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Understanding the Origin of the Regioselectivity in Non-Polar [3+2] Cycloaddition Reactions Through the Molecular Electron Density Theory

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Understanding the Origin of the Regioselectivity in Non-Polar [3+2] Cycloaddition Reactions Through the Molecular Electron Density Theory Article Understanding the Origin of the Regioselectivity in Non-Polar [3+2] Cycloaddition Reactions through the Molecular Electron Density Theory Luis R. Domingo 1,* , Mar Ríos Gutiérrez 1,2,* and Jorge Castellanos Soriano 3 1 Department of Organic Chemistry, University of Valencia, Dr. Moliner 50, Burjassot, 46100 Valencia, Spain 2 Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada 3 Department of Chemistry, Polytechnic University of Valencia, Camí de Vera, s/n, 46022 Valencia, Spain; [email protected] * Correspondence: [email protected] (L.R.D.); [email protected] (M.R.G.) Received: 5 September 2020; Accepted: 10 November 2020; Published: 13 November 2020 Abstract: The regioselectivity in non-polar [3+2] cycloaddition (32CA) reactions has been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-311G(d,p) level. To this end, the 32CA reactions of nine simplest three-atom-components (TACs) with 2-methylpropene were selected. The electronic structure of the reagents has been characterized through the Electron Localisation Function (ELF) and the Conceptual DFT. The energy profiles of the two regioisomeric reaction paths and ELF topology of the transition state structures are studied to understand the origin of the regioselectivity in these 32CA reactions. This MEDT study permits to conclude that the least electronegative X1 end atom of these TACs controls the asynchronicity in the C X (X=C, N, O) single − bond formation, and consequently, the regioselectivity. This behaviour is a consequence of the fact that the creation of the non-bonding electron density required for the formation of the new single bonds has a lower energy demand at the least electronegative X1 atom than at the Z3 one. Keywords: non-polar [3+2] cycloaddition reactions; regioselectivity; molecular electron density theory; electronegativity; molecular mechanism 1. Introduction Cycloaddition reactions are one of the most useful tools in organic synthesis as they permit to obtain cyclic organic compounds with a regio- and/or stereoselective fashion [1,2]. [3+2] cycloaddition (32CA) reactions are an important class of cycloaddition allowing the formation of five-membered heterocycles of great pharmaceutical and industrial interest [3,4]. This kind of cycloaddition implies the 1,3-addition of an ethylene derivative to a three-atom-component (TAC) (see Scheme1). Depending Organicson its2020 structure,, 1, TACs can be classified as bent TACs (B-TACs) or linear TACs (L-TACs). 2 of 18 SchemeScheme 1. 32CA 1. 32CA reaction reaction scheme scheme and and simplified simplified Lewis structure structure of of bent bent (B) (B) and and linear linear (L) TACs.(L) TACs. Many of the TACs participating in 32CA reactions are non-symmetric with respect to the central Organics 2020, 1, 19–35; doi:10.3390/org1010003 www.mdpi.com/journal/organics atom. When ethylenes, such as 1-substituted or 1,1-disubstituted ethylenes, are also non-symmetric, at least a pair of regioisomeric cycloadducts can be formed along the reaction (see Scheme 2). Unlike Diels–Alder (DA) reactions, which are highly regioselective yielding a single cycloadduct [5], 32CA reactions are not as selective, yielding a mixture of the two feasible regioisomers. As regioisomers are structural isomers with physical and chemical different properties, only one of them will have a synthetic interest; consequently, formation of a mixture of two regioisomers involves a loss of the synthetic yield. Thus, the understanding of the origin of the regioselectivity in 32CA reactions is an important goal in order to predict the formation of reaction mixtures. Scheme 2. Formation of regioisomeric cycloadducts in 32CA reactions involving non-symmetric reagents. The regioselectivity of polar 32CA reactions was investigated in 2004 [6] by using the global and local reactivity indices defined within the Conceptual DFT (CDFT) [7,8]. That study suggested that for asynchronous 32CA reactions associated to polar processes, the regioselectivity is consistently explained by the most favourable two-centre interaction between the most nucleophilic and electrophilic sites of the reagents [6]. While the analysis of the electrophilicity [9] ω and nucleophilicity [10] N indices allows characterizing the chemical properties of the reagents participating in polar processes, analysis of the Parr functions [11] allows characterizing the most electrophilic and nucleophilic centres of a molecule. However, unlike DA reactions, many 32CA reactions have low polar character, even non-polar, and consequently, the polar model to predict regioselectivity fails in this type of cycloaddition reactions. In 2016, Domingo proposed the Molecular Electron Density Theory [12] (MEDT) for the study of the reactivity in Organic Chemistry, in which changes in the electron density, and not MO interactions, as the Frontier Molecular Orbital (FMO) theory proposed [13], are responsible for the feasibility of an organic reaction. Accordingly, in MEDT, several quantum-chemical tools based on the analysis of the electron density, such as the analysis of the CDFT reactivity indices [7,8], the topological analysis of the Electron Localisation Function (ELF) [14] and the Quantum Theory of Atoms in Molecules (QTAIM) [15], are used to rigorously study the chemical reactivity in Organic Chemistry [12]. Recent advances made in the theoretical understanding of 32CA reactions based on MEDT have allowed establishing a very good correlation between the electronic structure of the simplest TACs and their reactivity towards ethylene [16]. Accordingly, depending on the electronic structure of the simplest TACs, pseudodiradical, pseudoradical, carbenoid and zwitterionic, 32CA reactions have been classified into pseudodiradical-type (pdr-type), pseudomonoradical-type (pmr-type), carbenoid-type (cb- type) and zwitterionic-type (zw-type) reactions [16], respectively, in such a manner that while pdr-type Organics 2020, 1, 2 of 18 Organics 2020, 1 20 Scheme 1. 32CA reaction scheme and simplified Lewis structure of bent (B) and linear (L) TACs. Many of the TACs TACs participating in 32CA reactions are non-symmetric with respect to the central atom. When When ethylenes, ethylenes, such such as as 1-substituted 1-substituted or or 1,1-disubstituted 1,1-disubstituted ethylenes, ethylenes, are are also also non-symmetric, non-symmetric, at least least a apair pair of ofregioisomeric regioisomeric cycloadducts cycloadducts can canbe formed be formed along along the reaction the reaction (see Scheme (see Scheme 2). Unlike2). Diels–AlderUnlike Diels–Alder (DA) reactions, (DA) reactions, which are which highly are highlyregioselective regioselective yielding yielding a single a cycloadduct single cycloadduct [5], 32CA [5], reactions32CA reactions are not are as notselective, as selective, yielding yielding a mixture a mixture of the of two the feasible two feasible regioisomers. regioisomers. As regioisomers As regioisomers are structuralare structural isomers isomers with with physical physical and and chemical chemical diff dierentfferent properties, properties, only only one one of ofthem them will will have have a synthetica synthetic interest; interest; consequently, consequently, fo formationrmation of of a amixture mixture of of two two regi regioisomersoisomers involves involves a a loss loss of of the synthetic yield. Thus, Thus, the the understand understandinging of of the the origin origin of of the the regioselectivity regioselectivity in in 32CA 32CA reactions reactions is is an importantimportant goal in order to predict the formation of reaction mixtures.mixtures. Scheme 2.2. FormationFormation of of regioisomeric regioisomeric cycloadducts cycloadducts in 32CA in 32CA reactions reactions involving involving non-symmetric non-symmetric reagents. reagents. The regioselectivity of polar 32CA reactions was investigated in 2004 [6] by using the global and localThe reactivity regioselectivity indices defined of polar within 32CA the reactions Conceptual was DFTinvestigated (CDFT) [in7, 82004]. That [6] studyby using suggested the global that and for localasynchronous reactivity 32CA indices reactions defined associated within the to polarConceptu processes,al DFT the (CDFT) regioselectivity [7,8]. That is consistentlystudy suggested explained that forby theasynchronous most favourable 32CA two-centre reactions interactionassociated betweento polar theprocesses, most nucleophilic the regioselec andtivity electrophilic is consistently sites of explainedthe reagents by [6 ].the While most the favourable analysis of thetwo-centre electrophilicity interaction [9] ! andbetween nucleophilicity the most [10 nucleophilic] N indices allows and electrophiliccharacterizing sites the chemicalof the propertiesreagents [6]. of theWhile reagents the participatinganalysis of inthe polar electrophilicity processes, analysis [9] ωof and the nucleophilicityParr functions [ 11[10]] allows N indices characterizing allows thecharacterizing most electrophilic the ch andemical nucleophilic properties centres of ofthe a molecule.reagents participatingHowever, unlike in polar DA processes, reactions, analysis many 32CA of the reactions Parr functions have low [11] polar allows character, characterizing even non-polar, the most electrophilicand consequently, and nucleophilic the polar model centres to predict of a regioselectivitymolecule. However, fails in unlike this type DA of reactions, cycloaddition many reactions. 32CA reactionsIn
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