Can an n(O) â Ï* Interaction Provide Thermodynamic Stability to

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Can an n(O)#pi* Interaction Provide Thermodynamic Stability to Naturally Occurring Cephalosporolides? Jacinto Sandoval-Lira, Juan M Solano-Altamirano, Omar Cortezano-Arellano, Silvano CruzGregorio, Rosa L Meza-León, Julio Manuel Hernández-Pérez, and Fernando Sartillo-Piscil J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03116 • Publication Date (Web): 16 Jan 2019 Downloaded from http://pubs.acs.org on January 16, 2019

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The Journal of Organic Chemistry

Can an n(O)→* Interaction Provide Thermodynamic Stability to Naturally Occurring Cephalosporolides? Jacinto Sandoval-Lira,†‡ Juan. M. Solano-Altamirano,† Omar Cortezano-Arellano,† Silvano CruzGregorio,† Rosa L. Meza-León, Julio M. Hernández-Pérez,†* and Fernando Sartillo-Piscil.†* †Centro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq. San Claudio, Col. San Manuel, 72570, Puebla, México. ‡ Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM. Personal de la UNAM. Carretera Km. 14.5, Unidad San Cayetano, Toluca - Atlacomulco, 50200 Toluca de Lerdo, México *To

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KEYWORDS: Nonanomeric interaction, cephalosporolides, NBO analysis, MP2

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Abstract: The stereo-controlled synthesis of naturally occurring products containing a 5,5-spiroketal molecular structure represent a major synthetic problem. Moreover, in a previous work, the stereocontrolled synthesis of cephalosporolide E (ceph E), which presumably was obtained from its epimer congener (ceph F) through an acid-mediated equilibration process, was reported. Consequently, we performed a theoretical investigation to provide relevant information regarding the title question, and it was found that the higher thermodynamic stability of ceph E, relative to ceph F, is caused by an n→* interaction between a lone electron pair of the oxygen atom of the spiroketal ring (nO) and the antibonding orbital of the carbonyl group (*C=O). Although similar stereoelectronic interactions have been disclosed in other molecular structures, its presence in ceph E, and very likely in other related naturally occurring products, represents a novel nonanomeric stabilizing effect that should be introduced in the chemistry scene.


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INTRODUCTION Unlike 6,6-spiroketal compounds, 5,5-spiroketals are not preferentially stabilized by the so-called the anomeric effect, which is an n→* interaction occurring between the lone pairs of the oxygen atom and the antibonding orbital, *, of the C−O bond [see Figure 1(a)].1 Consequently, it is common to find naturally occurring and synthetic 5,5-spiroketal compounds, both in nature and in the reaction flask as unpredictable epimeric mixtures at the spiroketal center. 2 The absence of the anomeric effects in 5,5spiroketals seems logical, because in these compounds, the C−O bond does not reach a perfect axial orientation, which is required for this stereoelectronic interaction to occur. 3 Nevertheless, it has been established that nonanomeric interactions, such as steric repulsions, intramolecular hydrogen bonding, and coordination to a metal cation [Figures 1(b)-1(d)], can dictate the conformation or the stereocontrolled formation of 5,5-spiroketal compounds.1,4 Therefore, whenever a stereo-controlled construction of a 5,5-spiroketal carbon is observed, one cannot help but seek for the origins of this rather rareness. Figure 1. (a) The anomeric effect, and (b)-(d) nonanomeric stabilizing or destabilizing factors in 5,5spiroketal compounds

In 2015, the group of Sartillo-Piscil reported the total synthesis of ceph E through a late-stage tandem radical/polar cyclization reaction from an N-phthalimide precursor 1 to the radical cation 2 (Scheme 1).5 Although the retrosynthetic plan was originally conceived to accomplish the total synthesis of ceph F, the reaction conditions employed in the last-step, together with the intrinsic nature of both ceph E and


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ceph F, led to the unexpectedly complete isolation of ceph E via the transient formation of ceph F (Scheme 1). This highly diastereoselective reaction represented the first example of a direct stereocontrolled construction of a 5,5-spiroketal center without the use of the common nonanomeric approaches showcased in Figures 1(b) to 1(d).6 Additionally, it was intuitively postulated that ceph E was the thermodynamic product, although no further information was revealed. Scheme 1. The tandem radical/polar crossover reaction used to obtain cephalosporololide E (ceph E) via the transient formation of ceph F.5

Consequently, in the present work we provide theoretical evidence regarding a novel nonanomeric stabilizing, which appears to be responsible for the thermodynamic stabilization of the naturally occurring ceph E, and very likely for other related naturally occurring cephalosporolides.

RESULTS AND DISCUSSION A simple structural analysis of the acid-catalyzed epimerization (Scheme 2) suggests that steric interactions, stemming from the cis-fused -lactone, should preclude the formation of ceph E (i.e. ceph F should be the major product). However, this is not observed, hence another force should be driving the reaction outcome, which should to be strong enough to overcome such steric repulsion. Consequently, we postulate that the origin of the ceph E stability is found in the n→* electronic interaction that occurs between the spiroketal oxygen, nO(12), and the carbonyl group, *(C2) (Figure 2). Similar n→* interactions, which are generically defined as orbital donor-acceptor interactions involving a nucleophilic atom and a carbonyl group, have been observed in several molecules.7-12 These interactions are believed to be the origin of diverse phenomena, such as chirality induction, 7a reduction ACS Paragon Plus Environment

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of electrophilicity of the acceptor carbonyl group,7b and stereoselectivity.7c Additionally, the presence of this interaction directs the conformational preference of substituted 2-(dimethylamino)biphenyl-2′carboxaldehydes,8 and confers structural stability to proteins.9-11 Figure 2. Putative n→* electronic interaction as the major contributor to the stability of cephalosporolide E

Scheme 2. The acid-catalyzed equilibration of cephalosporolides E (Ceph E) and F (Ceph F)

In what follows, we provide the theoretical evidence that supports the existence of this non-covalent n→* interaction and confirms that is directly involved in the thermodynamic stabilization of a natural occurring 5,5-spiroketal product, and much likely in further related compounds. Thermodynamic stability Our theoretical study begins by computing the energy profile of the acid-catalyzed conversion from ceph F to ceph E via A

B equilibrium (Scheme 2). To this end, we rotated the dihedral angle , ACS Paragon Plus Environment

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defined by C6, C7, C9, and C10 atoms using 15 degrees steps. Structure A was taken as the initial geometry, and  was increased until the aliphatic chain (which is attached to the oxocarbenium ion and is initially located at the opposite side of the lactone ring of A, see Figure 3) performs a complete rotation. Partial geometry optimizations and zero-point energy (ZPE) corrections were performed at every step. Figure 3. Rotational energy profile of the A

In Figure 3, the energy profile of the A

B equilibrium (see also the lower row of Scheme 2)

B equilibrium is showed. Here, empty points indicate steps

wherein partial optimizations were computed. Solid red points highlight the four critical points, which were obtained by performing complete optimizations taking the closest geometry (i.e. the closest empty dot) as the starting geometry. 3D Representations depict the optimized geometries that correspond to each one of these critical points. Of the latter, the two minima are associated to oxocarbenium ions A and B, and the two maxima are related to the transition states TS1 and TS2. Table 1 lists the specific dihedral angles, at which the critical points occur, and their energies, relative to the intermediate B (which is the global minimum).


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Table 1. Energies and dihedral angles of the fully optimized critical points TS1, A, TS2, and B Critical

TS1

A

TS2

B

-140.5

-51.5

19.4

134.4

14.70

3.22

9.47

0.0

Point Dihedral angle,  (Degrees) Energy (kcal/mol)

From Figure 3 and Table 1 one can remark the following. Intermediates A and B are indeed minimum energy conformers and are more stable than other geometries where the aliphatic chain is farther from the oxocarbenium ring. Even though at first sight, the conformer B appears to have a high steric hindrance, it is in fact more stable than conformer A by 3.22 kcal/mol. Moreover, the energy barrier from A to B is of 6.25 kcal/mol, and from B to A is of 9.47 or 14.70 kcal/mol (depending on the direction of rotation of the angle ). Stabilizing n→* interactions and NBO analysis In the optimized structures A and B, the respective hydroxyl group (O12) is close to the cation atom (C7), rendering both structures prone to typical nucleophilic approach (Figure 4). The O12-C7 distances are 2.46 Å in A and 2.15 Å in B, whereas the angles O12-C7-O8 are 100.4° and 98.1°, for A and B respectively.


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Figure 4. Optimized geometries of A and B, at MP2(FULL)/cc-pVDZ level

The short distances between O12 and C7 suggest that intramolecular interactions might occur. Hence, we used Natural Bond Orbital (NBO) analysis to study donor−acceptor interaction of intermediates A and B. Certainly, the orbital overlapping (see Figure 5, and Computational details) confirms the presence of intramolecular nO12→*C7=O8 interactions in both conformers. Figure 5. Orbital overlapping in oxocarbenium ions A and B associated with the respective interactions nO12→*C7=O8

The second order perturbation energies (aka stabilization energies), which are denoted as E(2) (see


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Equation (1) of Computational details), are 14.72 kcal/mol and 44.42 kcal/mol for A and B, respectively; hence in intermediate B, the electron delocalization is more effective. Both the shorter O12-C7 distance and its greater E(2) of oxocarbenium B favors the nucleophilic attack O12 to C7, and consequently favors the overall formation of protonated ceph E (ceph EH+). In addition, the energy differences and barriers of both intermediate formation mechanisms from A to ceph FH+ and from B to ceph EH+ are small (see Supplementary Information). In the cation B, an additional intramolecular interaction is present, nO12→*C2=O13, which involves the hydroxyl oxygen O12 and the carbonyl group of the lactone ring (C2=O13). Its E(2) energy is 1.62 kcal/mol, the bond distance between O12-C2 is 2.86 Å, and the bond angle O12-C2-C13 is 96.2° (Figure 6). It should be note that the proximity between the hydroxyl group and the lactone ring provides, counter-intuitively, an electronic stabilizing effect that overcomes the destabilizing steric repulsion. Hence, this n→* non-bonded interaction is the leading force that provides the greater stability and the conformational preference to B over A. Figure 6. (a) Parameters of the optimized geometry of B and (b) its intramolecular interaction nO12→*C2=O13. See also Scheme 2

In addition, NBO analysis was carried out on the fully optimized structures of cephs E and F (Figure 7). Ceph E is 2.54 kcal/mol lower in energy compared to ceph F. In both structures, E and F, there exist overlapping between an n lone pair orbital of the respective spiroketal oxygen with the adjacent


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 antibonding orbital C-O. These interactions are denoted as nO8→*C7-O12 and nO12→*C7-O8, respectively (Figure 7), and are precisely the interactions associated with the anomeric effect.3b,13 The stabilization energy difference ∆E(2) between ceph E and ceph F is < 1 kcal/mol (the nO8→*C7-O12 interactions are 19.21 kcal/mol and 18.30 kcal/mol for cephs E and F, respectively). Similarly, the nO12→*C7-O8 stabilization energies are 21.37 and 21.56 kcal/mol, for cephs E and F, respectively. Consequently, even though the anomeric effect is present in these 5,5-spiroketals, it has very little influence on the stability of ceph E. Figure 7. Relevant NBO interactions in ceph E (a) nO8 → *C7-O12 and (b) nO12 → *C7-O8; and in ceph F (c) nO8 → *C7-O12 and (d) nO12 → *C7-O8


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Figure 8. (a) Parameters of the optimized geometry of cephalosporolide E and (b) its nO12→*C2=O13 interaction

As we anticipated, ceph E also exhibits an nO12→*C2=O13 interaction, which is quite similar to the observed interaction in the oxocabenium precursor B (see Figure 8). For this nO12→*C2=O13 interaction of E, the distance O12−C2 is 2.80 Å, the O12−C2−O13 angle is 109.1°, and the stabilization energy E(2) is 1.82 kcal/mol. Although similar n→* interactions have been found in other molecules,7-12 wherein some structural properties are attributed to the n→* interaction, it is remarkable that the E(2) of the nO12→*C2=O13 interaction in E represents a greater stabilizing contribution relative to the previously reported cases. For instance, the E(2) of the anhydroarabinonucleoside is 1.09 kcal/mol (for an nO→*C=N interaction),11a 0.27 kcal/mol of amides (for a nO→*C=O interaction),11b 0.88 kcal/mol of thioamides (for nS→*C=S interactions),11b and 0.64 kcal/mol of N-trimethylacetyl (for an nO→*C=O interaction).12 The n→* interaction strength So far, the NBO analyses tell us, qualitatively, that an electronic interaction is indeed present on each conformer E and F, however it would be desirable to quantify their strength. Unfortunately, there is no ACS Paragon Plus Environment

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standard method to theoretically ascertain the strength of an intramolecular interaction (for instance Neelakantan et al.14 have made efforts on describing non-covalent interactions using a wide number of theoretical methods). For addressing this issue and considering that altering the electronic nature of the lactone carbonyl group should alter the putative stabilizing effect of the nO12→*C2=O13 interaction, we performed a comparative study between cephs E and F with their analogous ceph models C/D and G/H (see Figure 9). By doing this, it will permit us to estimate the effect of the nO→*C=Y interaction on the stereochemical preference of these 5,5-spiroketals (here Y stands generically for O, CH 2 or NH2+). To obtain the analogous structures C and D, it was switched the oxygen carbonyl atom, in cephs F and E, by a methylene (=CH2) group (Figure 9). The underlying idea driving these trials consists on showing that, in C and D, the *C=CH2 orbital should have a higher energy, relative to the *C=O orbital, which should widen the nO→*C=Y energy gap, and consequently weaken the n O→*C=Y interaction. Contrastingly, in G and H, which were constructed by replacing the oxygen carbonyl atom, in cephs F and E, by a NH2+ group, the energy of the *C=NH2+ orbital should be lower, also relative to the *C=O orbital, which should shorten the nO→*C=Y energy gap, hence strengthening the nO→*C=Y interaction. Figure 9. Cephalosporolides analogous C, D, G, and H. Cephs C and G are derived from F; and D and H from E

According to the data obtained from the full geometry optimizations of C and D (Table 2, vide supra), structure D is more stable than C. The energy difference between C and D is ECD = EC – ED = 1.59 kcal kcal/mol, while the difference between F and E is EFE = EF – EE = 2.54 kcal/mol. In addition, ACS Paragon Plus Environment

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spiro D revealed a weak nO12→*C2=CH2 interaction, as is shown by the O12-C2 distance of 2.93 Å and the stabilization energy, E(2), of 0.69 kcal/mol (see also Figure 10 for the NBO overlap). As expected, the E(2) of the nO12→*C2=CH2 interaction in D is lower than the nO12→*C2=O13 interaction of ceph E, which is of 1.82 kcal/mol. On the other hand, the energy difference between the optimized geometries of G and H is EGH = EG – EH = 6.30 kcal/mol, which is greater than for the pair F and E (EFE = EF – EE = 2.54 kcal/mol). As expected, H exhibits a strong nO12→*C2=NH2+ hyperconjugation, whose O12-C2 distance and E(2) energy are 2.64 Å and 3.58 kcal/mol, respectively (Figure 11). Thus, the effects of the nO12→* C2=NH2+ interaction upon the pair G/H are enhanced compared to the similar effects upon the pair F/E. This is also reflected in the stabilization energy of the nO12→* C2=NH2+ (3.58 kcal/mol), which is higher than the E(2) of E (1.82 kcal/mol). Briefly, exchanging the O13 by (=CH2) or (=NH2+) either weakens or strengthens the nO12→* interaction, but not the conformational bias.

Figure 10. (a) Parameters of the optimized geometry of D and (b) its nO12→*C2=CH2 interaction


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Figure 11. (a) Parameters of the optimized geometry of H and (b) its nO12→*C2=NH2+ interaction

Steric effects Another interesting question to be addressed is the following: does indeed the nO12→*C2=O13 interaction overcomes the steric effects (i.e. Pauli repulsion)? For answering this question, we performed an NBO analysis upon the cephalosporolides K, L, M, and N, which possess two methyl groups prone to flank the carbonyl group (Figure 12). Figure 12. Structures of cephs K, L, M and N. K and N are similar to ceph E, at the spiro center, whereas L and M to ceph F


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Initial geometries of L and N were taken from X-ray crystallography data, which have been reported by Tong.15 From these, we performed geometry optimizations of all four stereoisomers (Figure 13). The total energy difference between K and L is EKL = EK – EL = 0.89 kcal/mol, i.e. K is more stable than L. The NBO analysis of K revealed an nO12→*C2=O13 interaction with E(2) = 1.59 kcal/mol, and a O12-C2 distance of 2.86 Å, which indicates a modest contact between both atoms On the other hand, for the pair M/N, the energy difference is EMN = EM – EN = 1.68 kcal/mol, being N more stable. The NBO analysis exhibited an nO12→*C2=O13 interaction, whose E(2) = 1.67 kcal/mol, and an O12 _C2 distance of 2.87 Å. Both nO12→*C2=O13 interactions in K and N are slightly weaker than their counterpart in E (see Table 2 and compare Figures 8 and 13). Since the only difference between E and K or N are the methyl groups alpha to the carbonyl group, one may attribute the weakening of the nO12→*C2=O13 interaction to steric effects caused by the methyl groups. Nonetheless, the contributions stemming from the n→* interactions suffice to preserve the same conformational trend between the K/L and N/M pairs, relative to the E/F pair.


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Figure 13. Optimized geometries of the stereoisomers K, L, M and N, and relevant geometric parameters for the nO12→*C2=O13 interaction in K and N. Energy differences are given by pairs (in each row) and they are taken with respect to the conformer whose relative energy is zero (i.e. K in the first row, and N in the second). Experimental values, if known, are depicted between parentheses.

Contribution of the nO→*C=Y interaction to the total energy To estimate the energy contribution of the nO→*C=Y interaction (Y = O, CH2 NH2+) to the total electron energy, we used the NBODEL (ELEMENT ij) technique to re-compute the total electron


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energy of the molecule removing the interaction of interest. Table 2 showcases the E(2)'s of nO→*C=Y interactions, along with the E(DEL), which is the total electron energy minus the energy obtained without the ij element associated to the nO→*C=Y hyperconjugation term (see Computational details for further details).

Table 2. Stabilization energies, E(2), variational deletions E(DEL), and percentage differences of the nO→*C=Y interactions (Y=O, CH2 NH2+) structures B, E, D, H, K, and N

Structure [Y] B [Y=O] E [Y=O]

E(DEL) (kcal/mol)

E(2) (kcal/mol)

% difference

1.18

1.62

-27.1

1.39

1.82

-23.6

0.54

0.69

-21.73

2.47

3.82

-35.34

1.23

1.59

-22.64

1.29

1.67

-22.75

D [Y=CH2]

H [Y=NH2+]

K [Y=O] N [Y=O]

Figure 14 depicts the correlation between E(2) and E(DEL) stemming from the nO→*C=Y interaction for B, D, E, H, K, and N. Both E(2) and E(DEL) are qualitatively consistent, as they differ by 21-36 % (see Table 2). Based on this correlation, we can state that the energy differences between


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conformers stem almost exclusively from the contributions of the nO→*C=Y interactions.

Figure 14. Correlation of E(2) vs E(DEL) for the 5,5 spiroketals B, D, E, H, K, and N. The linear fit (dashed line) is given by E(2) = (1.6486(E(DEL))-0.3532) kcal/mol, and R2 = 0.9878

CONCLUSIONS In summary, we have presented theoretical evidence for the existence of a novel non-anomeric stabilization effect, which is present in the naturally occurring 5,5-spiroketals cephalosporolide E (ceph E) and related cephalosporolide compounds. Through an NBO analysis, we found that the thermodynamic stability of ceph E is originated by an n→* interaction, which occurs between the oxygen atom of the spiro ring and the carbonyl group of the lactone ring. This interaction also directs the acid-equilibration process between cephs E and F via the intermediate cation B. Whereas this n→* interaction may be considered as a weak interaction, it is in fact strong enough to overcome steric interactions (i.e. Pauli repulsions). Counterintuitively, it was demonstrated that the anomeric effect is not


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relevant to the stability of cephs E and F.

COMPUTATIONAL DETAILS Calculations were performed using second-order perturbation theory (MP2(FULL)) combined with the cc-pVDZ basis set. Geometry optimizations were carried out using Gaussian 09 program. 16 Minimum energy conformations were confirmed through frequency analyses, which were performed at the same level of theory used for geometry optimizations. All minima showed real eigenvalues, while transition states rendered one imaginary frequency each. Chemcraft 1.6 17 was used to visualize the output files. Natural bond orbital theory (NBO)18 analyses were conducted for studying electronic interactions and bonding, and the program NBO6,19 coupled with GAMESS (version 2013-R1),20 was used for performing the calculations per se. The NBO analyses were always carried out on optimized geometries, using the MP2 non-relaxed density. We also performed NBO analyses at the CAM-B3LYP/cc-pVDZ level (see Supporting Information, Table S2), and we found the same trends, both for E(2) and NBO(DEL), as reported here. In NBO theory, filled NBO orbitals correspond to localized Lewis structures, and unoccupied orbitals are related to antibonding or Rydberg orbitals. In this context, inter- and intra-molecular interactions occur through the overlap of NBO orbitals. In an electron donor-acceptor interaction, the most important overlap occurs between filled and unoccupied NBO orbitals, where the filled (unoccupied) orbital belongs to the donor (acceptor). Furthermore, this interaction can be quantified through the energy associated to the overlap between the above NBO orbitals, and the energy is obtained from a second order perturbation approach energy as follows:

Here qi is the occupancy number of the i-th donor orbital, j and  are diagonal elements (i.e. the i-th


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and j-th orbital energies), and F(i,j) are off-diagonal elements of the NBO Fock matrix, and =F(i,i). Within the NBO analysis, the strength of an interaction is estimated from

increases as

, i.e. the strength

does. Throughout this work, we denote the donor-acceptor interaction between the

filled and unoccupied NBO orbitals as n→*, and its stabilization energy,

, simply as E(2). The

effect of the n→* interaction energy on the total electron energy was estimated through the NBO DEL analysis (ELEMENT ij). We used the isosurface value of 0.05 for all plots wherein we depict NBO´s.

SUPPORTING INFORMATION Supporting information is available free of charge on the ACS Publication website, which contains the following: Further details on the oxocarbenium ion cyclization. NBO analysis carried out upon CAMB3LYP/cc-pVDZ geometries. Optimized geometries of cephs A, B, E, F, D, C, H, G, K, L, M, and N, as well as the structures of TS1 and TS2, at the MP2/cc-pVDZ level of theory.

AUTHOR INFORMATION *E-mail: [email protected], [email protected]. FSP: https://orcid.org/0000-0002-4322-7534. JMHP: https://orcid.org/0000-0002-1178-2146. JMSA: https://orcid.org/0000-0001-8773-4215. JSL: https://orcid.org/0000-0003-4153-6939.

CONFLICTS OF INTEREST There are no conflicts to declare


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ACKNOWLEDGMENTS Financial support was provided by the CONACyT (project number: 255891) and the Marcos Moshinsky Foundation (FSP). Partial support from BUAP-VIEP. J. M. H. P. acknowledges the computer resources, technical expertise and support provided by the Laboratorio Nacional de Supercómputo del Sureste de México, which is part of the CONACYT network of national laboratories.

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