Exploration of the Mechanism, Chemospecificity, Regiospecificity and Stereoselectivity of the Cycloaddition Reaction between Hydroxyparthenolide and Nitrilimine: MEDT Study

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Exploration of the Mechanism, Chemospecificity, Regiospecificity and Stereoselectivity of the Cycloaddition Reaction between Hydroxyparthenolide and Nitrilimine: MEDT Study

https://doi.org/10.21203/rs.3.rs-1338725/v1

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The cycloaddition reaction between hydroxyparthenolide and nitrilimine has been investigated in molecular electron density theory (MEDT) at the B3LYP/6-31(d) computational level. The reaction paths including the six cycloaduit were explored. The DFT calculations show that the cyclization takes place on the C₁=C₂ double bond, which indicates that this reaction is chemiospecific and regiospecific in full compliance with the experimental results.In addition, we have studied the mechanism of this reaction, we found that this reaction followed asynchronous mechanism.

MEDT

Regiospecificity

DFT

Parr functions

Hydroxyparthenolide

Nitrilimine.

The dipolar cycloaddition [2+3] belong to the large family of pericyclic reactions, is a method of choice for the production of five-membered cyclic and heterocyclic compounds [1–7]. These reactions are also used for the fabrication of natural products such as sugar derivatives [8, 9], β-lactams [10], amino acids [11], alkaloids [12–14] and products of pharmacological interest such as pyrazolines with several activities. biologicals (anti-inflammatory and analgesic agents [15], analgesic [16], herbicides agents [17]).

Spiro products are bi-cyclic molecules whose two rings are connected by an atom (scheme1), which can be considered as very important compounds in industry and in biological application [18–20]. Spiro derivatives have been used to produce polymers, dyes, plastic foams, drugs, pesticides and herbicides [21]. Many spiro compounds possess mutagenic activities [22]. Spiro chemistry has therefore attracted the attention of many chemists, since several of the spiro compounds play an important role in organic chemistry [23–26]. One of the most useful synthetic applications of spiro are the 1,3-dipole cycloaddition reactions of dipoles with alkenes directly attached to the ring [27, 28].

Dipoles have four π electrons distributed over 3 neighboring atoms. Each dipole has at least one resonant structure where the opposing charges are in a 1.3 relationship (Figure S1). It is this structural feature that has led to the term 1,3-dipolar cycloaddition reaction [29].

Very recent studies of cycloaddition show the existence of a correlation between the electronic structure of dipoles and their reactivity.This makes it possible to classify 32CA reactions into four types: pdr type, pmr-type, zw-type and cb-type [30–32].

Recently, the MEDT theory has emerged as an alternative to FMO for the study of structural and reaction of chemical systems. The MEDT theory succeeds in providing theoretical information on chemical reactivity and selectivity [33–38].In this context, we have used this theory to elucidatethe mechanism and various selections of the cyclooadition reaction between hydroxyparthenolide and nitrileimine, experimentally studied by Outahar et al [39] (Scheme 1).

Recently, theoretical methods based on density functional theory (DFT) have emerged as an alternative to traditional ab-initio methods for the structural and reaction study of chemical systems. In this work, the geometries have been optimized at the B3LYP/6-31G(d) [40,41] calculation level on Gaussian 09 [42], using Berny's algorithm [43,44]. Atomic electronic populations and reactivity indices were calculated using natural population (NPA). The transition states, were located at the B3LYP/6-31G (d) level, their existence was confirmed by the presence of one and only one imaginary frequency in the Hessian matrix. The IRC [19] was performed and plotted to show that the TS is well connected to both minima (reagents and product). The effect of the solvent was taken into account by a single point calculation on the geometries optimized using the model PCM (polarizable continuum Model) of Tomas [45-48]. The global electrophilicity index ω[49], was given by the following expression \({\omega }=\frac{{\mu }^{2}}{2\eta }\), in terms of the electronic chemical potential µ and the chemical hardness η. Both quantities could be approached in terms of the one-electron energies of the frontier molecular orbital HOMO and LUMO, \({{\epsilon }}_{\text{H}}\) and \({\epsilon }_{L}\)as µ = \(\frac{{\epsilon }_{H} + {\epsilon }_{L}}{2}\)and , respectively. The empirical nucleophilicity index N [50] based on the HOMO energies defined as \(E = {E}_{HOMO}\left(Nu\right) - {E}_{HOMO}\left(TCE\right)\)the nucleophilicity was referred to tetracyanoethylene (TCE). Electrophylic \({\text{P}}_{\text{k}}^{+}\) and nucleophilic \({\text{P}}_{\text{k}}^{-}\) Par functions were obtained through analysis of the Mulliken atomic spin density (ASD) of the radical anion and radical cation of the reagents. [51,52]. The study of the electron localization function (ELF) was carried out with the TopMod package using the corresponding mono determinant wave functions [53,54].

Prediction of the electrophilic/nucleophilic character of the reagents

In order to determine the electrophilic/nucleophilic character of the reagents (hydroxyparthenolide 1 and nitrileimine 2), we calculated the electronic chemical potential μ, the hardness η, the nucleophilic index N and the electrophilic index ω. and are shown in Table 1.

Table 1 show that the electronic chemical potential of the nitrileimine 2 and hydroxyparthenolide 1 are similar; which implies that this reaction has a non-polar character. The nucleophilie and eletrophilie index of the nitrileimine 2, are 3.48 and 1.74 eV respectively and that of hydroxyparthenolide 1 are 3.01 and 1.44 eV respectively. Therefore, both reagents are classified as potent nucleophiles and potent eletrophiles, in addition these reagents have similar characteristics, so we will use charge transfers at the level of the transition state to classify them, the transfer of charge in the transition state will take place from the nitrileimine 2 to the hydroxyparthenolide 1, the fact that the hydroxyparthenolide 1 will participate as eletrophile and nitrileimine 2 will participate as nucleophile, as this reaction is non-polar, numerous studies show that the formation of the first bond in cycloaddtions reactions takes place on the most electrophilic center of ethylene derivative [55,32]. We have represented in figure 1 the eletrophilic Parr functions of dipolarophile (hydroxyparthenolide 1).

Figure 1 indicates that the Mulliken atomic spin densities of hydroxyparthenolide 1 are clustered on the exocyclic C₁=C₂ double bond, while almost no surface is noted around the endocyclic C₃=C₄ double bond. This result indicates that the C₁=C₂double bond is the most reactive part of hydroxyparthenolide 1, which confirms the total chemoselectivity experimentally observed.

Energetic study

Hydroxyparthenolide 1 has two double bonds. Due to his chiral character, as well as the non-symmetry of the two reactants, 8 competitive reaction paths are possible. They are linked to the different chemo-, regio- and diastereofacial approaches. The formation of a single product P-4 indicates that this 32CA reaction exhibited chemo-, regio-, and diastereofacial-selective.

To interpret the deferent selectivities observed experimentally (chemo-, regio- and diastereo-facial), six approach modes associated to the chemoselective attack of the C₁=C₂ and C₃=C₄ double bonds of hydroxyparthenolide 1, and two regioisomeric approach modes of nitrileimine 2 and the attack on both sidesof the double bond C₁=C₂ of Hydroxyparthenolide1, the syn and the anti, were considered,six transition states TS, TS-1 to TS-6, and the corresponding cycloadducts were characterized and located.The relative energies, in gas phase and in DCM, are assigned in Scheme 2, while the total electronic energies are given in table S1.

The scheme 2 indicate that the activation energies of six reaction paths are: TS-1 (9.2 Kcal/mol), TS-2 (7.2 Kcal/mol), TS-3 (18.1 Kcal/mol), TS-4 (2.2 Kcal/mol),TS-5 (19.4 Kcal/mol) and TS-6 (16.9 Kcal/mol), indicating that reaction path 4 is kinetically more favored. It corresponds to the formation of the spirocycloadducts P-4.The six reaction paths having an exothermic character are as follows: P-1 (-53.4Kcal/mol), P-2 (-53.5 Kcal/mol), P-3 (-44.5 Kcal/mol), P-4(-3.7 Kcal/mol), P-5 (-37.8 Kcal/mol) and P-6 (-40.9 Kcal/mol), which shows that the product P-4 has a lesser exothermic character, consequently the productP-4 is obtained from a kinetic control.The use of dichloromethane as a solvent increases the activation energy of the six reaction paths by: TS-1 (3.9 Kcal/mol), TS-2 (3.9Kcal/mol), TS-3 (10.5Kcal/mol),TS-4 (3.5Kcal/mol),TS-5 (3.4 Kcal/mol) and TS-6 (5.9 Kcal/mol), and reduces the exothermic character by: P-1 (4.5Kcal/mol), P-2 (4.6 Kcal/mol), P-3 (2 Kcal/mol), P-5 (3.2Kcal/mol) and P-6 (8 Kcal/mol) while the exothermic character of the product P-4 increases by (17.9Kcal/mol), which shows that dichloromethane disadvantages this reaction.

We have shown in figure 2 the free energy profile of this reaction, the total of the thermodynamic values are exposed in Table S2. Taking into account the term TΔS increases enormously the relative free energies of Gibbs compared to the relative enthalpies between 11 and 15 kcal/mol, this increase is due to the entropy which disadvantages the bimolecular process.

The free Gibbs activation energies associated with the formation of the cycloducts P-1, P-2, P-3, P-4, P-5 and P-6 via TS-1, TS-2, TS-3,TS-4, TS-5 and TS-6 are 26.45, 23.92, 19.98, 18.24, 37.65 and 35.98 kcal/mol, respectively;the formation of these products are respectively exergonic at 31.42, 31.86, 23.42, 8.13, 15.02 and 13.60 kcal/mol. Consequently, these 32CA reactions being irreversible and the formation of the cycloaduct P-4 is more favorable, indicating that this cycloaddition raection is chemo-, stereo- and regiospecificity, which has been observed experimentally.

The geometries of the transition states associated with the six reaction paths are shown in Figure 3. A comparative analysis of the geometric parameters of the transition states localized in the gas phase and those found in DCM shows that the implicit consideration of the solvent in the optimizations geometry does not produce noticeable changes.

Important conclusions can be drawn from the geometric parameters of the transition states shown in Figure 3: i) the bond lengths clearly indicate that the new single bonds are formed in an asynchronous fashion ii) the inclusion of solvent effects makes the TSs slightly earlier and more asynchronous. Finally, the polar character of these zw32-like CA reactions was assessed by calculating the values of the GEDT at the corresponding TS.at TS-1, 0.08;at TS-2, 0.08;at TS-3, 0.04;at TS-4, 0.04;at TS-5, 0.1;and at TS-6, 0.03, these low values clearly indicate that these cycloaddition reactions have a nonpolar character.

ELF topological investigation

To reveal the description of the formation of the new single bonds along the more favorable reaction path of the cycloaddition reaction between hydroxyparthenolide and nitrilimine, An ELF topological investigation of selected points of the IRC curve. The populations of the most relevant ELF valence basins involved in the formation of the single bonds C-C and C-N of the selected structures are arranged in Table S3, while the positions corresponding ELF basin attractors are exposed in Figure 4.

In structure 1, we observe the presence of two monosynaptic basins V(N1)=3.55e and V(C3)=0.67e and five bisynaptic basins namely V(N1,N2)=1.95e, V(C1,C2)=1.72e, V'(C1,C2)=1.76e, V(N2,C3)=2.01e and V'(N2,C3)=3.96e, this structure corresponds to the separate reactants. During structure 2 until structure 22, we observe a decrease in the value of the monosynaptic basin V(N1) up to the value 3.46e, and the increase in the monosynaptic value V(C3), which will take thevalue V(C2)=1.01e in structure 22. In structure 23, we have the appearance of a monosynaptic basin carried by the nitrogen atom 2 V(N2)=0.81e, this value will increase to 2.08e in structure 33, in theStructures 33 and 34 show the appearance of a monosynaptic basin carried by carbon C2, which takes the value V(C2)=0.36e.The monosynaptic basins V(C2) and V(C3), will unify to form the first single bond with an electronic population V(C2,C3)=1.72e, once this bond is formed, we have the appearance ofa monosynaptic basin carried by carbon C1, V(C1)=0.13e, this increases during structures 37 up to 48, which will take the value V(C1)=0.41e in structure 49. In structure 50 the monosynaptic pools V(N1) and V(C1) will form the second single bond. During structures 51 to 60 there is a relaxation towards the final product.So from this study it can be concluded that the cycloaddition reaction between hydroxyparthenolide(1) and nitrilimine (2) follows an asynchronous mechanism.

The [3+2] cycloaddition of hydroxyparthenolide (1) and nitrilimine (2) has been studied within the molecular electron density theory (MEDT) at the6-31(d) computing level. From MEDT, we can conclude that:

The reagents nitrileimine 2 and hydroxyparthenolide 1 have similar global indices;which means that this reaction has a non-polar character and we explored load transfer in TS to classify reactants, the hydroxyparthenolide1 will participate as eletrophile and nitrileimine2 will participate as nucleophile, in this non-polar reaction.
The Mulliken atomic spin densities of hydroxyparthenolide1 are assembled on double bond C₁=C₂, signifies that thisdouble bond is the most reactive than double bond C₃=C₄, which shows that this cycloaddition reaction is chemospecific.
The employment of dichloromethane as a solvent augments the activation energies and diminishes the exothermic character, demonstrating that dichloromethane disadvantages this reaction.
The energy analysis clearly shows that the P4 product is very favorable, indicating that this cycloadditionraection is chemo-, stereo- and regiospecificity, in total agreement with experience.
ELF study designatesthat this cycloaddition reaction has asynchronous mechanism.

Conflicts of interest/Competing interests The authors declare that they have no conflict of interest and no competing interests exist.

Declarations Funding The authors received no specific funding for this work.

Ethics approval The manuscript is prepared in compliance with the Ethics in Publishing Policy as described in the Guide for Authors.

Consent to participate The manuscript is approved by all authors for publication.

Consent for publication The consent for publication was obtained fromall participants.

Availability of data and material All data generated or analyzed during this study are included in this published article.

Code availability The calculations were performed using: Gaussian 09W, GaussView 5.0 (provided by Gaussian 09, GaussView.05). Model PCM (polarizable continuum Model) and Berny's algorithm.

Authors' contributions Z. Ouahdi, N. Ourhriss, A. Ouald Aytouna and A. Barhoumi: Article writing. M.E. Belghiti, A. Moubarik, H. El Alaoui El Abdallaoui, M. El idrissi and A. Zeroual: Directing. Discussion; Mohammed El idrissi and Abdellah Zeroual Final review and editing.

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Table 1 Electronic chemical potential, hardness, electrophilicity and nucleophilicity of the two reagents (hydroxyparthenolide 1 and nitrileimine 2), the values are given in eV

	η	µ	ω	N
1	5.23	-3.89	1.44	3.01
2	4.32	-3.88	1.74	3.48

Scheme files are available in Supplemental Files section.

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Exploration of the Mechanism, Chemospecificity, Regiospecificity and Stereoselectivity of the Cycloaddition Reaction between Hydroxyparthenolide and Nitrilimine: MEDT Study

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