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Article

On the Question of the Regio-Orientation, Stereo-Orientation and Molecular Mechanism in the Cascade Cycloaddition/Rearrangement/Elimination Processes Leading to Nitro-Substituted Thiopyran Analogs: DFT Computational Study

by
Mikołaj Sadowski
1,
Ewa Dresler
2 and
Radomir Jasiński
3,*
1
Cracow University of Technology, CUT Doctoral School, Faculty of Chemical Engineering and Technology, Warszawska 24, 31-155 Cracow, Poland
2
Łukasiewicz Research Network—Institute of Heavy Organic Synthesis “Blachownia”, Energetyków 9, 47-225 Kędzierzyn-Koźle, Poland
3
Cracow University of Technology, Department of Organic Chemistry and Technology, Warszawska 24, 31-155 Cracow, Poland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(18), 8948; https://doi.org/10.3390/ijms26188948
Submission received: 18 August 2025 / Revised: 11 September 2025 / Accepted: 12 September 2025 / Published: 14 September 2025
(This article belongs to the Special Issue From Electronic Structure to Application: Computational Insights into Bioactive and Functional Molecules)
Browse Figures
Versions Notes

Abstract

Sulfur-containing heterocyclic structures play an important role in modern biotechnology. Their synthesis is made possible by means of the hetero Diels–Alder reaction involving unsaturated sulfur compounds. In the framework of this paper, the molecular mechanism of the cycloaddition reactions between tioanalogs of the butadiene generated in situ with the participation of the Lawesson reagent and the E-2-phenyl-1-nitroethene was evaluated on the basis of the DFT quantum chemical calculations. It was found that the most favored reaction path is realized according to a stepwise mechanism with the participation of the zwitterionic intermediate. To study this further, the molecular mechanism of the deamination process of the primary cycloadducts was also analyzed. It was found that this mechanism is substantially different to the case of other known β-elimination processes and is achieved via a stepwise scheme. In addition to these investigations, the LA catalysis of the deamination process was also explored.

1. Introduction

Sulfur-containing heterocyclic structures play an important role in modern biotechnology, pharmacy, and related areas because of their different bioactivities such as anticancer [1], antiviral [1,2], antifungal [3,4,5], insecticidal [1,6], and herbicidal activity [1,7]. Some compounds from this group can be obtained from natural matrices [8,9]. However, a more popular way to obtain sulfur-containing heterocycles is organic synthesis. In particular, the most universal approach is based on the application of (2 + 2)- [10,11], (3 + 2) [12,13], and (4 + 2) cycloaddition processes [12,14]. The hetero Diels–Alder (HDA) reaction can be used for the preparation of thiopyrane analogs starting from conjugated dienes and tioketones or tioanalogs of the buta-1,3-diene and alkenes as 2-π-components. These processes should be treated formally as (4 + 2) cycloadditions. In contrast to the “carbo” Diels–Alder (DA) reactions [15,16], in most cases, the hetero Diels–Alder processes require the presence of Lewis acid (LA) catalysts [17,18]. Only some incidental cycloaddition reactions of this type occur under thermal conditions [19,20]. Recently, Karpov and coworkers [21] described a protocol for the preparation of new nitrofunctionalized analogs of tiopyrane on the basis of the reaction between tioanalogs of butadiene generated in situ with the participation of the Lawesson reagent (Scheme 1). The key stage of this process, used for the construction of the heterocyclic segment, is probably the (4 + 2) cycloaddition reaction.
The reaction course and mechanism are probably difficult and include an undetermined addition/elimination sequence (Scheme 2). Thus, it is not possible to explain it without additional, comprehensive mechanistic studies. In particular, several important problems were detected:
-
The question of the regioselectivity of the cycloaddition reaction (Scheme 1). The regio-orientation of the detected final products suggests that the 1,5-diphenyl-3-dimethylamino-4-nitrohexane-6-tio-cyclohexa-1-ene (3 or 4) should be considered the primary cycloaddition product. It is, however, possible that this product is formed as a result of the cycloreversion of less thermodynamically stable 1,4-diphenyl-3-dimethylamino-5-nitrohexane-6-tio-cyclohexa-1-ene (5 or 6) that forms more easily from the kinetic point of view. This type of balance between thermodynamic and kinetic factors regarding the problem of cycloaddition regioselectivity was observed in the case of reactions with participation of conjugated nitroalkenes [22,23,24,25].
-
The problem of the stereoselectivity of the cycloaddition reaction (Scheme 1). In the framework of both regioisomeric approaches, two stereoisomeric reaction channels are possible due to the tendency to form 3,4-cis- and 3,4-trans cycloadducts. Assuming the syn-mechanism of the deamination stage, the last one should be more probable. However, this mechanism was not analyzed in any way. In the case of the stepwise elimination mechanism, the final product can be formed from both stereoisomeric 1,5-diphenyl-3-dimethylamino-4-nitrohexane-6-tio-cyclohexa-1-enes 4 and 5. Recently, different types of stepwise mechanisms were documented for elimination reactions earlier defined as a single-step [26,27,28].
-
Mechanistic aspect of the cycloaddition process. Three decades ago, the single-step mechanism with the pericyclic reorganization of the electron density was widely accepted [29]. However, recent discoveries undermine this point of view [30]. At this moment it is known that in many cases, the single-step mechanism is not pericyclic [31,32,33]. Moreover, the single-step scheme can compete with stepwise mechanism with biradical [34] or zwitterionic intermediates [35,36]. These issues are not clear regarding this title process.
-
The deamination reaction is generally considered a difficult process in comparison to other 1,2-elimination reactions. The theoretically possible, competitive channel of the extrusion of the nitrous acid cannot be, however, achieved realistically. These types of extrusion are generally realized as single-step, pseudocyclic processes [37,38] under mild reaction conditions.
-
The deamination process of 2-amino-1-nitroethyl molecular segments is generally significantly accelerated by the presence of the LA-catalysts such as boron hydride or boron trifluoride [39,40,41]. Therefore, in the last part of our research we decided to shed light on the kinetic aspects and the molecular mechanism of the transfer of respective LA to the cycloaddition product and the further decomposition via elimination stage.
Due to issues explained below, the mechanistic aspects of the reactions between tioanalogs of buta-1,3-diene and conjugated nitroalkenes require a comprehensive exploration and interpretation. We decided to resolve these problems on the basis of the density functional theory (DFT) calculations and the analysis in the framework of the molecular electron density theory (MEDT) [42]. These studies were performed for the model process with the participation of 2-phenyl-4-dimethylamino-1-tio-buta-1,3-diene (1) and E-2-phenylnitroethene (2) (Scheme 1 and Scheme 2).

2. Results and Discussion

In the first part of our study, we decided to carry out a detailed analysis of electronic properties of components for model reactions in framework of the conceptual functional density theory (CDFT) [43,44]. On this basis, the discussion about the global and local aspects of organic reactivity was performed. Recently, a similar approach has been successfully applied to the interpretation of a wide range of bimolecular reactions [45,46,47,48].
Electronic properties of E-2-phenylnitroethene 2 were discussed in detail very recently [49]. It was found that the nitroalkene 2 should be treated as a strong electrophile (ω = 2.67 eV), characterized by electrophilically activated 2 position of the nitrovinyl molecular segment. On the other hand, the global electrophilicity of the second addition component is substantially lower (ω = 1.00 eV). Therefore, in the light of Domingo terminology [50], the difference between electrophilicities requires treating analyzed processes as clearly polar, determined by the forward electron density flux (FEDF) [51]. Subsequently, it was found that molecule 1 is characterized by a great value of the global nucleophilicity index (N = 1.76 eV). The difference between local nucleophilicities within molecule 1 is, however, not significant. Therefore, the local reactivity of this reaction component will be a result of the balance between local electronic factors and steric repulsions. In conclusion, in this case, the CDFT approach does not offer the possibility of predicting the reaction’s regioselectivity.
Next, the reaction profiles for all possible cycloaddition paths (Scheme 2) were analyzed, based on the results of the ωB97XD/6-311G(d) calculations. The presence of the DCM in the reaction was simulated via the polarizable continuum model (PCM) using the integral equation formalism variant (IEFPCM) as the default SCRF (self-consistent reaction field) method (see the Computational Details section). It was found that the nature of reaction profiles is completely different for reactions leading to regioisomeric 1,5-diphenyl-3-dimethylamino-4-nitrohexane-6-tio-cyclohexa-1-enes 4/5 (paths A and B) and 1,4-diphenyl-3-dimethylamino-5-nitrohexane-6-tio-cyclohexa-1-enes 6/7 (paths C and D) (Figure 1, Figure 2 and Figure 3).
Within paths A and B, the intermolecular interactions lead initially to the formation of pre-reaction complexes (MCA and MCB, respectively). This transformation is realized as barrierless and is associated with the reduction in the enthalpy of the reaction system. For path A, this change is equal to 10 kcal/mol, whereas for path B, analogous change is greater and equals more than 20 kcal/mol (Table 1). The influence of entropic factors on the relative stability of mentioned intermediates is very important. This factor is approximately 40 cal/molK for both considered transformations. In the case of path A, this fact determines the positive value of the Gibbs free energy of the formation of MCA. This excludes the possibility of existence of the MCA as a stable intermediate. In the case of path B, the Gibbs free energy of the formation of MCB is still negative, which stimulates the potential stability of the pre-reaction complex as a reaction intermediate. This fact favors the way of the title reaction via path B to a larger extent than via path A. Independently of different energetic characteristic, both pre-reaction complexes exhibit similar structural character. In particular, interatomic distances S1–C2, C2–C3, C3–C4, and C5–C6 (Figure 2) distances derived from addend molecules have not changed in comparison to geometry within individual 1 and 2 structures (Table 2). In the framework of MCs, 1 and 2 substructures adopt orientation, which determines further conversion to respective transition state. Therefore, MCA and MCB should be treated as orientation complexes. It should be, however, underlined that at this stage, key distances between reaction centers (Table 2) do not adapt values typical for new sigma bonds in transition states [52,53,54,55]. Lastly, within MCs, the electron density transfer between substructures is not achieved (GEDT = 0.00 e). Therefore, the optimized structures should not be considered charge transfer complexes. Similar pre-reaction intermediates were very recently detected regarding to different type cycloaddition processes [56,57,58].
The further conversion of pre-reaction intermediates MCA and MCB leads directly to respective transition state (TS1A and TS1B, respectively). Within these transition states, only one (C6–S1 bond) of the two sigma bonds necessary for the completion of target heterocyclic ring is formed. The formation of TS1A and TS1B is associated with the great transfer of the electron density (see GEDT (global electron density transfer) values in Table 2). This confirms the polar nature of explored process. The IRC (intrinsic reaction coordinate) calculations connect mentioned TSs with the transition valley of the respective reaction intermediate (IA and IB for paths A and B, respectively). The nature of these intermediates was explored on the basis of detailed ELFs (electron localization functions) experiments. We performed this study for the IB structure.
In the NPA (natural population analysis (Figure 4), in the reaction site, only one carbon atom (C4) has a slightly positive charge (+ 0.16); the atom corresponding to C4 in the assumed reaction course (C5) has a charge of −0.17. All non-hydrogen atoms neighboring the C4 atom have negative charges.
In the ELF analysis, a monosynaptic valence basin V(C5) with population of 0.71 e is present. The basin’s attractor is located on a line connecting C4 and C5 atoms (Figure 5).
The monosynaptic V(C5) basin when interpreted with the C5 atom natural charge allows us to assume that the intermediate IB has excessive electron density located at the C5 carbon atom. This paired with the positive charge at C4 carbon atom shows that the intermediate IB exhibits zwitterionic nature (Figure 6).
The cyclization of IA and IB intermediates is carried out as a single-step process via TS2A and TS2B transition states, respectively. This only requires very little energy and is connected with the formation of the C4–C5 new sigma bond. Both considered TSs exhibit a polar nature. The IRC calculations confirm that TS2A and TS2B are directly connected with respective cycloadducts (4 and 5, respectively).
The initial phase of reaction according to paths C and D is analogous to the case of paths A and B. In this phase, pre-reaction complexes (MCC and MCD, respectively) are formed. The nature of localized intermediates is generally similar to MCA and MCB. The scenario of their further conversion is, however, different. In both cases, the transition of the reaction system along the reaction coordinate is realized via single transition state (TSC and TSD, respectively, for paths C and D). Within these TSs, two new sigma bonds are formed (C4–C5 and C6–S1). The asynchronicity of the formation of new bonds within localized structures is not high (Table 2). Independently of this fact, TSC and TSD exhibit great polar nature. This is evident in the light of the GEDT values. The nature of both TSs was confirmed by the IRC calculations. IRC experiments connect localized transition states directly with valleys of respective cycloadducts.
In general, only one isomeric channel of conversion of the starting molecular system is possible from the kinetic point of view. This is the reaction via path B. Competitive reaction ways (A, C, and D) should be treated as forbidden. Therefore, the adduct 5 can only be treated as a starting material for the transformation into target molecule 3 (Scheme 3). This fact excellently correlates with the selectivity observed experimentally (Scheme 1). Next, the reaction according to path B is achieved via a very low activation barrier. In consequence, these transformations can occur at room temperature, which perfectly correlates with experimental facts [21]. We found that in contrast to other known thermal β-elimination reactions [37,38,59], the elimination of the dimethylamine from molecule 5 is not realized as a single-step process with the participation of the pseudocyclic transition state.
The intermediate IE (Scheme 3, Figure 7) is unstable from the thermodynamic point of view and easily converts into target molecule 3. This process is carried out via the TS2E transition state and is associated with the dissociation of the single bond between the N7 nitrogen atom from the ammonium group and the C4 carbon atom of the heterocyclic ring (Figure 7).
Within the first reaction stage, the hydrogen atom from the C6 carbon is transferred to the nitrogen atom of the dimethylamine group. This process is realized via the single transition state. This is the TS1E structure (Table 3). Within this stage, the C5–H8 single bond dissociates. At the same time, the new N7–H8 single bond is formed. The geometry of the optimized transition state exhibits the nature typical for proton [1.3]-sigmatropic rearrangement [60,61,62].
The obtained transitional state was characterized by ELF and NPA analyses.
The TS1E ELF analysis (Figure 8) shows monosynaptic basins at the C5 and N7 atoms V(C5) and V(N7) integrating, respectively, 1.41 e and 1.81 e. The attractors present at the disynaptic basin V(C4,N7) and V(C4,C5) are shifted from the regular position observed for attractors of irreducible disynaptic basins. Normally, the attractor lies on a line connecting the centers of the synapses the basin lies at. Here, positions of the attractors suggest that the bonds represented by the basins V(C4,N7) and V(C4,C5) are slightly strained, with populations of 1.69 e and 2.02 e, respectively.
According to the NPA results (Figure 9), the C4 and N7 atoms have assigned charges of −0.21 and −0.52, respectively. The H8 atom has a positive charge of 0.44.
The TS1E seems to be of polar nature and to be geometrically strained, as seen in Figure 7, by the bond–bond repulsion, seen as a shift of attractors from their normal positions and by the “buckling” in the topology of V(C4,N7) and V(C4,C5). The structure of the TS1E is shown in Figure 10.
The TS2E was analyzed by ELF (Figure 11). The irreducible valence basin V(C4,C5) with population of 3.04 e signifies the presence of the 1.05 order bond. In the NHMe2 region there is no region between the C4 and N7 atoms. The region that was responsible for the C4–N7 single bond in the TS1E is now a monosynaptic basin V(N7) with population of 1.73 e representing a lone pair of the nitrogen atom. The C5 atom has a monosynaptic valence basin V(C5) containing 0.56 e. According to the NPA (Figure 12), the charge of the C5 carbon atom integrates to −0.07, leading us to interpret the TS2E as a partially recombined pseudoradical (Figure 13).
Obtained parameters of the activation for the considered deamination process show that this process should be treated as allowed under considered conditions. This conclusion correlates well with generally known experimental observations regarding these types of processes [39,40,41]. In particular, it is evident that these processes are rather difficult from the kinetic point of view. In the light of our study, this is a consequence of energetical aspects of the first step of the deamination process, realized according to the [1.3]-sigmatropic shift mechanism. Therefore, we decided to analyze the influence of catalytic impact of the boron hydride on the reaction course. Earlier, we explored several different types of the LA catalyzed processes with the participation of the BH3 [27,63,64]. Within this analysis, the THF·BH3 complex was used as a source of the boron hydride, because it is a very popular synthon [65,66,67,68]. We detected two nucleophilic centers, which potentially can be considered good boron hydride acceptor: the nitrogen atom of the dimethylamino group and the oxygen atom of the nitro group. The transmission of the BH3 segment from the THF·BH3 complex is achieved as single-step process (Figure 14), and requires the enthalpy of activation at the level of several kcal/mol. In the case of the first considered reaction (transmission of the BH3 segment on the nitrogen atom of the dimethylamino group), within the localized transition state (TSF), one new single bond is formed between the N7 nitrogen atom and the B9 boron atom. In the case of the second considered reaction (transmission of the BH3 segment on the oxygen atom of the nitro group via TSG1), one new single bond is formed between the O11 oxygen atom and the B9 boron atom. In both cases, the formation of one new bond is conjugated with the dissociation of the bond between the B9 boron atom and the oxygen O10 atom from the THF segment. Therefore, from the structural point of view, the localized transition state is very similar to well-known transition states in the SN2 substitution reactions realized at the sp3 carbon atom [69,70,71]. Similar structures were localized earlier in the case of reaction between the THF·BH3 complex and the trimethylphosphine [72]. The electronic structures of the localized TSs were explored regarding the BH3 substitution, and TS1G was chosen as a model transition state.
Ijms 26 08948 sch004
Scheme 4. The scheme of the LA-catalyzed deamination of the adduct 3.
Scheme 4. The scheme of the LA-catalyzed deamination of the adduct 3.
Ijms 26 08948 sch004
Only the active site in the TS1G was considered (Figure 15 and Figure 16). The boron atom (B9) has a negligible positive charge of 0.11, while both O10 and O11 oxygen atoms are negatively charged (−0.58 and −0.36, respectively) (Figure 14). In the ELF analysis of the TS1G it can be seen that both O10 and O11 atoms have monosynaptic basins directed at the B9 atom (V(O10) = 2.29 e; V(O11) = 2.63 e), while the boron atom has an almost monosynaptic basin (V(B9) = 0.01 e) not visible at the 0.75 ELF isovalue plot, but barely visible at ELF isovalue 0.1 (Figure 16). The attractor of the V(B9) basin is clearly visible though (Figure 15), leading us to believe that, here, the interaction between a lone pair of oxygen atoms and an “empty orbital” of the boron atom is observed via ELF and DFT methods.
Although the formation of both IF and I1G complexes is fast from the kinetic point of view, their ability to deaminate is completely different. In particular, in the case of the first complex, we did not detect any reaction channels connected with the deamination processes. In contrast, in the case of the I1G complexes, we optimized the reaction path leading to the target molecule 3. This process occurs as a cascade reaction with three transition states.
The first stage of the transformation of the I1G into 3 is the hydrogen [1.3]-sigmatropic shift process. Similarly to the case of non-catalyzed process, within this stage, the C5–H8 single bond is broken. At the same time, the new N7–H8 single bond is formed. However, the enthalpy of activation for this transformation is almost 6 kcal/mol lower in comparison to the non-catalyzed reaction. As a result of this transformation, the I2G intermediate is formed. This was confirmed by the IRC calculations. The further conversion of the I2G intermediate is realized via the TS3G transition state. This transformation is associated with the dissociation of the dimethylamine molecule from the I2G intermediate. The obtained I3G intermediate can convert to the target molecule by transferring the boron hydride segment to a THF molecule. This process is achieved according to the description above of the SN2-like mechanism via TS4G transition state (Figure 17).

3. Computational Details

The exploration of the reaction profiles was performed on the basis of the quantum chemical DFT calculations. The ωB97XD/6-311G(d) level of theory from the Gaussian 16 software package [73,74] was used. The same level of theory was used in our research group regarding other, different types of addition, elimination, and rearrangement processes [35,36,75,76]. In all cases, satisfactory correlation between experimental results and quantum chemical calculations were obtained. Parallelly, however, analogous calculations were performed using the 6-311 + G(d,p) basis set for model process of the deamination of 5, because diffuse and polarization function can be important for describing anions, zwitterions, and highly polar transition states, including proton-transfer stages. It was found that differences between Gibbs free energies of the activation of the analyzed path obtained via ωB97XD/6-311G(d) and ωB97XD/6-311 + G(d,p) do not exceed 1–1.5 kcal/mol. At the same time, the qualitative nature of Gibbs free energy profiles are identical (Figure S1 in the Supplementary Materials). Next, we compared key geometrical parameters for critical structures. This analysis (Table S1 in the Supplementary Materials) does not exhibit an important difference between data from ωB97XD/6-311G(d) and ωB97XD/6-311 + G(d,p). Therefore, we concluded that the application of the ωB97XD/6-311G(d) level of theory is satisfactorily justified, and is more attractive taking into account the computation time and the cost of computing power.
All localized and optimized stationary points were characterized using vibrational analysis. It was found that starting molecules, intermediates, and products had positive Hessian matrices. On the other hand, all transition states (TS) showed only one negative eigenvalue in their Hessian matrices. The calculations were performed for T = 297K. Transition states are described as TS, pre-reaction complexes as MC, and reaction intermediates as I.
Intrinsic reaction coordinate (IRC) calculations were performed for the verification of all localized transition states. The presence of the solvent in the reaction environment (DCM) was included using the IEFPCM algorithm [77]. The global electron density transfer (GEDT) [78] was calculated according to the following formula (1):
GEDT = −ΣqA
where qA is the net charge, and the sum is taken over all the atoms of nitroalkene.
The same level of theory was used within ELF analysis.
Global electronic properties of reactants were estimated according to the equations recommended earlier by Parr and Domingo [79,80,81]. According to Domingo’s recommendation, for this purpose, the ωB97XD/6-311G(d) level of theory was used. All molecules were fully optimized. Next, the electronic chemical potentials (μ) and chemical hardness (η) were evaluated in terms of one-electron energies of FMO (EHOMO and ELUMO) using the following equations:
Μ ≈ (EHOMO + ELUMO)/2 η ≈ ELUMO − EHOMO
Next, the values of µ and η were then used for the calculation of the global electrophilicity index (ω) according to the following formula:
ω = μ2/2η
Subsequently, global nucleophilicity (N) [82] can be expressed with the following equation:
N = EHOMO − EHOMO (tetracyanoethene)
The local electrophilicity (ωk) condensed to atom k was calculated by projecting the index ω onto any reaction center k in the molecule using Parr functions P+k [83]:
ωk = P+k·ω
The local nucleophilicity (Nk) condensed to atom k was calculated using global nucleophilicity N and Parr functions P−k [83] according to the following formula:
Nk = P−k·N

4. Conclusions

The ωB97XD/6-311G(d) (PCM) quantum chemical calculations shed light on the molecular mechanism of the reaction between tioanalogs of the butadiene generated in situ with the participation of the Lawesson reagent and 2-phenylnitroethene. The first reaction stage is a (4 + 2) polar cycloaddition process. It was found, however, that only one of four theoretically possible cycloaddition reaction paths can be achieved. Additionally, the cycloaddition process is realized not via the “classical” single-step mechanism, but via the stepwise one, with the participation of the zwitterionic intermediate. Next, the mechanism of elimination of the N,N-dimethylamine from the primary cycloadduct was also examined. We found that this transformation is also carried out via the atypical scheme, according to the stepwise mechanism. Lastly, we analyzed the Lewis-acid promoted catalyst effect on the elimination course. In general, the title reaction should be classified as a rare-type, of the domino, multi-step processes with the participation of the stepwise cycloaddition reaction and the stepwise elimination process.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms26188948/s1.

Author Contributions

Conceptualization, R.J.; software, E.D.; formal analysis, R.J., M.S. and E.D.; investigation, R.J., M.S. and E.D.; writing—original draft preparation, R.J.; supervision, R.J. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Wei, J.; Chen, L.; Zhu, K.; Liu, Y.; Li, H.; Zhao, M.; Wu, Y. Design, Synthesis, and Fungicidal Activity Evaluation of 2-Methyl-5-Phenylthiazole-4-Carboxamides Bearing Morpholine, Thiomorpholine, or Thiomorpholine 1,1-Dioxide Moiety. Chem. Heterocycl. Compd. 2024, 60, 536–543. [Google Scholar] [CrossRef]
  2. Lelyukh, M.I.; Komarenska, Z.M.; Chaban, T.I.; Chaban, I.H. An Overview of the Synthetic Routes toward [1,2,4]Triazolo[3,4-b][1,3,4]Thiadiazoles (Microreview). Chem. Heterocycl. Compd. 2024, 60, 342–344. [Google Scholar] [CrossRef]
  3. Longo, L.S., Jr.; Siqueira, F.A. Synthesis of Imidazo[2,1-b]thiazol-5-amines Using Groebke–Blackburn–Bienaymé Multicomponent Reaction (Microreview). Chem. Heterocycl. Compd. 2024, 60, 339–341. [Google Scholar] [CrossRef]
  4. Chaban, T.I.; Klenina, O.V.; Chaban, I.H.; Lelyukh, M.I. Recent Advances in the Synthesis of Thiazolo[4,5-b]Pyridines. Part 2: Focus on Thiazole Annulation to Pyridine Ring. Chem. Heterocycl. Compd. 2024, 60, 130–132. [Google Scholar] [CrossRef]
  5. Chaban, T.I.; Lelyukh, M.I.; Chaban, I.H.; Kasyanchuk, O.Y. Approaches to the Synthesis of Thiazolo[3,2-a]Pyridines (Microreview). Chem. Heterocycl. Compd. 2024, 60, 124–126. [Google Scholar] [CrossRef]
  6. Sadowski, M.; Dresler, E.; Zawadzinska-Wrochniak, K.; Wroblewska, A.; Jasinski, R. Syn-Propanethial S-Oxide as the Natural Available Building Block for the Preparation of Nitrofunctionalized Sulfur-Containing Five-Membered Heterocycles: MEDT Study. Molecules 2024, 29, 4892. [Google Scholar] [CrossRef]
  7. Batenko, N.; Gaile, A. 2-Substituted Benzothiazole-Based Sensors for Optical Detection of Biogenic Amines and Ammonia (Microreview). Chem. Heterocycl. Compd. 2025, 61, 51–53. [Google Scholar] [CrossRef]
  8. Alobaide, Z.N.; Habel, A.; Awin, T.; Buzgaia, N.; Elamari, A.; Elteera, F.; Elabbar, F. Arum cyrenaicum: A Comprehensive Review of Phytochemistry and Bioactivity. Sci. Rad. 2024, 3, 218–227. [Google Scholar] [CrossRef]
  9. Gassim, H.B.M.; Hassan, A.M.; Abadi, R.S.M.; Mustafa, Y.A.A. Phytochemical Constituents and Antioxidant Activity of Ricinus communis Linn Leaf and Seeds Extracts. Sci. Rad. 2024, 3, 74–88. [Google Scholar] [CrossRef]
  10. Nicolaou, K.C.; Snyder, S.A.; Montagnon, T.; Vassilikogiannakis, G. The Diels–Alder Reaction in Total Synthesis. Angew. Chem. Int. Ed. 2002, 41, 1668–1698. [Google Scholar] [CrossRef]
  11. Łapczuk-Krygier, A.; Kącka-Zych, A.; Kula, K. Recent Progress in the Field of Cycloaddition Reactions Involving Conjugated Nitroalkenes. Curr. Chem. Lett. 2019, 8, 13–38. [Google Scholar] [CrossRef]
  12. Łapczuk, A. The [3+2] Cycloaddition Reaction as an Attractive Way for the Preparation of Nicotine Analogs (Microreview). Chem. Heterocycl. Compd. 2023, 59, 109–111. [Google Scholar] [CrossRef]
  13. Hou, S.-Y.; Yan, B.-C.; Sun, H.-D.; Puno, P.-T. Recent Advances in the Application of [2+2] Cycloaddition in the Chemical Synthesis of Cyclobutane-Containing Natural Products. Nat. Prod. Bioprospect. 2024, 14, 37. [Google Scholar] [CrossRef] [PubMed]
  14. Sarkar, D.; Bera, N.; Ghosh, S. [2+2] Photochemical Cycloaddition in Organic Synthesis. Eur. J. Org. Chem. 2020, 2020, 1310–1326. [Google Scholar] [CrossRef]
  15. Eschenbrenner-Lux, V.; Kumar, K.; Waldmann, H. The Asymmetric Hetero-Diels–Alder Reaction in the Syntheses of Biologically Relevant Compounds. Angew. Chem. Int. Ed. 2014, 53, 11146–11157. [Google Scholar] [CrossRef] [PubMed]
  16. Jørgensen, K.A. Catalytic Asymmetric Hetero-Diels–Alder Reactions of Carbonyl Compounds and Imines. Angew. Chem. Int. Ed. 2000, 39, 3558–3588. [Google Scholar] [CrossRef]
  17. Schmidt, R.R. Hetero-Diels–Alder Reaction in Highly Functionalized Natural Product Synthesis. Acc. Chem. Res. 1986, 19, 250–259. [Google Scholar] [CrossRef]
  18. Jørgensen, K.A. Hetero-Diels–Alder Reactions of Ketones—A Challenge for Chemists. Eur. J. Org. Chem. 2004, 2004, 2093–2102. [Google Scholar] [CrossRef]
  19. Woliński, P.; Kącka-Zych, A.; Wróblewska, A.; Wielgus, E.; Dolot, R.; Jasiński, R. Fully Selective Synthesis of Spirocyclic-1,2-Oxazine N-Oxides via Non-Catalysed Hetero Diels–Alder Reactions with the Participation of Cyanofunctionalized Conjugated Nitroalkenes. Molecules 2023, 28, 4586. [Google Scholar] [CrossRef]
  20. Woliński, P.; Kącka-Zych, A.; Mirosław, B.; Wielgus, E.; Olszewska, A.; Jasiński, R. Green, One-Pot Synthesis of 1,2-Oxazine-Type Herbicides via Non-Catalyzed Hetero Diels–Alder Reactions Comprising (2E)-3-Aryl-2-Nitroprop-2-Enenitriles. J. Clean. Prod. 2022, 356, 131878. [Google Scholar] [CrossRef]
  21. Karpov, I.D.; Kolobov, A.V.; Filippov, I.P.; Rostovskii, N.V.; Ovchinnikov, K.L. A One-Pot Synthesis of 3-Nitro-2H-Thiopyrans and Their Selective Reduction to 3-Nitro-3,4-Dihydro-2H-Thiopyrans. Chem. Heterocycl. Compd. 2024, 60, 251–256. [Google Scholar] [CrossRef]
  22. Kras, J.; Wróblewska, A.; Kącka-Zych, A. Unusual Regioselectivity in [3+2] Cycloaddition Reactions between (E)-3-Nitroacrylic Acid Derivatives and (Z)-C,N-Diphenylimine N-Oxide. Sci. Rad. 2023, 2, 112–117. [Google Scholar] [CrossRef]
  23. Stecko, S.; Paśniczek, K.; Jurczak, M.; Urbańczyk-Lipkowska, Z.; Chmielewski, M. Kinetic and Thermodynamic Aspects in the 1,3-Dipolar Cycloaddition of Five-Membered Cyclic Nitrones to α,β-Unsaturated γ- and δ-Lactones. Tetrahedron Asymmetry 2007, 18, 1085–1093. [Google Scholar] [CrossRef]
  24. Sudibyo, H.; Budhijanto, B.; Marbelia, L.; Güleç, F.; Budiman, A. Kinetic and Thermodynamic Evidences of the Diels–Alder Cycloaddition and Pechmann Condensation as Key Mechanisms of Hydrochar Formation during Hydrothermal Conversion of Lignin-Cellulose. Chem. Eng. J. 2024, 480, 148116. [Google Scholar] [CrossRef]
  25. Karaś, A.; Łapczuk, A. Computational Model of the Formation of Novel Nitronorbornene Analogs via Diels–Alder Process. React. Kinet. Mech. Catal. 2025, 138, 2671–2689. [Google Scholar] [CrossRef]
  26. Kącka, A.; Jasiński, R. A Dramatic Change of Kinetic Conditions and Molecular Mechanism of Decomposition Processes of Nitroalkyl Carboxylates Catalyzed by Ethylammonium Cations. Comput. Theor. Chem. 2017, 1104, 37–42. [Google Scholar] [CrossRef]
  27. Kącka, A.; Domingo, L.R.; Jasiński, R. Does a Fluorinated Lewis Acid Catalyst Change the Molecular Mechanism of the Decomposition Process of Nitroethyl Carboxylates? Res. Chem. Intermed. 2018, 44, 325–337. [Google Scholar] [CrossRef]
  28. Kącka-Zych, A.; Ríos-Gutiérrez, M.; Domingo, L.R. A Molecular Electron Density Theory Study of the Lewis Acid–Catalyzed Decomposition Reaction of Nitroethyl Benzoate Using Aluminum Derivatives. J. Phys. Org. Chem. 2019, 32, e3938. [Google Scholar] [CrossRef]
  29. Houk, K.N.; Lin, Y.T.; Brown, F.K. For the Concerted Mechanism of the Diels–Alder Reaction of Butadiene with Ethylene. J. Am. Chem. Soc. 1986, 108, 554–556. [Google Scholar] [CrossRef]
  30. Jasiński, R. On the Question of Stepwise [4+2] Cycloaddition Reactions and Their Stereochemical Aspects. Symmetry 2021, 13, 1911. [Google Scholar] [CrossRef]
  31. Yepes, D.; Murray, J.S.; Pérez, P.; Domingo, L.R.; Politzer, P.; Jaque, P. Complementarity of Reaction Force and Electron Localization Function Analyses of Asynchronicity in Bond Formation in Diels–Alder Reactions. Phys. Chem. Chem. Phys. 2014, 16, 6726–6734. [Google Scholar] [CrossRef]
  32. Pedrón, M.; Delso, I.; Tejero, T.; Merino, P. Concerted Albeit Not Pericyclic Cycloadditions: Understanding the Mechanism of the (4+3) Cycloaddition between Nitrones and 1,2-Diaza-1,3-dienes. Eur. J. Org. Chem. 2019, 2019, 391–400. [Google Scholar] [CrossRef]
  33. Domingo, L.R. State of the Art of the Bonding Changes along the Diels–Alder Reaction between Butadiene and Ethylene: Refuting the Pericyclic Mechanism. Org. Chem. Curr. Res. 2013, 2, 120. [Google Scholar] [CrossRef]
  34. Jasiński, R. A Reexamination of the Molecular Mechanism of the Diels–Alder Reaction between Tetrafluoroethene and Cyclopentadiene. React. Kinet. Mech. Catal. 2016, 119, 49–57. [Google Scholar] [CrossRef]
  35. Sadowski, M.; Dresler, E.; Wróblewska, A.; Jasiński, R. A New Insight on the Molecular Mechanism of the Reaction between 2-Methoxyfuran and Ethyl (Z)-3-Phenyl-2-Nitroprop-2-enoate: MEDT Computational Study. Molecules 2024, 29, 4876. [Google Scholar] [CrossRef] [PubMed]
  36. Dresler, E.; Wróblewska, A.; Jasiński, R. Understanding the Molecular Mechanism of Thermal and LA-Catalysed Diels–Alder Reaction between Cyclopentadiene and Isopropyl 3-Nitroprop-2-Enate. Molecules 2023, 28, 5289. [Google Scholar] [CrossRef]
  37. Sadowski, M.; Kula, K. Unexpected Course of Reaction Between (1E,3E)-1,4-Dinitro-1,3-butadiene and N-Methyl Azomethine Ylide—A Comprehensive Experimental and Quantum-Chemical Study. Molecules 2024, 29, 5066. [Google Scholar] [CrossRef]
  38. Lu, Y.-X.; Lv, X.-J.; Liu, C.; Liu, Y.-K. Triethylamine-Promoted Henry Reaction/Elimination of HNO2/Cyclization Sequence of Functionalized Nitroalkanes and 2-Oxoaldehydes: Diversity-Oriented Synthesis of Oxacycles. Org. Lett. 2023, 25, 4033–4037. [Google Scholar] [CrossRef]
  39. Blomquist, A.T.; Shelley, T.H., Jr. Preparation of 2-Nitro-1-Alkenes from Nitro Amines. J. Am. Chem. Soc. 1948, 70, 147–149. [Google Scholar] [CrossRef]
  40. Kametani, T.; Nemoto, H. A New Stereocontrolled Synthesis of D-Ring Aromatic Steroid. Tetrahedron Lett. 1979, 20, 3309–3310. [Google Scholar] [CrossRef]
  41. Emmons, W.D.; Cannon, W.N.; Dawson, J.W.; Ross, R.M. Low Temperature Pyrolysis of Boron Trifluoride—Mannich Base Complexes. 2-Nitro-1-Alkenes. J. Am. Chem. Soc. 1953, 75, 1993–1994. [Google Scholar] [CrossRef]
  42. Domingo, L.R. Molecular Electron Density Theory: A Modern View of Reactivity in Organic Chemistry. Molecules 2016, 21, 1319. [Google Scholar] [CrossRef]
  43. Domingo, L.R.; Ríos-Gutiérrez, M.; Pérez, P. Applications of the Conceptual Density Functional Theory Indices to Organic Chemistry Reactivity. Molecules 2016, 21, 748. [Google Scholar] [CrossRef] [PubMed]
  44. Domingo, L.R.; Ríos-Gutiérrez, M.; Pérez, P. Electrophilicity w and Nucleophilicity N Scales for Cationic and Anionic Species. Sci. Rad. 2025, 4, 1–17. [Google Scholar] [CrossRef]
  45. Aitouna, A.O.; Rossafi, B.; El Alaoui, H.E.A.; Zeroual, A. Molecular Electron Density Study on the [3+2] Cycloaddition Reaction between Diphenylnitrylimine and Cinnamaldehyde. Sci. Rad. 2025, 4, 18–28. [Google Scholar] [CrossRef]
  46. Abdoul-Hakim, M.; Kenzy, C.; Subramaniam, M.; Zeroual, A.; Syed, A.; Bahkali, A.H.; Verma, M.; Wang, S.; Garmes, H. Elucidating Chemoselectivity and Unraveling the Mechanism of 1,3-Dipolar Cycloaddition between Diphenyl Nitrilimine and (Isoxazol-3-yl)methylbenzimidazole through Molecular Electron Density Theory. Chem. Heterocycl. Compd. 2024, 60, 617–626. [Google Scholar] [CrossRef]
  47. Aitouna, A.O.; Syed, A.; Alfagham, A.T.; Mazoir, N.; de Julián-Ortiz, J.V.; Elgorban, A.M.; El Idrissi, M.; Wong, L.S.; Zeroual, A. Investigating the Chemical Reactivity and Molecular Docking of 2-Diazo-3,3,3-Trifluoro-1-Nitropropane with Phenyl Methacrylate Using Computational Methods. Chem. Heterocycl. Compd. 2024, 60, 592–599. [Google Scholar] [CrossRef]
  48. Fałowska, A.; Grzybowski, S.; Kapuściński, D.; Sambora, K.; Łapczuk, A. Modeling of the General Trends of Reactivity and Regioselectivity in Cyclopentadiene–Nitroalkene Diels–Alder Reactions. Molecules 2025, 30, 2467. [Google Scholar] [CrossRef]
  49. Kula, K.; Zawadzińska, K. Local Nucleophile-Electrophile Interactions in [3+2] Cycloaddition Reactions between Benzonitrile N-Oxide and Selected Conjugated Nitroalkenes in the Light of MEDT Computational Study. Curr. Chem. Lett. 2021, 9, 9–16. [Google Scholar] [CrossRef]
  50. Domingo, L.R.; Sáez, J.A. Understanding the Mechanism of Polar Diels–Alder Reactions. Org. Biomol. Chem. 2009, 7, 3576–3583. [Google Scholar] [CrossRef]
  51. Domingo, L.R.; Ríos-Gutiérrez, M. A Useful Classification of Organic Reactions Based on the Flux of the Electron Density. Sci. Rad. 2023, 2, 1–24. [Google Scholar] [CrossRef]
  52. Kula, K.; Łapczuk, A.; Sadowski, M.; Kras, J.; Zawadzińska, K.; Demchuk, O.M.; Gaurav, G.K.; Wróblewska, A.; Jasiński, R. On the Question of the Formation of Nitro-Functionalized 2,4-Pyrazole Analogs on the Basis of Nitrylimine Molecular Systems and 3,3,3-Trichloro-1-Nitroprop-1-ene. Molecules 2022, 27, 8409. [Google Scholar] [CrossRef] [PubMed]
  53. Dresler, E.; Wróblewska, A.; Jasiński, R. Understanding the Regioselectivity and the Molecular Mechanism of [3+2] Cycloaddition Reactions between Nitrous Oxide and Conjugated Nitroalkenes: DFT Computational Study. Molecules 2022, 27, 8441. [Google Scholar] [CrossRef] [PubMed]
  54. Zawadzińska, K.; Gadocha, Z.; Pabian, K.; Wróblewska, A.; Wielgus, E.; Jasiński, R. First Examples of [3+2] Cycloadditions with the Participation of the (E)-3,3,3-Tribromo-1-Nitroprop-1-ene. Materials 2022, 15, 7584. [Google Scholar] [CrossRef] [PubMed]
  55. Fryźlewicz, A.; Olszewska, A.; Zawadzińska, K.; Woliński, P.; Kula, K.; Kącka-Zych, A.; Łapczuk-Krygier, A.; Jasiński, R. On the Mechanism of the Synthesis of Nitrofunctionalised Δ2-Pyrazolines via [3+2] Cycloaddition Reactions between α-EWG-Activated Nitroethenes and Nitrylimine TAC Systems. Organics 2022, 3, 59–76. [Google Scholar] [CrossRef]
  56. Wroblewska, A.; Sadowski, M.; Jasiński, R. Selectivity and the Molecular Mechanism of the Au(III)-Catalysed [3+2]-Cycloaddition Reaction between (Z)-C,N-Diphenylnitrone and Nitroethene in the Light of the Molecular Electron Density Theory Computational Study. Chem. Heterocycl. Compd. 2024, 60, 639–645. [Google Scholar] [CrossRef]
  57. Dresler, E.; Wróblewska, A.; Jasiński, R. Energetic Aspects and Molecular Mechanism of 3-Nitro-substituted 2-Isoxazolines Formation via Nitrile N-Oxide [3+2] Cycloaddition: An MEDT Computational Study. Molecules 2024, 29, 3042. [Google Scholar] [CrossRef]
  58. Dresler, E.; Woliński, P.; Wróblewska, A.; Jasiński, R. On the Question of Zwitterionic Intermediates in the [3+2] Cycloaddition Reactions between Aryl Azides and Ethyl Propiolate. Molecules 2023, 28, 8152. [Google Scholar] [CrossRef]
  59. Kącka-Zych, A. Understanding the molecular mechanism rearrangement of internal nitronic ester into nitronorbornene in the light of MEDT study. Molecules 2019, 24, 462. [Google Scholar] [CrossRef]
  60. Borodkin, G.I. Fluorination of Heterocyclic Compounds Accompanied by Molecular Rearrangements. Chem. Heterocycl. Compd. 2024, 60, 323–335. [Google Scholar] [CrossRef]
  61. Jasiński, R. On the Question of the Molecular Mechanism of N-Nitropyrazole Rearrangement. Chem. Heterocycl. Compd. 2020, 56, 1210–1212. [Google Scholar] [CrossRef]
  62. Klein, J.; Becker, J.Y. Metalation Reactions—XIV: The Generality of the 1,3-Sigmatropic Shift of Hydrogen in Allenyllithium Compounds. Tetrahedron 1972, 28, 5385–5392. [Google Scholar] [CrossRef]
  63. Lapczuk-Krygier, A.; Jaskowska, J.; Jasinski, R. The influence of Lewis acid catalyst on the kinetic and molecular mechanism of nitrous acid elimination from 5-nitro-3-phenyl-4,5-dihydroisoxazole: DFT computational study. Chem. Heterocycl. Compd. 2018, 54, 1172–1774. [Google Scholar] [CrossRef]
  64. Kula, K.; Kącka-Zych, A.; Łapczuk-Krygier, A.; Jasiński, R. Analysis of the possibility and molecular mechanism of carbon dioxide consumption in the Diels-Alder processes. Pure Appl. Chem. 2021, 93, 427–446. [Google Scholar] [CrossRef]
  65. Chit, T.; Morimoto, H.; Andres, H. Preparation, NMR characterization, and labeling reactions of tritiated borane-THF complex and high specific radioactivity. J. Org. Chem. 1995, 60, 7503–7507. [Google Scholar] [CrossRef]
  66. Wrackmeyer, B.; Schwarze, B. Reaction of borane in tetrahydrofuran with 1,1,3,3-tetramethyldisilazane and cyclic disilazanes—Competition between N–Si and N–H bond cleavage. Z. Naturforsch. B 1996, 51, 1707–1715. [Google Scholar] [CrossRef]
  67. Todd, R.C.; Hossain, M.; Josyula, K.V.; Gao, P.; Kuo, J.; Tan, C.T. New amine-stabilized deuterated borane–tetrahydrofuran complex (BD3–THF): Convenient reagent for deuterium incorporations. Tetrahedron Lett. 2007, 48, 2335–2337. [Google Scholar] [CrossRef]
  68. Yoon, N.M.; Pak, C.S.; Krishnamurthy, S.; Stocky, T.P. Selective reductions. XIX. Rapid reaction of carboxylic acids with borane-tetrahydrofuran. Remarkably convenient procedure for the selective conversion of carboxylic acids to the corresponding alcohols in the presence of other functional groups. J. Org. Chem. 1973, 38, 2786–2792. [Google Scholar] [CrossRef]
  69. Gonzales, J.M.; Cox, R.S.; Brown, S.T.; Allen, W.D.; Schaefer, H.F. Assessment of Density Functional Theory for Model SN2 Reactions: CH3X + F− (X = F, Cl, CN, OH, SH, NH2, PH2). J. Phys. Chem. A 2001, 105, 11327–11346. [Google Scholar] [CrossRef]
  70. Capurso, M.; Gette, R.; Radivoy, G.; Dorn, V. The Sn2 Reaction: A Theoretical-Computational Analysis of a Simple and Very Interesting Mechanism. Proceedings 2019, 41, 81. [Google Scholar] [CrossRef]
  71. Morán-González, L.; Besora, M.; Maseras, F. Seeking the Optimal Descriptor for SN2 Reactions through Statistical Analysis of Density Functional Theory Results. J. Org. Chem. 2022, 87, 363–372. [Google Scholar] [CrossRef] [PubMed]
  72. Demchuk, O.M.; Jasinski, R.; Strzelecka, D.; Dziuba, K.; Kula, K.; Chrzanowski, J. A Clean and Simple Method for Deprotection of Phosphines from Borane Complexes. Pure Appl. Chem. 2018, 90, 49–62. [Google Scholar] [CrossRef]
  73. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Petersson, G.A.; Nakatsuji, H.; et al. Gaussian 16, Revision C.01; Fox, Gaussian, Inc.: Wallingford, CT, USA, 2016. [Google Scholar]
  74. Pritchard, B.P.; Altarawy, D.; Didier, B.; Gibson, T.D.; Windus, T.L. A New Basis Set Exchange: An Open, Up-to-date Resource for the Molecular Sciences Community. J. Chem. Inf. Model. 2019, 59, 4814–4820. [Google Scholar] [CrossRef]
  75. Łapczuk, A.; Rios-Gutierrez, M. Mechanistic aspects of the [3+2] cycloaddition reaction of the trifluroacetonitrile with diarylnitrilimines in the light of the MEDT quantum chemical study. Molecules 2025, 30, 2410. [Google Scholar] [CrossRef]
  76. Woliński, P.; Zawadzińska-Wrochniak, K.; Dresler, E.; Jasiński, R. On the Question of the Course of the Hetero Diels–Alder Reactions Between N-(2,2,2-Trichloroethylidene)Carboxamides and Dicyclohexylcarbodiimide: A New Case of the Stepwise Zwitterionic Cycloaddition Process. Molecules 2025, 30, 2692. [Google Scholar] [CrossRef]
  77. Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. Energies, Structures, and Electronic Properties of Molecules in Solution with the C-PCM Solvation Model. J. Comput. Chem. 2003, 24, 669–681. [Google Scholar] [CrossRef]
  78. Domingo, L.R. A new C–C bond formation model based on the quantum chemical topology of electron density. RSC Adv. 2014, 4, 32415–32428. [Google Scholar] [CrossRef]
  79. Domingo, L.R.; Aurell, M.J.; Pérez, P.; Contreras, R. Quantitative Characterization of the Global Electrophilicity Power of Common Diene/Dienophile Pairs in Diels–Alder Reactions. Tetrahedron 2002, 58, 4417–4423. [Google Scholar] [CrossRef]
  80. Parr, R.G.; Szentpály, L.; Liu, S. Electrophilicity Index. J. Am. Chem. Soc. 1999, 121, 1922–1924. [Google Scholar] [CrossRef]
  81. Domingo, L.R. 1999–2024, a Quarter Century of the Parr’s Electrophilicity ω Index. Sci. Rad. 2024, 3, 157–186. [Google Scholar] [CrossRef]
  82. Domingo, L.R.; Chamorro, E.; Pérez, P. Understanding the Reactivity of Captodative Ethylenes in Polar Cycloaddition Reactions: A Theoretical Study. J. Org. Chem. 2008, 73, 4615–4624. [Google Scholar] [CrossRef] [PubMed]
  83. Domingo, L.R.; Perez, P.; Saez, J.A. Understanding the local reactivity in polar organic reactions through electrophilic and nucleophilic Parr functions. RSC Adv. 2013, 3, 1486–1494. [Google Scholar] [CrossRef]
Ijms 26 08948 sch001
Scheme 1. Experimentally observed results of the title reaction of 2-phenylnitroethene 2 in the DCM (dichloromethane) solution.
Scheme 1. Experimentally observed results of the title reaction of 2-phenylnitroethene 2 in the DCM (dichloromethane) solution.
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Scheme 2. Theoretically possible, regio- and stereoisomeric HDA 1 + 2 cycloaddition paths.
Scheme 2. Theoretically possible, regio- and stereoisomeric HDA 1 + 2 cycloaddition paths.
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Figure 1. Enthalpy profile for the 1 + 2 HDA reaction in the DCM solution and the further deamination process according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
Figure 1. Enthalpy profile for the 1 + 2 HDA reaction in the DCM solution and the further deamination process according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
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Figure 2. Views of critical structures of paths A and B of the 1 + 2 HDA reaction in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
Figure 2. Views of critical structures of paths A and B of the 1 + 2 HDA reaction in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
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Figure 3. Views of critical structures of paths C and D of the 1 + 2 HDA reaction in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
Figure 3. Views of critical structures of paths C and D of the 1 + 2 HDA reaction in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
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Figure 4. Natural charges of significant atoms (in electrons) in the IB as computed at the ground state via ωB97X-D/6-311G(d,p) (PCM) quantum chemical calculations; charges > 0.2 e are given in red, charges < −0.2 e are given in blue. For clarity: bond order and bond lengths were neglected; insignificant parts are shown in gray and abbreviated.
Figure 4. Natural charges of significant atoms (in electrons) in the IB as computed at the ground state via ωB97X-D/6-311G(d,p) (PCM) quantum chemical calculations; charges > 0.2 e are given in red, charges < −0.2 e are given in blue. For clarity: bond order and bond lengths were neglected; insignificant parts are shown in gray and abbreviated.
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Figure 5. ELF results for IB as computed via ωB97X-D/6-311G(d,p) (PCM) calculations. To the right: topology of the ELF function, isovalue 0.75. Monosynaptic valence basins are given in red, disynaptic in green, protonated basins in cyan, and core basins in magenta. To the left: positions of ELF attractors (in magenta) and populations of significant basins. For clarity, some parts of the system are omitted.
Figure 5. ELF results for IB as computed via ωB97X-D/6-311G(d,p) (PCM) calculations. To the right: topology of the ELF function, isovalue 0.75. Monosynaptic valence basins are given in red, disynaptic in green, protonated basins in cyan, and core basins in magenta. To the left: positions of ELF attractors (in magenta) and populations of significant basins. For clarity, some parts of the system are omitted.
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Figure 6. Lewis-like structure of IB, for clarity insignificant parts are abbreviated.
Figure 6. Lewis-like structure of IB, for clarity insignificant parts are abbreviated.
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Scheme 3. The scheme of the thermal deamination of the adduct 3.
Scheme 3. The scheme of the thermal deamination of the adduct 3.
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Figure 7. Views of critical structures of reaction paths E illustrated on the Scheme 3 (deamination process) in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
Figure 7. Views of critical structures of reaction paths E illustrated on the Scheme 3 (deamination process) in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
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Figure 8. ELF results for TS1E as computed via ωB97X-D/6-311G(d,p) (PCM) calculations. To the right: topology of the ELF function, isovalue 0.75. Monosynaptic valence basins are given in red, disynaptic in green, protonated basins in cyan, and core basins in magenta. To the left: positions of ELF attractors (in magenta) and populations of significant basins. For clarity, some parts of the system are omitted.
Figure 8. ELF results for TS1E as computed via ωB97X-D/6-311G(d,p) (PCM) calculations. To the right: topology of the ELF function, isovalue 0.75. Monosynaptic valence basins are given in red, disynaptic in green, protonated basins in cyan, and core basins in magenta. To the left: positions of ELF attractors (in magenta) and populations of significant basins. For clarity, some parts of the system are omitted.
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Figure 9. Natural charges of significant atoms (in electrons) in the TS1E as computed at the ground state via ωB97X-D/6-311G(d,p) (PCM) quantum chemical calculations; charges > 0.2 e are given in red, charges < −0.2 e are given in blue. For clarity, bond order and bond lengths were neglected; insignificant parts are shown in gray and abbreviated.
Figure 9. Natural charges of significant atoms (in electrons) in the TS1E as computed at the ground state via ωB97X-D/6-311G(d,p) (PCM) quantum chemical calculations; charges > 0.2 e are given in red, charges < −0.2 e are given in blue. For clarity, bond order and bond lengths were neglected; insignificant parts are shown in gray and abbreviated.
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Figure 10. Lewis-like structure of TS1E. For clarity, insignificant parts are omitted.
Figure 10. Lewis-like structure of TS1E. For clarity, insignificant parts are omitted.
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Figure 11. ELF results for TS2E as computed via ωB97X-D/6-311G(d,p) (PCM) calculations. To the right: topology of the ELF function, isovalue 0.75. Monosynaptic valence basins are given in red, disynaptic in green, protonated basins in cyan, and core basins in magenta. To the left: positions of ELF attractors (in magenta) and populations of significant basins. For clarity, some parts of the system are omitted.
Figure 11. ELF results for TS2E as computed via ωB97X-D/6-311G(d,p) (PCM) calculations. To the right: topology of the ELF function, isovalue 0.75. Monosynaptic valence basins are given in red, disynaptic in green, protonated basins in cyan, and core basins in magenta. To the left: positions of ELF attractors (in magenta) and populations of significant basins. For clarity, some parts of the system are omitted.
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Ijms 26 08948 g012
Figure 12. Natural charges of significant atoms (in electrons) in the TS2E as computed at the ground state via ωB97X-D/6-311G(d,p) (PCM) quantum chemical calculations; charges > 0.2 e are given in red, charges < −0.2 e are given in blue. For clarity, bond order and bond lengths were neglected; insignificant parts are shown in gray and abbreviated.
Figure 12. Natural charges of significant atoms (in electrons) in the TS2E as computed at the ground state via ωB97X-D/6-311G(d,p) (PCM) quantum chemical calculations; charges > 0.2 e are given in red, charges < −0.2 e are given in blue. For clarity, bond order and bond lengths were neglected; insignificant parts are shown in gray and abbreviated.
Ijms 26 08948 g012
Ijms 26 08948 g013
Figure 13. Lewis-like structure of TS2E. For clarity, insignificant parts are omitted.
Figure 13. Lewis-like structure of TS2E. For clarity, insignificant parts are omitted.
Ijms 26 08948 g013
Ijms 26 08948 g014
Figure 14. Views of critical structures of substitution reactions on the boron atom illustrated in Scheme 4 in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
Figure 14. Views of critical structures of substitution reactions on the boron atom illustrated in Scheme 4 in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
Ijms 26 08948 g014
Ijms 26 08948 g015
Figure 15. Natural charges of significant atoms (in electrons) in the TS1G as computed at the ground state via ωB97X-D/6-311G(d,p) (PCM) quantum chemical calculations; charges > 0.2 e are given in red, charges < −0.2 e are given in blue. For clarity, bond order and bond lengths were neglected; insignificant parts are shown in gray and abbreviated. For clarity, some parts of the system are omitted.
Figure 15. Natural charges of significant atoms (in electrons) in the TS1G as computed at the ground state via ωB97X-D/6-311G(d,p) (PCM) quantum chemical calculations; charges > 0.2 e are given in red, charges < −0.2 e are given in blue. For clarity, bond order and bond lengths were neglected; insignificant parts are shown in gray and abbreviated. For clarity, some parts of the system are omitted.
Ijms 26 08948 g015
Ijms 26 08948 g016
Figure 16. ELF results for TS1G as computed via ωB97X-D/6-311G(d,p) (PCM) calculations. To the right: topology of the ELF function, isovalue 0.75, and the plot of ELF surrounding the B9 atom, at isovalue of 0.1, with led monosynaptic basin visible. Monosynaptic valence basins are given in red, disynaptic in green, protonated basins in cyan, and core basins in magenta. To the left: positions of ELF attractors (in magenta) and populations of significant basins.
Figure 16. ELF results for TS1G as computed via ωB97X-D/6-311G(d,p) (PCM) calculations. To the right: topology of the ELF function, isovalue 0.75, and the plot of ELF surrounding the B9 atom, at isovalue of 0.1, with led monosynaptic basin visible. Monosynaptic valence basins are given in red, disynaptic in green, protonated basins in cyan, and core basins in magenta. To the left: positions of ELF attractors (in magenta) and populations of significant basins.
Ijms 26 08948 g016
Ijms 26 08948 g017
Figure 17. Views of critical structures of transformation of the I1G intermediate into target product (see Scheme 4) in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
Figure 17. Views of critical structures of transformation of the I1G intermediate into target product (see Scheme 4) in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
Ijms 26 08948 g017
Table 1. Kinetic and thermodynamic parameters for the 1 + 2 HDA reaction in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations (∆H, ∆G are in kcal/mol; ∆S are in cal/molK.
Table 1. Kinetic and thermodynamic parameters for the 1 + 2 HDA reaction in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations (∆H, ∆G are in kcal/mol; ∆S are in cal/molK.
PathTransition∆H∆S∆G
A1 + 2→MCA−10.0−39.41.7
1 + 2→TS1A2.2−52.517.9
1 + 2→IA2.6−50.917.8
1 + 2→TS2A2.7−52.518.3
1 + 2→4−24.3−53.1−8.5
B1 + 2→MCB−20.3−41.6−7.9
1 + 2→TS1B−5.1−53.110.7
1 + 2→IB−3.6−52.612.0
1 + 2→TS2B−3.6−52.612.1
1 + 2→5−27.9−50.0−13.0
C1 + 2→MCC−9.6−40.82.5
1 + 2→TSC13.9−52.929.6
1 + 2→6−19.6−53.2−3.8
D1 + 2→MCD−10.6−44.92.8
1 + 2→TSD12.6−52.328.2
1 + 2→7−22.6−54.4−6.4
Table 2. Key parameters for critical structures of the 1 + 2 HDA reaction in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
Table 2. Key parameters for critical structures of the 1 + 2 HDA reaction in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations.
PathStructureInteratomic Distances [Å]GEDT [e]
S1–C2C2–C3C3–C4C4–C5C5–C6C6–S1
11.6911.4031.396
2 1.332
AMCA1.6921.4021.3973.6841.3333.665
TS1A1.7401.3631.4362.9131.4122.167−0.50
IA1.7631.3521.4492.8011.4481.985−0.66
TS2A1.7671.3461.4602.3991.4711.924−0.60
41.7731.3351.5051.5621.5281.832
BMCB1.6931.4091.3853.7621.3343.901
TS1B1.7541.3641.4242.8021.4451.987−0.48
IB1.7561.3571.4372.3621.4601.958−0.55
TS2B1.7561.3571.4372.3621.4601.958−0.55
51.7761.3351.5081.5301.5321.830
CMCC1.6891.4031.3963.2411.3303.497
TSC1.7341.3601.4392.3701.4232.071−0.40
61.7751.3331.5051.5631.5261.825
DMCD1.6891.4041.3963.4731.3333.469
TSD1.7241.3611.4382.2371.4092.172−0.31
71.7771.3331.5021.5631.5461.784
Table 3. Kinetic and thermodynamic parameters for different schemes of the deamination of 5 in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations (∆H, ∆G are in kcal/mol; ∆S are in cal/molK).
Table 3. Kinetic and thermodynamic parameters for different schemes of the deamination of 5 in the DCM solution according to ωB97XD/6-311G(d) (PCM) quantum chemical calculations (∆H, ∆G are in kcal/mol; ∆S are in cal/molK).
PathTransition∆H∆S∆G
E5→TS1E41.7−3.342.7
5→IE15.9−4.817.4
5→TS2E21.9−2.422.6
5→3 + N(H)Me221.144.77.8
FTHF·BH3 + 5→TSF5.0−43.418.0
THF·BH3 + 5→IF + THF−4.7−13.8−0.6
GTHF·BH3 + 5→TS1G8.7−39.920.6
THF·BH3 + 5→I1G + THF11.2−5.612.8
I1G→TS2G36.0−5.137.5
I1G→I2G2.0−6.03.8
I1G→TS3G13.2−1.013.4
I1G→I3G + N(H)Me219.743.46.7
THF + I3G→TS4G0.9−31.610.3
THF + I3G→3 + THF·BH3−9.76.8−11.7
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Sadowski, M.; Dresler, E.; Jasiński, R. On the Question of the Regio-Orientation, Stereo-Orientation and Molecular Mechanism in the Cascade Cycloaddition/Rearrangement/Elimination Processes Leading to Nitro-Substituted Thiopyran Analogs: DFT Computational Study. Int. J. Mol. Sci. 2025, 26, 8948. https://doi.org/10.3390/ijms26188948

AMA Style

Sadowski M, Dresler E, Jasiński R. On the Question of the Regio-Orientation, Stereo-Orientation and Molecular Mechanism in the Cascade Cycloaddition/Rearrangement/Elimination Processes Leading to Nitro-Substituted Thiopyran Analogs: DFT Computational Study. International Journal of Molecular Sciences. 2025; 26(18):8948. https://doi.org/10.3390/ijms26188948

Chicago/Turabian Style

Sadowski, Mikołaj, Ewa Dresler, and Radomir Jasiński. 2025. "On the Question of the Regio-Orientation, Stereo-Orientation and Molecular Mechanism in the Cascade Cycloaddition/Rearrangement/Elimination Processes Leading to Nitro-Substituted Thiopyran Analogs: DFT Computational Study" International Journal of Molecular Sciences 26, no. 18: 8948. https://doi.org/10.3390/ijms26188948

APA Style

Sadowski, M., Dresler, E., & Jasiński, R. (2025). On the Question of the Regio-Orientation, Stereo-Orientation and Molecular Mechanism in the Cascade Cycloaddition/Rearrangement/Elimination Processes Leading to Nitro-Substituted Thiopyran Analogs: DFT Computational Study. International Journal of Molecular Sciences, 26(18), 8948. https://doi.org/10.3390/ijms26188948

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