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Article

A New Insight into the Molecular Mechanism of the Reaction between 2-Methoxyfuran and Ethyl (Z)-3-phenyl-2-nitroprop-2-enoate: An Molecular Electron Density Theory (MEDT) Computational Study

by
Mikołaj Sadowski
1,
Ewa Dresler
2,
Aneta Wróblewska
3 and
Radomir Jasiński
1,*
1
Department of Organic Chemistry and Technology, Cracow University of Technology, Warszawska 24, 31-155 Kraków, Poland
2
Łukasiewicz Research Network—Institute of Heavy Organic Synthesis “Blachownia”, Energetyków 9, 47-225 Kedzierzyn-Kozle, Poland
3
Department of Organic Chemistry, University of Lodz, Tamka 12, 91-403 Lodz, Poland
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(20), 4876; https://doi.org/10.3390/molecules29204876
Submission received: 25 September 2024 / Revised: 6 October 2024 / Accepted: 8 October 2024 / Published: 14 October 2024
(This article belongs to the Special Issue Multiconfigurational and DFT Methods Applied to Chemical Systems—2nd Edition)
Browse Figures
Versions Notes

Abstract

:
The molecular mechanism of the reaction between 2-methoxyfuran and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate was investigated using wb97xd/6-311+G(d,p)(PCM) quantum chemical calculations. It was found that the most probable reaction mechanism is fundamentally different from what was previously postulated. In particular, six possible zwitterionic intermediates were detected on the reaction pathway. Their formation is determined by the nature of local nucleophile/electrophile interactions. Additionally, the channel involving the formation of the exo-nitro Diels–Alder cycloadduct was completely ruled out. Finally, the electronic nature of the five- and six-membered nitronates as potential TACs was evaluated.

1. Introduction

The most universal protocol for the preparation of six-membered carbocyclic molecules is the [4+2] cycloaddition (42CA) process involving conjugated dienes [1,2,3,4,5] discovered by Otto Diels and Kurt Alder [6]. It is important to note that analogous processes exist in organic chemistry, involving heteroanalogs of dienes, such as conjugated nitroalkenes [7,8,9,10], nitrosocompounds [11,12,13], azoalkenes [14], and others [15,16,17,18]. Among a wide range of 42CA-type transformations, reactions involving cyclopentadiene, furan, and thiophene play a particularly important role. These reactions provide an efficient protocol for the synthesis of norbornene derivatives, as well as their heterocyclic analogs, which are of significant practical interest [19,20,21,22,23].
Although the heteroaromatic furan molecule is not formally a conjugated diene, it exhibits reactivity similar to cyclopentadiene according to the 42CA scheme [24,25,26]. This type of transformation is particularly accelerated by the significant difference in the global electrophilicities of the cycloaddition components [27,28]. Some time ago, Itoh and Kishimoto [29] reported the results of experimental research on the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2). Specifically, in the post-reaction mixture, the authors detected two major products: 2-metxohy-5-(2-carboethoxy-2-nitro-1-phenylethyl)-furane (3) and 4,5-cis-3-carboethoxy-4-phenyl-5-carbomethoxy-isoxazoline 2-oxide (Z-4) (Scheme 1).
Based on these observations, the authors proposed two alternative mechanisms for the formation of the detected products (Scheme 2). The first approach involves the formation of a Diels–Alder type exo-nitro adduct (DAexo) in the initial reaction stage. In this scheme, the DAexo molecular system is treated as a common intermediate for the formation of the target products 3 and Z-4. The alternative approach suggests that a (Z)witterionic adduct is formed in the first reaction stage. This intermediate can then be converted to the detected products via respective rearrangement pathways.
Unfortunately, the mechanistic considerations presented should be treated only as intuitive propositions rather than definitive explanations. This proposal contains several weak points, as follows, and many key issues were not thoroughly analyzed, necessitating reexamination and deeper investigation:
(i)
The formation of the detected adducts via an intermediate stage is rather evident. The number of possible intermediates is, however, substantially higher. Next, the detected products may form via a common intermediate or through two different types of intermediates. Such scenarios have recently been analyzed in reactions between conjugated dienes and alkenes [30].
(ii)
The authors assumed a priori the formation of exo-type Diels–Alder cycloadducts. However, many experimental results indicate that in Diels–Alder reactions between conjugated dienes and conjugated nitroalkenes, the endo-nitro isomer is always preferred [31,32]. Unfortunately, the possibility of forming these types of cycloadducts was not considered in the mechanistic discussion.
(iii)
Assuming a zwitterionic mechanism for the title reaction, not just one, but six isomeric zwitterionic intermediates should be considered [33]. Different zwitterions may convert to the same or different final products. Furthermore, the mutual conversion of zwitterions through a rotation of the single bond within >C-C-NO2 moiety is feasible and should be considered.
(iv)
In reactions involving conjugated nitroalkenes, the classical “carbo” Diels–Alder scheme can compete with the hetero Diels–Alder reaction, where the nitroalkene acts as a heteroanalog of the diene [9,34].
(v)
Assuming the formation of the Diels–Alder product within the initial reaction stage, a one-step cycloaddition mechanism cannot be assumed a priori. Recently, many examples of stepwise Diels–Alder reactions have been shown to proceed through the formation of biradical or zwitterionic intermediates [35].
(vi)
Although the stereoconfiguration of 4,5-cis-3-carboethoxy-4-phenyl-5-carbomethoxy-isoxazoline 2-oxide was fully established on the basis of the RTG experiment, the stereoconfiguration of the Michael-type adduct (3) remains unclear. In practice, more than one structure of this type of adduct is possible [32,36].
The authors identified only 77% of the post-reaction mixture, and the composition of the residue is unknown. This fraction can include product(s) other than those presented in Scheme 1.
Therefore, in this study, we aimed to address and explain all of the mechanistic aspects mentioned above. Specifically, we explored all theoretically possible pathways of the reaction system’s transformation (Scheme 3). For this purpose, we applied Density Functional Theory (DFT) calculations at the wb97xd/6-311+G(d,p) level of theory.

2. Results and Discussion

2.1. Electronic Interactions

According to the current understanding [37,38], changes in electron density along a chemical reaction are responsible for the chemical reactivity of organic molecules. In practice, for bimolecular organic polar processes, the formation of new bonds is determined by interactions between the most electrophilically activated reaction center of the first molecule and the most nucleophilically activated center of the second [39,40]. This approach has been successfully applied to predict the reactivity of many polar components as well as the regioselectivity of various organic reactions [41,42,43,44,45,46].
The relevant descriptors for the components of the reaction in question are summarized in Table 1. It was found that the electronic chemical potential (Z)-3-phenyl-2-nitroprop-2-enoate (2) is −4.51 eV. As a result, the reaction with 2-methoxyfuran (1) should be determined by the electron density transfer from the furan molecule to the nitroalkene. Thus, according to Domingo’s terminology [47], this reaction should be classified as a Forward Electron Density Flux (FEDF) process. Moreover, the global electrophilicity of the nitroalkene (2.24 eV) is substantially higher than the analogous parameter estimated for methoxyfuran (0.39 eV). Therefore, the key interatomic interactions must be regarded as polar in nature.
As a consequence, the regio-orientation in the first stage of the reaction is primarily determined by the interaction between the C5 nucleophilic atom in the furan 1 molecule and the beta-carbon atom in the nitrovinyl moiety of (2) (Scheme 4). This type of mutual orientation aligns perfectly with the further exploration of the reaction profiles and is consistent with the observed regioselectivity of the reaction [29].

2.2. Energetic Considerations

For all transformations leading to the target products (Diels–Alder adducts, hetero Diels–Alder products, Michael adducts, and five-membered internal nitronates), the initial reaction stage always involves the formation of the respective pre-reaction molecular complex MC (Scheme 3, Table 2). Depending on the mutual orientation of the reactant molecules, six structures of pre-reaction complexes are possible: MCA, MCB, and MCC within the endo approach, and MCD, MCE, and MCF within the exo approach, respectively. The formation of these MCs is associated with a reduction in the enthalpy of the reaction system by several kcal/mol. However, at the same time, the entropy of the reaction system is significantly reduced. Consequently, the Gibbs free energies for the formation of the respective MCs are positive, which excludes the possibility of MCs existing as relatively stable intermediates.
Further conversion of the pre-reaction complexes is possible via six different transition states (TSA, TSB, and TSC within the endo approach, and TSD, TSE, and TSF within the exo approach, cartesian coordinates for transition states can be found in the supplementary materials), leading to the respective acyclic adducts. These processes are associated with an increase in the enthalpy of the reaction system by 14.4–17.3 kcal/mol relative to the corresponding MC. The nature of the localized saddle points was confirmed by vibrational analysis and intrinsic reaction coordinate (IRC) computations (see Computational Details section). In all six reaction channels, the IRC trajectories connect the transition states (TSs) to the valleys of the respective acyclic adducts, which can be considered reaction intermediates (Iendo1, Iendo2, and Iendo3 for paths A, B, and C, respectively; and Iexo1, Iexo2, and Iexo3 for paths D, E, and F, respectively). It is important to note that all attempts to locate reaction channels leading directly to the DA or HDA type of adducts were unsuccessful.
All localized intermediates are labile, allowing free rotation around the C4-C5 single bond. These processes require only low activation energy (Table 2). It is interesting to note that, in the case of Iexo1, gradual rotation in the direction that theoretically should lead to the formation of Iexo3 actually results in the formation of the hetero Diels–Alder adduct HDAexo (path G in Scheme 3). This process occurs via the transition state TSG and requires an activation energy of approximately 1.4 kcal/mol. Similarly, the gradual rotation of Iexo3, following the path that might lead to Iexo1, also results in the formation of the same HDAexo (path H in Scheme 3). Both processes proceed via the common transition state TSG.
Alternatively, the other hetero Diels–Alder adduct can be formed based on the endo-isomeric intermediate. Specifically, Iendo1 can cyclize to form HDAendo. This process requires a Gibbs free energy of activation of about 2 kcal/mol and proceeds via the TSI transition state.
A competitive channel for the conversion of intermediates Iexo1 and Iexo1 involves cyclization reactions leading to the formation of respective nitronorbornene molecular systems via pathways J and K (yielding products DAendo and DAexo, respectively). From a kinetic point of view, the formation of the carbocyclic norbornene skeletons is relatively more challenging than cyclization to the hetero Diels–Alder products. Furthermore, thermodynamic factors exclude the possibility of these norbornenes being stable products. Thus, it is unlikely that nitronorbornenes are present in the unidentified part of the post-reaction mixture. It should also be emphasized that both kinetic and thermodynamic factors favor the formation of DAendo over DAexo.
The next possible transformation of the intermediates involves the formation of Michael-type adducts (paths L, M, N, and O). In the reaction system considered, two isomeric forms of this skeleton are possible: Z-3 and E-3 (Scheme 3). As previously mentioned, the isomerism of the obtained Michael adduct has not been definitely assigned. From a kinetic perspective, both transformations require relatively high Giggs free energies of activation. However, it should be emphasized that Itoh and Kishimoto [29] conducted the synthesis under thermodynamic control. We found that, from a thermodynamic standpoint, adducts Z-3 and E-3 are more stable than the Diels–Alder and/or hetero Diels–Alder adducts. This observation correlates well with the experimental results, as these products were identified in the post-reaction mixture rather than the Diels–Alder and/or hetero Diels–Alder adducts.
The final reaction pathway considered is the formation of the nitronate Z-4. This is possible only through the rearrangement of the intermediate Iexo3 and actually requires a Gibbs free energy of activation of about 9 kcal/mol. Notably, the Z-4 product is the most thermodynamically stable of all of the theoretically possible reaction products. Consequently, under thermodynamic control, Z-4 should be identified as the major product in the post-reaction mixture. This conclusion aligns perfectly with the experimental results reported by Itoh and Kishimoto [29].

2.3. Critical Structures

First, we analyzed the nature of the pre-reaction molecular complexes MCs (Figure 1). In these types of complexes, the substructures of the reactants adopt orientations that determine their subsequent conversion to the respective intermediate I. Thus, these localized structures should be considered as orientation complexes. It should be noted that within the framework of MCs, no new sigma bonds are formed. The distances between the substructures exceed the typical range for sigma bonds in transition states [7,43,48,49,50]. Additionally, the geometries of the substructures are nearly identical to those of the individual reactants. At this stage, the substructures are stabilized by electrostatic interactions, but no significant electron density transfer occurs between them (GEDT = 0.00e). Similar types of pre-reaction molecular complexes have been recently observed in other bimolecular organic reactions [41,51,52,53,54].
As the reaction coordinate progresses, the gradual reduction in the distances between the substructures leads to the formation of the respective transition states (TSA, TSB, and TSC for the endo approach, and TSD, TSE, and TSF for the exo approach). In particular, the C5-C6 distance (Figure 2) decreases most rapidly, reaching approximately 2–2.1 Å. This observation aligns with the local nucleophile/electrophile interactions discussed earlier. In all TSs, electron density transfer between substructures is observed (GEDT = 0.20e, 0.33e, 0.35e, 0.20e, 0.48, and 0.48e for TSA, TSB, TSC, TSD, TSE, and TSF, respectively). This confirms, without any doubts, the polar nature of the process.
The direct products of the transformation of the mentioned TSs are respective acyclic intermediates (Iendo1, Iendo2, and Iendo3 for paths A, B, and C; and Iexo1, Iexo2, and Iexo3 for paths D, E, and F). Their nature was explored on the basis of an ELF study of the model molecule Iendo1.
In particular, the ELF topological analysis of Iendo1 revealed two irreducible [55] monosynaptic valence basins (Figure 3) at the C-4 carbon atom (Figure 4), one with a population of 0.57e and the other with 0.49e (Figure 4). The C-4 carbon atom also has a charge of −0.11 (Scheme 5), while the other reaction center, C-2, is strongly positively charged (0.84e) (Scheme 5). Although the valence basins and the slightly negative charge at C-4 might suggest a carbene-type intermediate [56], the total population of both V(C-4), approximately 1e, is insufficient to confirm a carbene structure. Combined with the highly positive charge at C-2, this suggests that the intermediate is a zwitterion. The influence of a strongly electron-withdrawing (EW) nitro-group on the C-4 atom might explain the slightly negative charge at the C-4 atom. The V(N,C-4) population is 3.06e, which indicates a strongly overpopulated single bond, reinforcing the influence of the EW nitro-group on the C-4 atom charge.
A separate group of detected transition states are structures associated with cyclization processes. Two types of these TSs are possible in the context of this reaction. The first group involves TSs leading to the formation of nitronorbornene skeletons (TSJ and TSK for the endo and exo approaches, respectively). In these TSs, a new C1-C6 single bond forms (C1–C6—Figure 5). The second group involves TSs leading to the formation of 1,2-oxazine N-oxide structures (TSJ and TSK for endo and exo approaches, respectively), where a new C3-O7 single bond is formed (Figure 6).
For comparison, the transition states leading from respective intermediates to Michael-type products (TSL and TSN, Figure 7) exhibit characteristics of transition states typical of [1.3]-sigmatropic hydrogen shifts [57,58,59]. In these structures, the H8 hydrogen atom loses its sigma bond with the C4 carbon atom, while a new C6-H8 sigma bond is formed.
The final type of transition state in the context of this transformation is TSP. This structure was identified on the pathway leading to the five-membered nitronate Z-4. In this transition state, the C4-O9 bond is broken, while a new C4-C7 single bond is formed (Figure 8). Formally, this transition state can be treated as typical for intramolecular substitution at an sp3 carbon atom [60].
The enthalpy profiles realized in the practice paths leading to the adducts 3 and 4 are presented in Figure 9.
Finally, we also sought to explore the electronic nature of the localized six- and five-membered nitronates, as these compounds should be considered as potential three-atom components in [3+2] cycloaddition processes [61,62,63]. The five-membered nitronate Z-4 features two nonreducible monosynaptic valence basins V(C), with populations of 0.37e and 0.22e, respectively (Figure 10). The charge on the C atom is negligible (Scheme 6). The disynaptic valence basin V(N,O) can be assigned as an underpopulated double bond, with a population of 3.60e (Figure 11). The N atom has a charge of 0.41e, while the O atom is negatively charged (−0.43e). The N–O bond is a slightly underpopulated single bond, and the O atom has a reducible monosynaptic basin with a total population of 5.76e, corresponding to three slightly underpopulated lone pairs. Based on the aforementioned computational results, the nitronate Z-4 can be considered a predominantly zwitterionic type (zw-type) TAC [64].
An analogous analysis of the six-membered nitronate HDAexo reveals comparable results. The C atom has a negligible charge and a monosynaptic valence basin V(C), with a population of 0.36e. The C-N bonding basin has a population of 3.88e, indicating an underpopulated double bond. The N atom has a charge of 0.40e, while the oxygen atom is negatively charged (−0.44e). The V(N,O) disynaptic basin has a population of 1.64e, consistent with a slightly underpopulated single bond. These results allow us to classify the six-membered nitronate as a zw-type TAC as well [64].

3. Computational Details

The computational study was performed using the wb97xd/6-311+G(d,p) level of theory with the Gaussian package as the software [65]. The PlGrid infrastructure at the national computing center “Cyfronet” was utilized. A similar computational level and methodology have already been successfully applied to explore the mechanistic aspects of various cycloaddition processes, including Diels–Alder reactions, hydrogen shifts, and sigmatropic rearrangements. All localized stationary points were verified through a full vibrational analysis. We found that starting molecules, intermediates, and products had positive Hessian matrices, while all optimized transition states (TSs) exhibited only one negative eigenvalue in their Hessian matrices.
Next, intrinsic reaction coordinate (IRC) calculations were performed for all optimized transition states. The obtained IRC trajectories confirmed, without doubt, the postulated nature of the TSs and their role within the energy profile. The presence of solvent (dichloromethane) in the reaction environment was included using the IEFPCM (Integral Equation Formalism Polarizable Continuum Model) algorithm [66]. Calculations of all critical structures were performed at a temperature of T = 298 K and a pressure of p = 1 atm. The results of calculations are summarized in Table 2.
The global electron density transfer (GEDT) [67] within critical structures was estimated using the following formula:
GEDT = −ΣqA
where qA is the net charge, and the sum is taken over all of the atoms of nitroalkene.
The global and local electronic properties of the reactants were estimated using equations recommended by Parr and Domingo [40,68,69]. In particular, the electronic chemical potentials (µ) and chemical hardness (η) were evaluated in terms of the one-electron energies of the frontier molecular orbitals (HOMO and LUMO) using the following equations:
µ ≈ (EHOMO + ELUMO)/2      η ≈ ELUMO − EHOMO
The values of µ and η were then used to calculate the global electrophilicity index (ω) using the following formula:
ω = μ2/2η
Global nucleophilicity (N) [70] was expressed using the following equation:
N = EHOMO − EHOMO(tetracyanoethene)
The local electrophilicity (ωk) at atom k was calculated by projecting the index ω onto any reaction center k in the molecule using Parr functions P+k [71]:
ωk = P+k·ω
The local nucleophilicity (Nk) condensed to atom k was calculated using global nucleophilicity N and Parr functions P−k [71] according to the following formula:
Nk = P−k·N
The results are summarized in Table 1.

4. Conclusions

Our WB97XD/6-311+G(d,p) (PCM) calculations clearly indicate that a fundamental revision of the view on the molecular mechanism of the reaction between 2-methoxyfuran and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate is necessary. The first stage of the title transformation involves the formation of pre-reaction complexes. These initially formed complexes can further convert into respective zwitterions, a process driven by the nucleophilic attack of the nucleophilically activated 5-position of the furan on the electrophilically activated 2-position of the nitrovinyl moiety. It is important to emphasize that the zwitterionic nature of the optimized intermediates was confirmed by an ELF analysis of the electronic structure.
The final composition of the post-reaction mixture can vary depending on whether the reaction is under kinetic or thermodynamic control. In the thermodynamic scenario (as described in the experimental study of this reaction), the zwitterion is converted to the five-membered nitronate via intramolecular substitution at the sp3 carbon atom. Thus, the molecular mechanism and the reaction course of the addition of 2-methoxyfuran to ethyl (Z)-3-phenyl-2-nitroprop-2-enoate are completely different from those of typical processes with the participation of furan analogs and electrophilic alkenes. According to ELF and Natural Population Analyses (NPA), the nitronates Z-4 and HDAexo are polar in nature and can be classified as zwitterionic-type TACs.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29204876/s1, cartesian coordinates for transition states.

Author Contributions

Conceptualization, R.J. and M.S.; methodology, R.J. and M.S.; validation, E.D., formal analysis, R.J. and A.W.; investigation, R.J. and M.S.; data curation, E.D. and A.W.; writing—original draft preparation, R.J. and M.S.; writing—review and editing, R.J. and M.S.; visualization, R.J. and M.S.; supervision, R.J. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Acknowledgments

We gratefully acknowledge the Polish high-performance computing infrastructure, PLGrid (HPC Centers: ACK Cyfronet AGH), for providing computing facilities and support within the computational grant No. PLG/2024/017194.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 04876 sch001
Scheme 1. Experimental results of the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2).
Scheme 1. Experimental results of the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2).
Molecules 29 04876 sch001
Molecules 29 04876 sch002
Scheme 2. Postulated mechanisms for the reaction between 2-methoxy (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2).
Scheme 2. Postulated mechanisms for the reaction between 2-methoxy (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2).
Molecules 29 04876 sch002
Molecules 29 04876 sch003
Scheme 3. Considered paths of the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2).
Scheme 3. Considered paths of the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2).
Molecules 29 04876 sch003
Molecules 29 04876 sch004
Scheme 4. Local electronic properties of 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2).
Scheme 4. Local electronic properties of 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2).
Molecules 29 04876 sch004
Molecules 29 04876 g001
Figure 1. Views of key structures for the formation of zwitterionic intermediates via the endo-attack of 2-methoxyfuran (1) on the ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) molecule according to wb97xd/6-311+G(d,p) (PCM) calculations.
Figure 1. Views of key structures for the formation of zwitterionic intermediates via the endo-attack of 2-methoxyfuran (1) on the ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) molecule according to wb97xd/6-311+G(d,p) (PCM) calculations.
Molecules 29 04876 g001
Molecules 29 04876 g002
Figure 2. Views of key structures for the formation of zwitterionic intermediates via the exo-attack of 2-methoxyfuran (1) on the ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) molecule according to wb97xd/6-311+G(d,p) (PCM) calculations.
Figure 2. Views of key structures for the formation of zwitterionic intermediates via the exo-attack of 2-methoxyfuran (1) on the ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) molecule according to wb97xd/6-311+G(d,p) (PCM) calculations.
Molecules 29 04876 g002
Molecules 29 04876 g003
Figure 3. Topology of Iendo1 ELF, rendered at an isovalue of 0.8. Core basins are shown in magenta, protonated basins in cyan, disynaptic basins in green, and monosynaptic basins in red. Parts of the function significant for intermediate-type identification are depicted as solid, while the rest are translucent.
Figure 3. Topology of Iendo1 ELF, rendered at an isovalue of 0.8. Core basins are shown in magenta, protonated basins in cyan, disynaptic basins in green, and monosynaptic basins in red. Parts of the function significant for intermediate-type identification are depicted as solid, while the rest are translucent.
Molecules 29 04876 g003
Molecules 29 04876 g004
Figure 4. Positions and populations of significant ELF attractors of unprotonated basins in Iendo1.
Figure 4. Positions and populations of significant ELF attractors of unprotonated basins in Iendo1.
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Molecules 29 04876 sch005
Scheme 5. Natural charges of significant atoms in the structure Iendo1, calculated using the wb97xd/6-311+G(d,p) (PCM) level of theory.
Scheme 5. Natural charges of significant atoms in the structure Iendo1, calculated using the wb97xd/6-311+G(d,p) (PCM) level of theory.
Molecules 29 04876 sch005
Molecules 29 04876 g005
Figure 5. Views of key structures for the formation of DA adducts from isomeric zwitterions formed in the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) according to wb97xd/6-311+G(d,p) (PCM) calculations.
Figure 5. Views of key structures for the formation of DA adducts from isomeric zwitterions formed in the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) according to wb97xd/6-311+G(d,p) (PCM) calculations.
Molecules 29 04876 g005
Molecules 29 04876 g006
Figure 6. Views of key structures for the formation of HDA adducts from isomeric zwitterions formed in the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) according to wb97xd/6-311+G(d,p) (PCM) calculations.
Figure 6. Views of key structures for the formation of HDA adducts from isomeric zwitterions formed in the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) according to wb97xd/6-311+G(d,p) (PCM) calculations.
Molecules 29 04876 g006
Molecules 29 04876 g007
Figure 7. Views of key structures for the formation of Michael-type adducts from isomeric zwitterions formed in the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) according to wb97xd/6-311+G(d,p) (PCM) calculations.
Figure 7. Views of key structures for the formation of Michael-type adducts from isomeric zwitterions formed in the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) according to wb97xd/6-311+G(d,p) (PCM) calculations.
Molecules 29 04876 g007
Molecules 29 04876 g008
Figure 8. Views of key structures for the formation of the Z-4 nitronate in the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) according to wb97xd/6-311+G(d,p) (PCM) calculations.
Figure 8. Views of key structures for the formation of the Z-4 nitronate in the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) according to wb97xd/6-311+G(d,p) (PCM) calculations.
Molecules 29 04876 g008
Molecules 29 04876 g009
Figure 9. Enthalpy profiles for the formation of the Z-3, E-3, and Z-4 adducts in the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) according to wb97xd/6-311+G(d,p) (PCM) calculations.
Figure 9. Enthalpy profiles for the formation of the Z-3, E-3, and Z-4 adducts in the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) according to wb97xd/6-311+G(d,p) (PCM) calculations.
Molecules 29 04876 g009
Molecules 29 04876 g010
Figure 10. Topology of Z-4 (left) and HDAexo (right) ELF, rendered at an isovalue of 0.8. Core basins are shown in magenta, protonated basins in cyan, disynaptic basins in green, and monosynaptic basins in red. Parts of the function, significant for intermediate type identification, are depicted as solid, while the rest are translucent.
Figure 10. Topology of Z-4 (left) and HDAexo (right) ELF, rendered at an isovalue of 0.8. Core basins are shown in magenta, protonated basins in cyan, disynaptic basins in green, and monosynaptic basins in red. Parts of the function, significant for intermediate type identification, are depicted as solid, while the rest are translucent.
Molecules 29 04876 g010
Molecules 29 04876 g011
Figure 11. Positions and populations of significant ELF attractors of unprotonated basins in Z–4 (left) and HDAexo (right).
Figure 11. Positions and populations of significant ELF attractors of unprotonated basins in Z–4 (left) and HDAexo (right).
Molecules 29 04876 g011
Molecules 29 04876 sch006
Scheme 6. Natural charges of significant atoms in structures Z–4 (left) and HDAexo (right), as computed using WB97XD/6-311+G(d,p) pcm CH2Cl2.
Scheme 6. Natural charges of significant atoms in structures Z–4 (left) and HDAexo (right), as computed using WB97XD/6-311+G(d,p) pcm CH2Cl2.
Molecules 29 04876 sch006
Table 1. Global electronic properties of 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2).
Table 1. Global electronic properties of 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2).
µ [eV]η [eV]ω [eV]N [eV]
1−2.236.340.393.72
2−4.514.532.242.34
Table 2. Kinetic and thermodynamic parameters for key transformations in the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) based on wb97xd/6-311+G(d,p) (PCM) calculations (ΔH, ΔG are in kcal/mol; ΔS are in cal/molK).
Table 2. Kinetic and thermodynamic parameters for key transformations in the reaction between 2-methoxyfuran (1) and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate (2) based on wb97xd/6-311+G(d,p) (PCM) calculations (ΔH, ΔG are in kcal/mol; ΔS are in cal/molK).
TransformationTransitionΔHΔSΔG
The formation of intermediates1+2 → MCA−7.1−40.34.9
MCA → TSA14.4−11.818.0
MCA → Iendo11.7−8.34.2
1+2 → MCB−4.5−32.85.3
MCB → TSB16.5−13.720.6
MCB → Iendo21.2−15.25.7
1+2 → MCC−5.2−38.26.2
MCC → TSC17.2−8.419.7
MCC → Iendo3−0.2−7.52.0
1+2 → MCD−6.6−39.75.3
MCD → TSD14.9−9.717.8
MCD → Iexo14.7−9.47.5
1+2 → MCE−4.4−36.46.4
MCE → TSE17.3−8.219.7
MCE → Iexo2−0.7−11.52.7
1+2 → MCF−5.4−34.64.9
MCF → TSF16.5−13.020.3
MCF → Iexo30.2−15.24.7
The rotation around the nitroethyl moiety within intermediatesTSrot(Iendo1 → Iendo2)4.8−4.56.1
Iendo1 → Iendo22.10.61.9
TSrot(Iendo2 → Iendo3)1.0−4.92.5
Iendo2 → Iendo3−2.12.3−2.8
TSrot(Iendo3 → Iendo1)3.5−7.85.8
Iendo3 → Iendo10.0−2.90.8
TSrot(Iexo1 →Iexo2)0.9−3.82.1
Iexo1 → Iexo2−3.20.8−3.6
TSrot(Iexo2 → Iexo3)2.1−4.93.6
Iexo2 → Iexo3−0.1−2.00.5
The formation of hetero Diels–Alder adductsIexo1 → TSG1.4−3.72.5
Iexo1 → HDAexo−2.8−3.8−1.7
Iexo3 → TSG4.8−3.05.7
Iexo3 → HDAexo0.5−3.21.5
Iendo1 → TSI0.7−4.32.0
Iendo1 → HDAendo−8.2−2.4−7.5
The formation of Diels–Alder adductsIendo1 → TSJ9.1−8.011.5
Iendo1 → DAendo−3.1−7.9−0.7
Iexo1 → TSK10.6−14.014.8
Iexo1 → DAexo−3.9−13.30.0
The formation of Michael adductsIexo2 → TSL32.50.532.3
Iexo2 → Z-3−17.36.6−19.3
Iexo3 → TSM32.62.431.9
Iexo3 → Z-3−17.28.6−19.8
Iendo2 → TSN33.41.832.9
Iendo2 → E-3−19.61.5−20.0
Iendo3 → TSO35.5−0.435.7
Iendo3 → E-3−16.94.8−18.4
The formation of nitronate Z-4Iexo3 → TSP8.80.48.7
Iexo3 → Z-4−26.24.7−27.5
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Sadowski, M.; Dresler, E.; Wróblewska, A.; Jasiński, R. A New Insight into the Molecular Mechanism of the Reaction between 2-Methoxyfuran and Ethyl (Z)-3-phenyl-2-nitroprop-2-enoate: An Molecular Electron Density Theory (MEDT) Computational Study. Molecules 2024, 29, 4876. https://doi.org/10.3390/molecules29204876

AMA Style

Sadowski M, Dresler E, Wróblewska A, Jasiński R. A New Insight into the Molecular Mechanism of the Reaction between 2-Methoxyfuran and Ethyl (Z)-3-phenyl-2-nitroprop-2-enoate: An Molecular Electron Density Theory (MEDT) Computational Study. Molecules. 2024; 29(20):4876. https://doi.org/10.3390/molecules29204876

Chicago/Turabian Style

Sadowski, Mikołaj, Ewa Dresler, Aneta Wróblewska, and Radomir Jasiński. 2024. "A New Insight into the Molecular Mechanism of the Reaction between 2-Methoxyfuran and Ethyl (Z)-3-phenyl-2-nitroprop-2-enoate: An Molecular Electron Density Theory (MEDT) Computational Study" Molecules 29, no. 20: 4876. https://doi.org/10.3390/molecules29204876

APA Style

Sadowski, M., Dresler, E., Wróblewska, A., & Jasiński, R. (2024). A New Insight into the Molecular Mechanism of the Reaction between 2-Methoxyfuran and Ethyl (Z)-3-phenyl-2-nitroprop-2-enoate: An Molecular Electron Density Theory (MEDT) Computational Study. Molecules, 29(20), 4876. https://doi.org/10.3390/molecules29204876

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