Chemistry is not Physics
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Dear
colleagues,
An
important MEDT study entitled "Revealing the Critical Role of Global
Electron Density Transfer in the Reaction Rate of Polar Organic Reactions
within Molecular Electron Density Theory" has been accepted for
publication in the journal Molecules (Molecules
2961399).
At the end
of the last century, the relevance of electron density transfer in the energy
stabilization of transition state structures (TSs) of polar reactions was
highlighted (J. Org. Chem.1999, 64, 5867).
In 2009, I
proposed the mechanism of polar Diels-Alder (P-DA) reactions by which most
experimental reactions take place (Org. Biomol. Chem. 2009, 7, 3576). The
electron density transfer occurring at the TSs from the nucleophilic to the
electrophilic species is responsible for the experimentally observed
acceleration. The effects of Lewis acid catalysts have been explained by a
significant increase in the electrophilicity of the carbonyl compounds, which
allows an increase in the electron density transfer (Molecules 2020, 25, 2535).
In 2014, the
concept of global electron density transfer (GEDT) against the concept of charge
Ttransfer (CT) used by physicists was proposed (RSC Adv. 2014, 4, 32415).
Although
very good linear correlations between the increase in GEDT and the decrease in
activation energies of polar reactions were shown, the physical phenomenon causing
the acceleration of a polar reaction had not been established.
Recently, an
energy partitioning analysis of interacting quantum atoms (IQA) (J. Chem. Theory Comput. 2005, 1, 1096), based on the atoms in molecules (AIM) topological
analysis, which allows the energy analysis of the electronic interactions
contributing to the total electronic energies of the molecules, has been
introduced in our MEDT studies..
This
analysis, carried out on the TSs associated with the P-DA reactions of
cyclopentadiene with the cyanoethylene series, experimentally studied by Sauer
in 1964, has allowed to establish the decisive role of the GEDT in the
acceleration found in polar reactions. This analysis establishes that the
increase of GEDT at the TSs increases the reaction rates of P-DA reactions
through an electronic stabilization of the electrophilic framework, in full
agreement with the concept of the electrophilicity w index
defined by Parr in 1999 (J. Am. Chem. Soc. 1999, 121, 1922).
Finally, the
present study, together with the recent MEDT study on the role of hydrogen
bonding in P-DA reactions (Tetrahedron
Chem. 2024, 10, 100064), allow a complete rejection of Bickelhaupt's activation
strain model, which uses an energy decomposition analysis that includes terms
for molecular orbital interactions. In most of Bickelhaupt's studies, the
authors claim that the reduction of "Pauli repulsions", rather than
molecular orbital interactions, are responsible for the observed accelerations
in many organic reactions.
Our IQA
analyses between the interacting centers involved in the formation of the new
C-C single bonds, carried out at the TSs of polar reactions, show that the
attractive electron-nuclei interatomic interactions are superior to the
repulsive ones, a phenomenon that would work against the stabilization of the
TSs based on the decrease of the Pauli repulsion.
Sincerely,
Luis
17/4/2024
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The MEDT today
Dear Colleagues,
Six seven ago, in 2016, I published two relevant manuscripts: (a) Molecular
Electron Density Theory (MEDT): A Modern View of Reactivity in Organic
Chemistry (Molecules 2016, 21, 1319); and (b) Applications of the Conceptual
Density Functional Theory Indices to Organic Chemistry Reactivity (Molecules
2016, 21, 748).
In the first one, a new theory of reactivity in Organic Chemistry, i.e.
MEDT, was proposed in which the changes in electron density along a chemical
reaction, and not molecular orbital (MO) interactions as proposed K. Fukui’s
Frontier Molecular Orbital (FMO) Theory (Nobel Prize in Chemistry in 1981 R.
with R. Hoffman), are responsible for the chemical reactivity of organic molecules.
MEDT rejects all
theories, models, and interpretations based on MO analyses such as Hoffmann’s
symmetry rules, K. N. Houk’s distortion/interaction energy model, and F. M. Bickelhaupt’s activation
strain model.
In the second one, I presented a revision of the most relevant theoretical
reactivity indices used in the study of organic reactivity, including the
electrophilicity w index, the nucleophilicity N index, and the Parr functions.
These reactivity indices, which are a powerful tool for experimental organic
chemists, play an important role in MEDT studies.
Today, MEDT has been cited in 330 manuscripts, while the review of CDFT
indices has been cited in 810 manuscripts.
If people recognized that by using the reactivity indices they are working
within the MEDT and cite it, the Houk’s and Bickelhaupt’s models based on MO interactions
would be widely rejected in organic chemistry and would be used only by
chemical physicists.
Prof Luis R.
Domingo, FRSC
Molecular Electron Density Theory
Molecules 2016, 21, 1319
download
Studies based on the MEDT make it possible to rule out outdated concepts developed within the Molecular Orbital theory such as:
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Publications based on MEDT
12. A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of Nitrones with Strained Allene. RSC Adv. 2017, 7, 26879-26887.
15. A Molecular Electron Density Theory study of [3+2] cycloaddition reactions of chiral azomethine ylides with ß-nitrostyrene. Theor. Chem. Acc. 2017, 136:104.
16. Understanding the Intramolecular Diels-Alder Reactions of N-Susbtituted N-allyl-furfurylamines. An MEDT Study. ChemistrySelect 2017, 2, 9736.
17. Understanding the mechanism of the decomposition reaction of nitroethyl benzoate through the Molecular Electron Density Theory. Theor. Chem. Acc. 2017, 136:129.
18. A Molecular Electron Density Theory study of the chemo- and regioselective [3+2] cycloaddition reactions between trifluoroacetonitrile N-oxide and thioketones
Chemical Physics 2018, 501, 128-137.
19. Experimental and Theoretical MEDT Study of the Thermal [3+2] Cycloaddition Reactions of Aryl Azides with Alkyne Derivatives. ChemistrySelect 2018, 3, 1215– 1223.
20. The Mysticism of Pericyclic Reactions. A Contemporary Rationalisation of Organic Reactivity Based on the Electron Density Analysis. Eur. J. Org. Chem. 2018, 1107–1120.
21. A Molecular Electron Density Theory Study of the Reactivity and Selectivities in [3+2] Cycloaddition Reactions of C,N-Dialkyl Nitrones with Ethylene Derivatives. J. Org. Chem. 2018, 83, 2182−2197.
22. A Molecular Electron Density Theory study of the [3+2] cycloaddition reaction between an azomethine imine and electron deficient ethylenes. J. Phys. Org. Chem. 2017, 31:e3830.
23. Molecular Electron Density Theory Study of Fused Regioselectivity in the Intramolecular [3+2] Cycloaddition Reaction of Nitrones. ChemistrySelect 2018, 3, 5412–5420.
24. A Molecular Electron Density Theory Study of the Role of the Copper-Metallation of Azomethine Ylides in [3+2] Cycloaddition Reactions. J. Org. Chem. 2018, 83, 10959-10973.
25. A Molecular Electron Density Theory Study of the Competitiveness of Polar Diels-Alder and Polar Alder Ene Reactions. Molecules 2018, 23, 1913.
26. A Molecular Electron Density Theory Study of the Chemoselectivity, Regioselectivity and Diastereofacial Selectivity in the Synthesis of an Anti-Cancer Spiro-Isoxazoline derived from α-Santonin. Molecules 2019, 24, 832.
27. Understanding the Mechanism of Nitrobenzene Nitration with Nitronium Ion. A Molecular Electron Density Theory Study. ChemistrySelect 2019, 4, 13313–13319
28. A Molecular Electron Density Theory Study of the Enhanced Reactivity of Aza Aromatic Compounds Participating in Diels-Alder Reactions. Org. Biomol. Chem. 2020, 18, 292 –304
29. A molecular electron density theory study of the Grignard reagent-mediated regioselective direct synthesis of 1,5-disubstituted-1,2,3-triazoles. J. Phys. Org. Chem. 2020, e4062
30. Unveiling the Different Chemical Reactivity of Diphenyl Nitrilimine and Phenyl Nitrile Oxide in [3+2] Cycloaddition Reactions with (R)-Carvone through the Molecular Electron Density Theory. Molecules 2020, 25, 1085.
31. A Molecular Electron Density Theory Study of the Reactivity of Tetrazines in Aza-Diels-Alder Reactions. RSC Adv. 2020, 10, 15394.
32. A molecular electron density theory study on an oxa-Diels-Alder reaction: exploration of different impacts of AlCl3 as a Lewis acid catalyst. ChemistrySelect 2020, 5, 5341.
33. Unveiling the Lewis Acid Catalysed Diels–Alder Reactions Through the Molecular Electron Density Theory. Molecules 2020, 25, 2535.
Review
Theoretical reactivity indices based on the conceptual Density
Functional Theory (DFT) have become a powerful tool for the semiquantitative
study of organic reactivity. A large number of reactivity indices have
been proposed in the literature. Herein, global quantities like the electronic chemical
potential m, the electrophilicity w, and the
nucleophilicity N indices, and local condensed indices
like the electrophilic and nucleophilic P(r) Parr functions, as the most relevant indices
for the study of organic reactivity, are discussed.
Understanding the high reactivity of carbonyl compounds towards nucleophilic carbenoid intermediates generated from carbene isocyanides
RSC Adv. 2015, 5, 84797-84809
Download the Open Access Article
Domingo has reached the following bibliometric rates:
Publications: 360
Citations: 14.400
Index h: 56
Thanks to those who have contributed to this vast work, and those who have read and cited the corresponding publications.
A New C-C Bond Formation Model Based on the Quantum Chemical Topology of Electron Density
ELF topological analyses of bonding changes in non-polar, polar and ionic organic reactions involving the participation of C=C(X) double bonds make it possible to establish a unified model for C-C bond formation. This model is characterised by a C-to-C coupling of two pseudoradical centers (J. Org. Chem. 2011, 76, 373) generated at the most significant atoms of the reacting molecules. The global electron density transfer (GEDT) process that takes place along polar and ionic reactions favours the creation of these pseudoradical centers at the most nucleophilic/electrophilic centers of the reacting molecules, decreasing activation energies. The proposed reactivity model based on the topological analysis of the changes in electron density along a reaction makes it possible to reject the frontier molecular orbital reactivity model based on the analysis of molecular orbitals.