Article Unveiling the Unexpected Reactivity of Electrophilic Diazoalkanes in [3+2] Cycloaddition Reactions within Molecular Electron Density Theory Luis R. Domingo 1,* , Mar Ríos-Gutiérrez 1 and Nivedita Acharjee 2 1 Department of Organic Chemistry, University of Valencia, Dr. Moliner 50, Burjassot, 46100 Valencia, Spain; [email protected] 2 Department of Chemistry, Durgapur Government College, J. N. Avenue, Durgapur, West Bengal 713214, India; [email protected] * Correspondence: [email protected] Abstract: The [3+2] cycloaddition (32CA) reactions of strongly nucleophilic norbornadiene (NBD), with simplest diazoalkane (DAA) and three DAAs of increased electrophilicity, have been studied within the Molecular Electron Density Theory (MEDT) at the MPWB1K/6-311G (d,p) computational level. These pmr-type 32CA reactions follow an asynchronous one-step mechanism with activation enthalpies ranging from 17.7 to 27.9 kcal·mol−1 in acetonitrile. The high exergonic character of these reactions makes them irreversible. The presence of electron-withdrawing (EW) substituents in the DAA increases the activation enthalpies, in complete agreement with the experimental slowing- down of the reactions, but contrary to the Conceptual DFT prediction. Despite the nucleophilic and electrophilic character of the reagents, the global electron density transfer at the TSs indicates rather non-polar 32CA reactions. The present MEDT study establishes the depopulation of the N–N–C core in this series of DAAs with the increase of the EW character of the substituents present at the carbon Citation: Domingo, L.R.; center is responsible for the experimentally found deceleration. Ríos-Gutiérrez, M.; Acharjee, N. Unveiling the Unexpected Reactivity Keywords: molecular electron density theory; norbornadiene; diazoalkanes; conceptual DFT; electron of Electrophilic Diazoalkanes in [3+2] localization function Cycloaddition Reactions within Molecular Electron Density Theory. Chemistry 2021, 3, 74–93. https://doi.org/10.3390/ 1. Introduction chemistry3010006 Norbornadiene (NBD) (bicyclo [2.2.1] hepta-2,5-diene), norbornene (bicyclo [2.2.1] hept-2-ene) and related compounds serve as key intermediates in natural product synthe- Received: 14 December 2020 sis [1–3] and polymer chemistry [1,4] owing to their angularly strained unusual geometry Accepted: 7 January 2021 and high reactivity. Recently, NBD has also found applications in molecular photoswitches Published: 10 January 2021 to absorb solar radiation [5], and by 2018, more than 30 thousand publications and patents had reported their production and applications in various fields [1]. The behavior of NBD Publisher’s Note: MDPI stays neu- derivatives in the Wagner–Meerwein rearrangement [6,7], photochemical di-π methane tral with regard to jurisdictional clai- rearrangement [8], Diels Alder reactions [9], catalytic reactions with alkynes [10] and sev- ms in published maps and institutio- eral other instances [1] have established their uniqueness as organic reagents and fostered nal affiliations. their wide synthetic applications in [3+2] cycloaddition (32CA) reactions to form isoxa- zolidines, triazoles, carbocycles and other heterocycles of biological and environmental relevance [11–15]. In 2001, Tam and coworkers [16,17] reported the highly regio- and Copyright: © 2021 by the authors. Li- stereoselective intramolecular 32CA reactions of NBD-tethered nitrones and nitrile oxides censee MDPI, Basel, Switzerland. (Scheme1). This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Chemistry 2021, 3, 74–93. https://doi.org/10.3390/chemistry3010006 https://www.mdpi.com/journal/chemistry Chemistry 2021, 3, FOR PEER REVIEW 2 of 20 ChemistryChemistry 20212021,, 33, FOR PEER REVIEW 2 of 7520 Scheme 1. Intramolecular 32CA reaction of norbornadiene (NBD)‐tethered nitrile oxide 1. Scheme 1. Intramolecular 32CA reaction of norbornadiene (NBD)-tethered(NBD)‐tethered nitrilenitrile oxideoxide 11.. The 32CA reactions of 7‐oxanorbornadiene with nitrile oxides were theoretically studiedThe by 32CA Tajabadi reactions et al. of[18] 7-oxanorbornadiene7 ‐inoxanorbornadiene 2015, concluding withtheir nitrileanti and oxides exo‐ stereoselective were theoreticallytheoretically one‐ studiedstep mechanism. byby TajabadiTajabadi In et et al. al.2017, [ 18[18]] in Domingoin 2015, 2015, concluding concluding et al. [19] their their reportedanti antiand and exothe -stereoselectiveexo complete‐stereoselective syn one-step facialone‐ mechanism.stepstereoselectivity mechanism. In 2017, in Inthe Domingo 2017,32CA reactionsDomingo et al. [19 of ]et reported acetonitrile al. [19] the reportedoxide complete and synthe7‐oxanorborn facialcomplete stereoselectivity‐ 5syn‐en‐ 2facial‐ones instereoselectivityas thean outcome 32CA reactions of in the the unfavorable of 32CA acetonitrile reactions steric oxide of interactions acetonitrile and 7-oxanorborn-5-en-2-ones alongoxide theand anti 7‐oxanorborn approach as an ‐(see5 outcome‐en Scheme‐2‐ones of theas2). an unfavorable outcome of steric the unfavorable interactions steric along interactions the anti approach along the (see anti Scheme approach2). (see Scheme 2). SchemeScheme 2.2. 32CA32CA reactionreaction ofof 7-oxanorborn-5-en-2-one7‐oxanorborn‐5‐en‐2‐one 33 withwith acetonitrileacetonitrile oxide oxide4 4.. Scheme 2. 32CA reaction of 7‐oxanorborn‐5‐en‐2‐one 3 with acetonitrile oxide 4. VeryVery recently, recently, two two different different studies studies [20 ,[20,21]21] have have addressed addressed the regio-, the regio stereo-,‐, stereo and‐ enan-, and tioselectivities of the 32CA reactions of 7-isopropylidenenorbornadiene and oxonorborna- enantioselectivitiesVery recently, twoof differentthe 32CA studies reactions [20,21] of have 7‐isopropylidenenorbornadiene addressed the regio‐, stereo‐ , andand diene with nitrones, azides, and nitrileimines. enantioselectivitiesoxonorbornadiene withof nitrones,the 32CA azides, reactions and nitrileimines. of 7‐isopropylidenenorbornadiene and The substituent effects on the rates of the 32CA reactions between NBD and dia- oxonorbornadieneThe substituent with effects nitrones, on azides,the rates and of nitrileimines. the 32CA reactions between NBD and zoalkanesdiazoalkanes (DAAs) (DAAs) were were experimentally experimentally evidenced evidenced by by Huisgen Huisgen in in 1963 1963 to to establish establish the the accountabilityThe substituent of the one-step effects mechanismon the rates for 32CAof the reactions. 32CA reactions [22] Considering between the NBD 32CA and re- diazoalkanesaccountability (DAAs) of the onewere‐step experimentally mechanism forevidenced 32CA reactions. by Huisgen [22] in Considering 1963 to establish the 32CA the actionsreactions of substitutedof substituted DAAs DAAs7–10 7–10with with NBD NBD11, (Scheme11, (Scheme3) Huisgen 3) Huisgen compared compared the one-step the one‐ mechanismaccountability (Path of the I, Scheme one‐step3) and mechanism the two-step for 32CA addition reactions. (Path II, [22] Scheme Considering3) possibilities the 32CA in step mechanism (Path I, Scheme 3) and the two‐step addition (Path II, Scheme 3) 32CAreactions reactions of substituted [22]. DAAs 7–10 with NBD 11, (Scheme 3) Huisgen compared the one‐ steppossibilities mechanism in 32CA (Path reactions I, Scheme [22]. 3) and the two‐step addition (Path II, Scheme 3) possibilities in 32CA reactions [22]. Scheme 3. 32CA reactions of substituted diazoalkanes (DAAs) 7–10 with NBD 11. Scheme 3. 32CA reactions of substituted diazoalkanes (DAAs) 7–10 with NBD 11. SchemeThe 3. addition32CA reactions tendency of substituted of simplest diazoalkanes DAA 7 with (DAAs) NBD7–10 11with was NBD maximum11. along this series,The while addition the 32CA tendency reaction of simplestslowed down DAA by7 withintroducing NBD 11 electron was maximum‐withdrawing along (EW) this carbonylThe additionsubstituents tendency at the carbon of simplest of the DAA DAA7 inwith 8 and NBD 9, and11 was finally, maximum DAA 10 along, with thistwo series, while the 32CA reaction slowed down by introducing electron-withdrawingelectron‐withdrawing (EW) carbonyl substituents, was completely inactive. Since the nucleophilic additions of NBD carbonyl substituentssubstituents at at the the carbon carbon of of the the DAAScheme DAA in in 83 and 8 and9, and9, and finally, finally, DAA DAA10, with10, with two two car- bonylcarbonyl substituents, substituents, was was completely completely inactive. inactive. Since Since the nucleophilic the nucleophilic additions additions of NBD of to NBD the Chemistry 2021, 3 76 terminal nitrogen of DAAs are well known [23], it was expected that DAAs act as an elec- trophilic species and NBD 11, with two electron rich C–C double bonds, as the nucleophilic one. Hence, EW substituents in DAA should enhance the addition tendency. However, this behavior was contrary to the experimental observation (Scheme3), and consequently, it demands a detailed explanation for the bond formation process and a rationalization of the decrease in reaction rate experimentally observed. The underlying theory adopted for explaining 32CA reactions was based on the Fron- tier Molecular Orbital [24] (FMO) concept for the last 50 years, until in 2016, Domingo pro- posed the Molecular Electron Density Theory [25,26] (MEDT) to recognize the decisive role of the changes in electron density on the molecular reactivity. The MEDT concept, which rejects any analysis