally, despite MEDT is truly preferable to traditional methods based on molecular orbitals, it is not popular enough yet in both physical and organic chemists communities. To globalize its use, it would be necessary to confirm that the contradictions between MEDT and traditional descriptions are not an artefact of the level of theory employed in the computational studies, and provide incontrovertible practical evidence for the utility of the MEDT paradigm.

In summary, refining old concepts—and finding new ones that are directly applicable to state-of-the-art quantum-chemical methods—is the overarching goal of this proposal. More specifically, the objective is to develop, extend and enrich MEDT by developing and applying new tools and methods for clarifying chemical reactivity. Finally, the most ambitious goal is to provide strong support for the MEDT paradigm to convince physical and organic chemists to use this new theory of chemical reactivity.

The proper understanding of how and why do reactions take place is important to society because it would lead to a better design of chemical reactions with practical utility, greater effectiveness and better use of resources and time, since it is possible to predict which combination of reagents will give better results to obtain the desired compounds without wasting them experimentally.
Upon arrival to McMaster University during the outgoing phase, the researcher started to familarize with the quantum-chemical tools, methods and programs developed by the Ayers group. Electron densities and other descriptors for MEDT were computed and applied to several reactions. Then, new spin-resolved indicators for elucidating local electron-density changes and reactivity in non-polar reactions were developed.

Simultaneously, MEDT has also been applied to the study of several organic reactions together with the researcher's host group and various international collaborations to give it more visibility and credibility. Among them, epoxidation reactions, aromatic nucleophilic substitutions, nitration reactions, catalyzed and non-catalyzed Diels–Alder reactions, polar and non-polar [3+2] cycloaddition (32CA) reactions involving several several types of pseudodiradical, pseudomonoradical, carbenoid and zwitterionic reagents, aza-Diels-Alder reactions and ionic Diels-Alder reactions, were investigated.

During the secondment period, the researcher started to familiarize with the Interacting Quantum Atoms (IQA) approach, with the AIMAll software to perform the corresponding calculations, and with the in-house program for post-analysis of IQA using the reduced energy gradient (REG) method recently developed by Popelier’s group at the University of Manchester, and started to study the stereochemistry in a series of electrocyclic reactions.

Finally, during the returning period, the beneficiary applied the training received on quantum chemical tools during the outgoing phase to study diverse chemical processes, especially focusing on determining the factors contributing to reaction barriers within the MEDT perspective. By the end of the project, the researcher mastered the application of the IQA approach combined with the REG method, and was able to explain the origin of the energy costs of several chemical reactions. This is notoriously useful for syntheses designs, as one can select appropriate compound substitution in order to lower the factors contributing to the barrier and thus have quicker and/or more selective processes.

During the return period, electrophilic aromatic substitutions, intramolecular ionic Diels-Alder reactions, Lewis-acid catalyzed 32CA reactions, oxa-Diels-Alder reactions, the structure of a metallorganic complex, the behaviour of the Cr(CO)3 complex in Diels-Alder reactions, and the application of reactivity indices in polar Diels-Alder reactions and in chemical selectivity, have been studied.

These results have been disseminated in international conferences and in the fellow's host group website. In addition, the fellow has also commented on her successful case in an MSCA informative session at the host institution, encouraging future researchers to participate in the programme.

Overall, the 3-year project has contributed to the development of MEDT as a powerful paradigm that provides a modern rationalization of organic chemical reactivity based on the analysis of electron density. The MEDT interpretation contrasts with the traditional understanding based on widely known classical theories founded on the analysis of molecular orbitals and is allowing to build a completely different, yet more appropriate, picture of organic chemistry which will have a significant impact on future syntheses designs and applications.
Spin-resolved indictors within the framework of spin-polarized conceptual DFT were developed and implemented in an open-source program. On the other hand, the uselfulness of the combined application of the IQA-REG and Bonding Evolution Theory (BET) methods to understand activation energies and reaction mechanisms is emphasized for the first time.

The studies performed during the development of the project not only broaden the scope of the applicability of MEDT and its confidence to give a new, modern interpretation of chemical reactivity, but also help expand the use of new quantum-chemical tools such as the IQA-REG method to study reactivity based on the analysis of electron density.

The possible potential impact of the project is the society's approach to a more rigorous knowledge of chemical organic reactivity, which would therefore lead to a better design of chemical reactions with practical utility, in the context of greater effectiveness and better use of resources and time, since it is possible to predict which combination of reagents will give better results to obtain the desired compounds without wasting them experimentally.

Finally, beyond the state-of-the-art quantum chemical methodologies applied and any other societal implications, the present project has allowed the fellow’s progress as an individual researcher, with enriched skills to build new future collaborations of potential relevance in the research field of interest, boosting the possibility to become a research group leader.
Quantum-chemical tools used by MEDT