Theoretical analysis of mechanism, regio- and stereoselectivity of 1, 3-dipolar cycloaddition of cyclic nitrone and substituted alkenes by DFT method.

doi:10.21203/rs.3.rs-3297189/v1

Download PDF

Research Article

Theoretical analysis of mechanism, regio- and stereoselectivity of 1, 3-dipolar cycloaddition of cyclic nitrone and substituted alkenes by DFT method.

https://doi.org/10.21203/rs.3.rs-3297189/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 14 Feb, 2024

Read the published version in Structural Chemistry →

You are reading this latest preprint version

This study presents a theoretical investigation of the 1,3-dipolar cycloaddition between cyclic nitrone a1 and substituted alkene b1. The mechanism, regioselectivity, and stereoselectivity of this 13DC reaction were analyzed using transition state theory and reactivity indices obtained from conceptual density functional theory (DFT) with DFT methods at B3LYP/6-31G(d) level of theory. The results indicate that this cycloaddition reaction proceeds via a synchronous one-step mechanism, exhibiting a non-polar nature and significant activation energies. These theoretical results are in agreement with the experimental observations. Moreover, topological analyses such as ESP, RDG-NCI, and ELF were employed to determine active sites, distinguish hydrogen bonds, van der Waals interactions, and steric repulsive interactions, and predict electron localization, respectively.

cycloaddition

regioselectivity

reactivity indices

DFT calculations

Topological analysis

The 1,3-dipolar cycloaddition (13DC) reaction has been extensively employed in synthesizing five-membered heterocyclic compounds [1]. Nitrones, a highly reactive group of reagents, readily partake in 13DC with various dipolarophiles, particularly alkenes, leading to the formation of significant isoxazolidines in excellent yields (Scheme 1) [2]. These cycloadducts have drawn significant attention owing to their potential biological effects. They can serve as precursors of b-amino alcohols through reductive cleavage of the N-O bond. Furthermore, they hold promise as crucial building blocks for synthesizing numerous natural products, including b-lactam antibiotics, alkaloids, as well as sugar and nucleoside analogs [3, 4]. Isoxazolidines possess medicinal properties such as anticonvulsant, antibacterial, antitubercular, antibiotic, and antifungal activities [4].

Over the past two decades, significant attention has been directed towards conducting asymmetric 1,3-dipolar cycloaddition reactions. These reactions have been achieved through the utilization of chiral nitrones [5], chiral olefins [6], and catalytic conditions involving Lewis acid complexes [7]. Through an analysis of the nitrone cycloaddition reaction, it has been observed that the introduction of new chiral centers can be influenced by thoughtfully designing the reaction system, thereby enabling precise control over regio- and stereoselectivity.

The intriguing characteristics of the 13DC reactions are primarily related to the regioselectivity of the products they produce. To determine the most probable pathway for a particular reaction, several approaches have been utilized. Among them, transition state theory is a widely used method to investigate reaction mechanisms and pinpoint the pathway that exhibits the least activation energy barrier. Various computational investigations have also been carried out on the interaction between nitrones and nitrile oxides with diverse dipolarophiles, possessing either electron-rich or electron-deficient attributes [8–9].

Another approach that can be employed to investigate the regioselectivity of reactions and gain insights into chemical reactivity differences is the Frontier Molecular Orbital Model (FMO) [10–11]. Recently, Nacereddine and colleagues [12] conducted a theoretical study utilizing FMO analysis to determine the regioselectivity of reactions involving a nitrone derivative and substituted alkenes. The FMO analysis revealed that the substituted alkenes can display both electrophilic and nucleophilic behavior, depending on their specific nature. Furthermore, other reactivity descriptors such as Fukui indices, local softness, and local philicity have been utilized to predict regioselectivity and elucidate variations in reactivity for particular reactions [13–14].

The primary objective of our research was to explore the theoretical approaches related to the 13DC reaction. Specifically, our focus was on investigating the reaction between cyclic nitrone a1 as the dipole and substituted alkene b1 as the dipolarophile, which leads to the formation of isoxazolidine c1, as depicted in Scheme 2 [15]. Our study aimed to gain a better understanding of the factors influencing the regio- and stereoselectivity in the 13DC reaction, while also delving into the underlying molecular mechanism involved in this process. To achieve this, we utilized topological analyses such as ESP (Electrostatic Potential), RDG-NCI (Reduced Density Gradient - Non-Covalent Interactions), and ELF (Electron Localization Function). These analyses allowed us to identify active sites, distinguish between different types of interactions like hydrogen bonds, van der Waals forces, and steric repulsions, and make predictions regarding electron localization within the reacting system.

In this study, all the calculations were carried out using the GAUSSIAN09 program [16]. To optimize the geometries of reactants, products, and transition states, density functional theory (DFT) methods were employed at the B3LYP/6-31G(d) level [17]. Frequency calculations were performed to characterize the stationary points and verify that the transition states possessed a single imaginary frequency, as expected. To confirm the connectivity between each saddle point and the two associated minima, intrinsic reaction coordinate (IRC) calculations were conducted in both the forward and backward directions [18]. These IRC calculations utilized the second-order González-Schlegel integration method [19–20]. For further analysis of the electronic structures of the stationary points, the Natural Bond Orbital (NBO) method was employed [21]. This comprehensive approach allowed us to gain valuable insights into the intricate details of the reaction pathways and the electronic properties of the involved species.

To account for the solvent effects of toluene, single-point energy calculations were carried out by optimizing the gas-phase structures at the B3LYP/6-31G(d) computational level. To include the influence of the solvent, the polarizable continuum model (PCM) developed by Tomasi's group was employed [22].

The global electrophilicity index (ω) is determined using the equation: ω = (µ2/2η) [23]. To calculate ω, we need to approximate the chemical hardness (η) and the electronic

chemical potential (µ) in terms of the one-electron energies of the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO), denoted as εHOMO and εLUMO, respectively. The chemical hardness (η) can be estimated as η ≈ εLUMO - εHOMO, representing the energy difference between the LUMO and HOMO orbitals, which gives us a measure of the system's resistance to electron exchange or polarization [24]. Similarly, the electronic chemical potential (µ) can be approximated as µ ≈ (εHOMO + εLUMO)/2, which represents the average energy of the HOMO and LUMO orbitals and provides insights into the system's ability to donate or accept electrons [24]. The relative nucleophilicity index (N) is determined based on the energies of HOMO within the Kohn-Sham scheme [25]. It can be defined as: N = EHOMO(Nu) - EHOMO(TCE), where TCE (tetracyanoethylene) is chosen as the reference due to its lowest HOMO energy [26]. In this study, the local indexes are computed in atomic condensed form, following the usual form [27]. The well-known Fukui function [28–29] for electrophilic attack (fk⁻) and nucleophilic attack (fk⁺) are utilized and can be expressed as follows:

f_k^– = [qk(N) – qk(N– 1)]

f_k⁺ = [qk(N + 1) – qk(N)]

The electronic population of site k in neutral, cationic, and anionic systems is represented by qk(N), qk(N – 1), and qk(N + 1) correspondingly. To determine the local electrophilicity, ωk, and nucleophilicity index, Nk, at atom k, one can easily calculate them by projecting the global electrophilic and nucleophilic Fukui function (f_k⁺_, f_k^– ) onto the specific atomic center k within the molecule. Hence, we can express ωk as ω fk + and Nk as N fk–, respectively [28–30].

The most effective approach to elucidate the reaction mechanism, particularly during electrophilic and nucleophilic attacks, is through the study of electronic surface behavior. A key aspect of this investigation involves the identification and confirmation of the transition state formed. In this study, TS1 was characterized using various methods, including ESP or MEP (molecular electrostatic potential), reduced density gradient/non-covalent interaction (RDG/NCI), and electron localization function (ELF). To conduct these topological calculations, the researchers utilized MultiWfn software [31] in combination with the VMD program [32].

In our research, our main objective is to offer a theoretical basis for the observed regioselectivity and stereoselectivity of the nitrone (a1) and alkene (b1) reaction depicted in Scheme 2. To accomplish this goal, we utilize various theoretical approaches, which include determining activation energies, employing the frontier molecular orbital (FMO) theory, and using reactivity indices derived from conceptual density functional theory (DFT). It is essential to emphasize that the reaction being studied is kinetically controlled, indicating that the final outcome of the reaction is governed by the relative activation energies of the different competing reaction pathways.

3.1. Prediction of NED/IED character

To clarify the NED (Normal Electron Demand) or RED (Reverse Electron Demand) characters of the cycloaddition reactions between the nitrone and a olefin, we calculated: the HOMO/LUMO gap energies for the two possible combinations between the dipole and the dipolarophile, the chemical electron potential µ, the electrophilicity index ω, and the nucleophilicity index (N) (see table.2). Table 2 shows that the gaps of the energies corresponding to the HOMO (dipole)/LUMO (dipolarophile) combination (7.30 eV) between dipole (a1) and the dipolarophile (b1) is greater than this corresponding to the HOMO (dipolarophile)/LUMO (dipole) combination (5.08 eV) (see Fig. 1). In other hand, the alkene has the lowest electrophilicity index (ω = 0.57) and the highest electronic potential (µ = -0.110) compared to the dipole (ω = 1.66, µ = -0.148). These results indicat that the dipolarophile (alkene) behave as an electron donor and dipole (nitrone) as an electron acceptor. Therefore, the 13DC reaction carry a RED (reverse electron demand) character. It can be seen that the alkene act as a nucleophile while nitrone acts as an electrophile. Therefore, the charge transfer on this reaction will take place from the alkene to the nitrone, in complete agreement with the calculated charge transfer analysis at TSs (see later).

Table 1

Border orbital energies ( HOMO /LUMO) and global properties of dipole (**a1)** and dipolarophile (**b1)** .
	HOMO	LUMO	µ	η	ω	DNmax	N
a1	-0,2378	-0,0581	-0,1480	0,1797	1,66	0,824	2,65
b1	-0,2452	0,0307	-0,1073	0,2759	0,57	0,389	2,45

3.2. Prediction and rationalization of experimental regioselectivity

In order to predict and rationalize the experimentally observed regioselectivity of the 13DC reaction between nitrone 1 and alkene 2 we used two theoretical approaches :

a- Activation energy calculations

The interaction between nitrone 1a and alkene 2a at the 13DC reaction can result in four isomeric structures, as depicted in Scheme 2. To investigate the 13DC reaction, Density Functional Theory (DFT) is employed. We present a computational analysis of the regioselectivity and stereoselectivity of the nitrone 1a (dipole) cycloaddition to alkene 2a (dipolarophile). Our primary objective is to calculate the energy barrier for the 13DC reaction. In these computations, the B3LYP/6-31G* method is utilized with toluene as the solvent. Figure 2 displays the transition states corresponding to the two cyclization modes, 1.3 and 2.3. The activation energy of TS1 (17.46 kcal/mol) is lower than that of TS2 (18.01 kcal/mol) when the spatial position of the R₂ = CH₂OH group is in backwar. Similarly, the activation energie for TS₃ (19.09 kcal/mol) is lower than that of TS₄ (20.15 kcal/mol) when the spatial position of the group R₂ = CH₂OH is in the forward (see Scheme 3). These results demonstrate that the regioisomers 1.3 are more kinetically favored than the regioisomers 1.4. Our results are in complete agreement with experimental.

Based on the information provided in Table 2, we observe that in this reaction, the cycloadduct CA1 (-25.38 kcal/mol) is thermodynamically more stabilized compared to the contributions of cycloadducts CA2 (-21 kcal/mol), CA3 (-24.73 kcal/mol), and CA4 (-24.25 kcal/mol), respectively. Consequently, we obtain only one cycloadduct observed experimentally.

Table 2

B3LYP/6-31G(d) relative energies (in kcal mol^− 1) for the reactants ,TSs and CAs involved in the 13DC between nitrone 1a and alkene 2a in vacuu, and solvent (toluene).
	E(u.a) in vacuum	E(u.a) in solv	∆E (kcal/mol)	∆E ( kcal/mol) In solv
a1 b1 TS₁ TS₂ TS₃ TS₄ CA₁ CA₂ CA₃ CA₄	-768.527882 -193.108433 -961.609358 -961.609594 -961.606878 -961.606886 -961.678890 -961.671264 -961.677899 -961.677942	-768.533365 -193.111633 -961.617172 -961.616293 -961.614571 -961.612887 -961.685445 -961.678480 -961.684403 -961.683644	-- -- 16.915 16.767 18.471 18.466 -21.27 -16.48 -20.64 -20.67	-- -- 17.46 18.01 19.09 20.15 -25.38 -21.00 -24.73 -24.25

When examining the reaction between nitrone a1 and alkene a2, the lengths of the newly formed bonds, C1-C3 and C2-O, in the 1.3 approach (TS1) are 2.11 and 2.17 Å, respectively. Conversely, in the 2.3 approach (TS2), the lengths of the newly formed bonds, C1-O and C2-C3, are 2.11 and 2.09 Å, respectively (see Fig. 2). The lengths of the new bonds formed, C1-C3 and C2-O are 2.082 and 2.168 Å in the 1.3 approach (TS3), while the lengths of the new bonds formed, C1-O and C2-C3, are are 2.082 and 2.074 Å in the 2.3 approach (TS4). Analysis of the geometries at the TS structures given in Fig. 2 shows that the asynchronous bond formation processe for TS₁(TS₃) is greater compared to that of TS₂(TS₄).

The concept of bond order (BO) [10] provides a valuable tool for conducting a thorough analysis of the degree of bond formation or breakage throughout a reaction pathway. This theoretical approach has proven effective in studying the molecular mechanism of chemical reactions. The evaluated bond order of C1-C3 and O-C2 bonds that form

bonds at transition states are: 0.414 and 0.321 for TS₁ and 0.4389 and 0.3337 for TS₃. The evaluated bond order of C2-C3 and O-C1 bonds that form bonds at transition states are: 0.1796 and 0.3679 for TS₂ and 0.4193 and 0.3855 for TS₄, respectively. Therefore, the asynchronous process of C1-C3 bond formation is more advanced than the O-C2 bond for the TS₁ and TS₃. While, the asynchronous process of O-C1 bond formation is more advanced than the C2-C3 bond for the TS₂. In opposite, the asynchronous process of C2-C3 bond formation is more advanced than the O-C1 bond for the TS₄. These results show that this reaction follows an asynchronous concerted mechanism.

The analysis of the electronic properties of this 13DC reaction revealed that the transition state involved the sharing of atomic charges between the dipole 1a and the alkene a2 (see Fig. 2). In the solvent toluene, the charge transfer (CT) in the transitions states, which fluxes from the dipolarophile a2 to the dipole 1a are 0.075, 0.075, 0.075 and 0.075 for TS₁, TS₂, TS₃ and TS₄, respectively, Indicating the non-polar nature of this 13DC reaction.

b- Analysis based on local properties.

Domingo proposed a model in 2009 [11] where the formation of a chemical bond is determined by the favorable interaction between an electrophile and a nucleophile. Specifically, the electrophile's most electrophilic site (identified by the highest ω_k value) interacts with the nucleophile's most nucleophilic site (identified by the highest N_k value). Figure 3 provides the values of local electrophilicity indices ωk for the O and C3 sites of the dipole, and local nucleophilicity indices N_k for the C1 and C2 sites of the dipolarophile. According to population analysis, the preferred interaction occurs between the C1 site of the alkene and the C3 site of the dipole to give the product a3(1). The analysis based on local properties indicates that regioisomer 1 is more favorable than regioisomer 2. This result is in agreement with the analyses shown by activation barrier calculations.

3.3. Tobologicals analyses

a-Electrostatic Potential (ESP) Analysis

ESP is a potent topological colored map with a variety of active electronic sites in the structural system. The results of this analysis were summarized in Fig. 4 for TS1 of the studied reaction. As the electrostatic potential assigned high electronic density in the blue surface regions, this refers to less tightly located electrons. Additionally, the electronic density was postulated as high to form as rich electronic regions, so these sites can react with electrophiles (nucleophilic attack of O1 on C2). This fact may be attributed to a significant electron withdrawal effect of methylol (CH₂OH) substituent, leaving a partial positive charge on C2 reactive site. Based on the ESP map, the most nucleophilic active sites represented in oxygen attached to nitrogen in the five membered ring reactant (a1). The red regions represent the poor-electronic sites appeared in other regions over the system.

b-Reduced Density Gradient / Non-Covalent Interaction (RDG-NCI) analysis

Some important non covalent interactions were generated by the aid of RDG technique accompanied with specified color codes [31]. Figure 5 shows RDG dramatic color change over the system according to sign(λ₂) ρ index, where the green spikes describe VdW electrostatic interaction and red spike refers to strong repulsion interactions. H-bond formation is a current state support the stability of generated transition state. Some H-bond character appeared at in the interaction centers. The presence of a significant repulsion interaction in the reactive region indicating delocalization of electronic density emerged from the two reactive parts. This fact mainly is due to other substituents like non-interactive O of (a1) and CH₂OH of b1 visualized in Fig. 5a. The spikes appeared in Fig. 5b based on the type of interaction present in the system is mentioned above.

c- Electron localization function

Other supported analysis describing the main path of reaction mechanism, is ELF. This type can predict the electron localized areas on the system surface and then specify the nature of the bond between atoms. Figure 6 Displays two planes (N-C3-C1 and N-O1-C2) of 2D surface map for the formed TS1. As the plane is generated with specifying three successive atoms, the map shows a significant variation in electron localization density with a characteristic color code [32] around the studied 3 atoms plane. In Fig. 3a, the electronic density around the interactive centers, C3 and C1, nearly negligible as the electronic red color parts distributed away from the main centers. While in Fig. 3b, the electronic density less deformed and significantly localized O1 and directed to C2. This discussion confirmed the initial nucleophilic attack step of the partially negative O1 on the partially positive C2.

In this work, we have investigated theoretically the regio- ans stereoselectivities of the 1,3-dipolar cycloaddition of nitrone a1 with the substituted alkene. a2. For the theoretical investigation, we have performed a computational study of the mechanism and the regio- and stereoselectivities of this reaction using DFT methods at the B3LYP/6-31G(d) theoretical level. The principal conclusions that can be deduced from our results are as follows:

Our results demonstrate that the 1,3-dipolar cycloaddition reaction between nitrone a1 and the substituted alkene a2 exhibit high regioselectivity and stereoselectivity (specifically, pathway 1.3). This selectivity leads kinetically and thermodynamically to the formation of a single cycloadduct a3 (1), which is in excellent agreement with experimental observations.

The examination of CT and geometries of transition states TSs reveals that the 13DC reaction occurs through a non-polar synchronous mechanism between nitrone 1a and alkene 2a. This is due to the nucleophilic nature of both reagents.

Analysis of the DFT reactivity indices at the ground state of the reagents involved in this 13DC reaction indicates that alkene a2 is a nucleophile and bitrone a1 is a electrophile .in complete agreement with the calculated charge transfer analysis at TSs.

The utilization of the Fukui functions method to analyze local reactivity indices accurately predicts the regioselectivity observed experimentally, in accordance with the results obtained from activation energy calculations.

ESP, RDG-NCI and ELF analyses were used to determine the active sites, distinguish hydrogen bonds, van der Waals interactions and steric repulsive interactions, and predict the electron localized areas on the system surface and then specify the nature of the bond between atoms, respectively.

Acknowledgements This work was supported by the Ministry of Higher Education and Scientic Research of the Algerian Government [project PRFU Code: B00L01UN280120230003].

Author contributions The author wrote the main manuscript text.

Funding Not Applicable

Conflict of interest The author declares that there are no conflicts of interest regarding the publication of this paper.

(a) Tufariello J J, (1984) In 1, 3-Dipolar Cycloaddition Chemistry, ed. A Padwa, John Wiley & Sons, New York (b) Torssell K B G (1988) In Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis. VCH, New York (c) Jones R CF, Martin J N (2002) The Chemistry of Heterocyclic Compounds. In Synthetic Applications of 1, 3- Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products. John Wiley & Sons, New York
(a) Frederickson M (1997) Tetrahedron 53: 403–425 (b) Gothelf K V , Jorgensen K A (1998) Chem.Rev 98: 863–909
Seerden J PG, Boeren M M M , Scheeren HW(1997) Tetrahedron 53: 11843
(a) Patterson W, Cheung PS , Ernest MJ (1992) J. Med. Chem 35: 507 (b) Wagner E, Becan L, Nowakowska E (2004) Med. Chem 12: 265
(a) Broggini G, Folcio F, Sardone N, Sonzogni M, Zecchi G (1996) Tetrahedron:Asymmetry 7: 797 (b) Van den Broek LAGM (1996) Tetrahedron 52:4467 (c) Brandi A, Cicchi S, Goti A(1994) Org. Chem 59: 131 (d) Mukai C, Kim IJ, Cho WJ, Kido M, Hanaoka MJ (1993) J. Chem. Soc Perkin Trans: 2495
(a) Ina H, Ito M, Kibayashi C (1996) J. Org. Chem 61:1023 (b) Panfil L, Belzecki C, Urbanczyk-Lipowska Z,Chmielewski M (1991) Tetrahedron 47:10087 (c) Xiang Y, Schinazi RF, Zhao K(1996) Bioorg. Med. Chem. Lett 6:1475 (d) Krol WJ, Mao SS, Steele DL, Townsend CA (1991) J. Org. Chem 56:728 (e) Naito T, Ikai M, Shirakawa M, Fujimoto K, Ninomiya I, Kiguchi T (1994) J. Chem. Soc Perkin Trans :773 (f) Ito M, Maeda M, Kibayashi C (1992) Tetrahedron Lett 33:3765.
(a) Gothelf KV, Jensen KB, Jørgensen KA (1999) Science Progress 82: 327 (b) Gothelf KV, Jørgensen KA (1996) Acta. Chem. Scand 50:652 (c) Gothelf KV, Jørgensen KA (2000) J. Chem. Soc, Chem. Commun 16: 1449
Zhao H, Li X, Ran X, Zhang W (2004) J. Mol. Struct 683:207-213
Merino P, Revuelta J, Tejero T, Chiacchio U, Rescifina A, Romeo G (2003) Tetrahedron 59: 3581-5392.
Fleming I (1976) Frontiers Orbitals and Organic Chemical Reactions.Wiley, London.
Houk KN (1975) Acc. Chem. Res 8:361-369
Nacereddine AK,Yahia W, Bouacha S, Djerourou A (2010) Tetrahedron Lett 51:2617-2621
Kang KH, Pae AN, Choi KI, Cho YS, Chung BY, Lee JE, Jung SH, Koh HY, Lee HY (2001) Tetrahedron Lett 42:1057-1060
Chen S, Ren J, Wang Z (2009) Tetrahedron 65; 9146-9151
Habib M, Hassiba C, Asma M, Mejdi S, Kaïss A, Rui MVA, Ali B, Lotfi A, Boulbaba S (2018) Applied Biochemistry and Biotechnology
Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Peralta Jr JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox D, (2009) Gaussian 09, Gaussian, Wallingford, CT
Schlegel HB (1982) J. Comput. Chem 3:214–218
Gordon M H, Pople JA (1988) J. Chem. Phys 89:5777–5786
Gonzalez C, Schlegel HB (1990) J. Phys. Chem 94:5523–5527
Gonzalez C, Schlegel HB (1991) J. Chem. Phys: 95, 5853–5860
(a) Reed AE, Weinstock RB, Weinhold F (1985) J. Chem. Phys 83:735–746 (b) Reed AE, Curtiss LA, Weinhold F (1988) Chem. Rev 88: 899–926
(a) Cances E, Mennucci B, Tomasi J (1997) J. Chem. Phys 107:3032–3041 (b) Cossi M, Barone V, Cammi R, Tomasi J (1996) Chem Phys. Lett 255:327–335 (c) Barone V, Cossi M, Tomasi J (1998) J. Comput. Chem 19:404–417
Parr RG, Szentpaly LV, Liu S (1999) J. Am. Chem. Soc 121:1922.
(a) Parr RG, Pearson RG (1983) J. Am. Chem. Soc 105:7512 (b) Parr RG, Yang W(1989) Density Functional Theory of Atoms and Molecules, Oxford University Press, New York
Kohn W, Sham LJ (1965) Phys. Rev 140:1133
Domingo LR, Perez P (2008) J. Org. Chem 73:4615– 2446
Yang W, Mortier WJ (1989) Am. Chem. Soc 108:5708–5711
Fukui K(1982) Science 218:747–750
Parr R G, Yang W(1985) J. Am. Chem. Soc 106:4049– 4050
Domingo LR, Aurell MJ, Perez P (2002) J. Phys. Chem 106:6871–6875
Lu T, Chen F (2012) Multiwfn: A multifunctional wavefunction analyzer 5:33
Humphrey W, A Dalke, Schulten K (1996) J. Molec. Graphics 14: 33-38

Schemes 1 to 3 are available in the Supplementary Files section

No competing interests reported.

Scheme1.png
Scheme 1. Synthesis of isoxazolidines by 13DC reaction of nitrones with alkenes substituted.
Scheme2.png
Scheme 2. Experimental results of the 1, 3-Dipolar cycloaddition reaction between cyclic nitrone (a1) and alkene (b1) for Synthesis of enantiopures isoxazolidines.
Scheme3.png
Scheme 3 . Energy profiles, in kcal/mol of the 13DC reaction between nitrone a1 and alkene b1.

Download PDF

Journal Publication

published 14 Feb, 2024

Read the published version in Structural Chemistry →

Editorial decision: Major revision
25 Sep, 2023
Reviews received at journal
02 Sep, 2023
Reviewers agreed at journal
29 Aug, 2023
Reviewers invited by journal
29 Aug, 2023
Editor assigned by journal
28 Aug, 2023
Submission checks completed at journal
28 Aug, 2023
First submitted to journal
25 Aug, 2023

You are reading this latest preprint version

Theoretical analysis of mechanism, regio- and stereoselectivity of 1, 3-dipolar cycloaddition of cyclic nitrone and substituted alkenes by DFT method.

Status:

Journal Publication

Version 1

Abstract

Figures

1 Introduction

2 Computational details

3 Results and discussion

3.1. Prediction of NED/IED character

3.2. Prediction and rationalization of experimental regioselectivity

3.3. Tobologicals analyses

4 Conclusions

Declarations

References

Schemes

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1