A Theoretical Study of the Regio

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Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, 1, 18-23

A Theoretical Study of the Regio- and Stereoselectivities of the 1,3dipolar Cycloaddition Reaction between C-phenyl-N-methylnitrone and Ethylvinylether A. Khorief Nacereddinea,b,*, W. Yahiaa , C. Sobhia, H. Layeba, Z. Lechtara and A. Djerouroua a

Laboratory of synthesis and Organic biocatalyst, Department of Chemistry, Faculty of Sciences, BadjiMokhtar Annaba University, BP 12, 23000 Annaba, Algeria b

High Normal School of Technological Teaching, Azzaba, Skikda, Algeria Abstract: A theoretical study of the regio- and stereoselectivities of the 1,3-dipolar cycloaddition reaction between the Cphenyl-N-methylnitrone and ethylvinylether was carried out using DFT methods at B3LYP/6-31G** level of theory. Analysis of the energies of the stationary points indicates that the product ortho-endo is favored both kinetically and thermodynamically. Analysis of the bond order and charge transfer in the transition states indicates that these reactions processed via a synchronous-concerted mechanism.

Keywords: Cycloaddition, regiosélectivity, stereoselectivity, molecular mechanism, DFT calculations. INTRODUCTION Nowadays, a major challenge in contemporary organic synthesis is to devise methods and strategies for the rapid and economic preparation of highly complex molecules from simple starting materials [1]. Among the alternative approaches to meet this challenge, those based on methods that allow the simultaneous creation of several bonds in a single operation, such as cycloadditionreactions are particularly appealing. 1,3-Dipolar cycloaddition reactions are one of the best and more general methods for the construction of five-membered rings in a convergent and stereocontrolled manner [2]. A tremendous amount of theoretical and experimental work devoted to the study of the mechanism and selectivities of DA reactions can be found in the literature. Herrera and co-workers [3] studied experimentally the 1,3-dipolar cycloaddition reaction between the C-aryl-N-phenylnitrone and capdodatives alkenes, and found that these reactions process via a regiospecific manner to gives the orthoprodutcsand a stereoselective approach to form the endo product. They have explained theoretically at this preference by the steric hindrance in the exo approach between the phenyl group of the nitrone and the aryl group of the alkene. Gandolfi [4] also studied the 1,3-DC of the simplest nitrone with vinylboranes. The calculations showed that the vinylboranes may undergo very fast [3+2] cycloaddition resulting in a single endo adduct. It was also pointed out that the boronyl substituent is

*Address correspondence to this author at the High Normal School of Technological Teaching, Azzaba, Skikda, Algeria; E-mail: [email protected] E-ISSN: 2309-4435/13

intimately involved in the reaction mechanism via very strong B–O interactions that are able to produce very low energy barriers, and complete endo selectivity, via a type of effective and selective intra-molecular catalysis. Houk et al. found an endo stereoselectivity for the 1,3-DC reaction of methyl vinyl ether with the simplest nitrone [5]. In the absence of steric hindrance, a favorable hyper conjugative anomeric-type interaction that appears between the two oxygen atoms of the nitrone and the vinyl ether stabilizes the endo/ortho TS by 0.8 kcal mol relative to the exo/ortho one. This low relative energy agrees with the fact that the endo/exo stereoselectivity for these 1,3-DC reactions depends on the bulk of the substituents present on both nitrone and substituted alkene. Our aim in this work was to undertook a theoretical study of the regio- and stereoselectivities of the 1,3dipolar cycloaddition reaction between C-Phenyl-Nmethylnitrone and ethylvinylether [6] (Scheme 1). Computational Methods All calculations were carried out with GAUSSIAN 03 along with the graphical interface, GAUSSIAN View 2004 [7]. Geometry optimization of the stationary points (reactants, transition structures, and products) was carried out using DFT methods at the B3LYP/631G+(d,p) level of theory [8]. The stationary points were characterized by frequency calculations in order to verify that minima and transition states had zero and one imaginary frequency, respectively. The electronic structures of the stationary points were analyzed by the natural bond orbital (NBO) method [9]. © 2013 Pharma Professional Services

A Theoretical Study of the Regio- and Stereoselectivities

N Me

O

Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 1

Ph +

O

Et

Me N O

Ph +

O Et

2

1

Me N O

19

O Et 40/60

Scheme 1: 1,3-Dipolar cycloaddition reaction between C-phenyl-N-methylnitrone and ethylvinylether.

2. RESULTS AND DISCUSSION 2.1. Stereoselectivity The 1,3-DC under study can be process via two regioisomeric channels and two stereoisomeric approaches. Thus, four transition states and four products have been studied (Scheme 2). The geometries of the four TSs are given in Figure 1 together with the newly forming bond lengths. Table 1 reports the energies (a.u.) and relative energies (kcal/mol). The analysis of the relative energies for the TSs reveals that the ortho approaches are favored over the meta ones; the TS-3-endo and TS-3-exo are less

energetic than TS-4-endo and TS-4-exo, in the range of 12 kcal mol. Therefore, there is a pronounced regioselectivity for this 1,3-DC reaction. The steric hindrance between the methoxy group of the alkene and the phenyl group present at the meta channels destabilizes these TSs relative to the ortho one (Figure 1). The stereoselectivity measured as the difference of activation enthalpy between the endo and exo TSs for the more favorable ortho attack indicates that this reaction prefers the endo selectivity; TS-3-endo is 1.16 kcal mol more energetic than TS-3-exo.It is found that in the endo transition structures TS-3-endo, besides the formation of the new bonds, secondary molecular orbital (SMO) interactions can be detected between C1–C2 (p) and C–N–O (p) orbitals (Figure 2). These Me N O Ph Et

O

O

Et meta channel

Me N O

Ph

3-endo

endo approach

Me N O Ph

Ph Et

O

Et O

1

O

+

O

2

3-exo

exo approach

Et

ortho channel

N Me

Me N O Ph

Ph

O Et

O Et

exo approach

Scheme 2: The possible channels and approaches of nitrone 1 toward alkene 2.

Me N O O Et

4-endo

endo approach

Me N O Ph

Me N O

Ph

Me N O O Et

4-exo

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Nacereddine et al.

1,99

2,11

2,00 2,17

TS-4-exo

TS-4-endo

ST-4-exo

2,19

ST-4-endo

2,10

2,04

2,16

TS-3-exo

TS-3-endo

Figure 1: Transition structures for the 1,3-DC reaction between the nitrone 1 and methyl vinyl ether 2.

SMO interactions are small in the exo transition structures, TS-3-exo, which explains the lower activation energy barrier in the former. Table 1: Energies (a.u) and Relative Energies E (Kcal/mol) of the Reagents, Transition States, and Products E(Kcal/mol)

System

E(a.u)

Nitrone

-400.86986

Alkene

-193.11929

TS-3-exo

-593.03583

22.59

TS-3-endo

-594.03705

21.43

TS-4-endo

-593.93383

34.71

TS-4-exo

-593.93230

35.67

Pt-3-exo

-594.51323

-12.61

Pt-3-endo

-594.51372

-12.92

Pt-4-endo

-594.02126

-10.15

Pt-4-exo

-594.01569

-10.53

2.2. Regioselectivity 2.2.1. FMO Analysis a. Prediction of the NED or IED Character In order to predict the electronic nature of this reaction, we have calculated the gaps of the possible interactions between the FMOs. From Table 2, we can notice that the gap HOMOalkene-LUMOnitrone (0.16eV) is

smaller than the gap HOMOnitrone-LUMOalkene (O.24eV) one. main interaction occurs between the HOMO of alkene and the LUMO of nitrone. Consequently, this 1,3-DC reaction has an IED character. b. Prediction of the Regioselectivity Using FMO Model According to the Houk rule [10], the large–large and small–small interactions are more favored than the large–small and small–large ones. The coefficients values of frontier orbitals HOMO (alkene) and LUMO (nitrone) are given in Table 3. Hence, it is clear that the most favored large–large interaction will take place between C1 of alkene and C3 of nitrone and the small– small interaction will take place between C2 alkene and O1of nitrone leading to the formation of ortho regioisomer. For more visualizing these interactions, we have schematized them in Scheme 3, together with the atom numbering. 2.2.2. DFT-Based Reactivity Indices Analysis a. Prediction of the NED or IED Character The NED (Normal Electron Demand) or IED (Inverse Electron Demand) character of the 13DC reaction of nitrone1 with alkene 2 has been predicted by calculation of DFT-based reactivity indexes [11], namely, electronic chemical potentials and electrophilicity indexes (Table 4). We can notice that of alkene (-0.09020) is greater than of nitrone (0.13198). Consequently, the charge transfer will take place from alkene 2 to nitrone 1. On the other hand, the



21

Large interaction

Small interaction

Figure 2: Secondary molecular orbital interactions in endo transition structures for 1,3-DC reactions between nitrone 1 and alkene 2.

electrophilicity values show that of nitrone (0.05864) is greater than of alkene (0.01591), indicating that nitrone1 will act as an electrophile whereas alkene 2 will act as a nucleophile. In conclusion, the 13DC reaction treated in this work has anIED character, in agreement with FMO analysis. Table 2: FMO Energies and Possible Interactions in the 1,3-DC Reactions of Nitrone1 with Alkene 2 HOMO

LUMO

NED

IED

Nitrone

-0.20624

-0.05773

0.24387

0.16031

Alkene

-0.21804

0.03763

Table 3: Molecular Coefficients of the FMOs for Nitrone 1 and Alkene 2 Reactant Nitrone

Alkene

HOMO O

C

O1

C3

0.61397

0.22243

0.00172

0.01343

C1

C2

C1

C2

0.10923

0.05466

0.00825

0.61602

Et Me

1

O

N

2

3

1

±

Table 5 reported the values of Fukui indices f and ± the local electrophilicities for atoms C1 and C2 of alkene 2 and atoms O1 and C3 of nitrone 1, calculated with NBO population analysis. The results show that the most favored interaction will take place between the C2 center of alkene 2 (possessing the highest value of ) and the O1 center of nitrone (possessing the + highest value of ) leading to formation of orthoregioisomers (Scheme 3). Consequently, the ortho regioselectivity is correctly predicted by DFT-based reactivity indices. 3. MOLECULAR MECHANISM 3.1. Charge Transfer Analysis

LUMO

O

b. Prediction of Regioselectivity Using DFT-Based Reactivity Indices

Scheme 3: Illustration of the favorable interactions using FMO model and DFT-based reactivity indices.

The charge transfer values [12] evaluated by natural population analysis in terms of the residual charge on the ethyvinylether 2 for the optimized transition structures are given in Table 6. The positive values are indicative that electron flow takes place from the HOMO of ethylvinylether 2 to the LUMO of nitrone 1. This indicates the non-polar character of these cycloadditions. This low charge transfer found for these IED 1,3-DC reactions can be related to the electronrich character of the nitrone, which prevents the charge transfer from the electron-rich alkene during the cycloaddition process.

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Nacereddine et al.

Table 4: The FMO Energies (a.u.), Electronic Chemical Potential (a.u.), and Electrophilicity Indices (a.u.) for the Reactants HOMO

LUMO

Nitrone

-0.20624

-0.05773

-0.13198

0.14851

0.05864

Alkene

-0.21804

0.03763

-0.09020

0.25567

0.01591

Table 5: Electrophilic and Nucleophilic Fukui Indices and Local Electrophilicities for the Reactive Atoms of the Nitrone and the Alkenes Reactant

Nitrone

atome

O1

C3

C1

C2

+

-0.146

-0.074

-0.112

-0.204

-

-0.315

-0.148

-0.180

-0.012

+

-0.00433

-0.00856

-0.00178

-0.00324

-

-0.01847

-0.00867

-0.00286

-0.00019

f

f

Alkene

Table 6: Charge Transferanalysis Transition state

Charge transfer(e)

ST-3-exo

0.186

ST-3-endo

0.194

ST-4-exo

0.119

ST-4-endo

0.156

BO values for the same forming bonds are 0.70 and 0.67, respectively. These results indicate that these TSs correspond to a synchronous process, where the two new r bonds are formed simultaneously. CONCLUSION

3.2. Bond Order Analysis The extent of bond formation or bond breaking along a reaction pathway is provided by the concept of bond order (BO). This theoretical tool has been used to study the molecular mechanism of chemical reaction [13]. The Wiberg bond indices [14] have been computed using NBO analysis [12] the obtained results are collected in Table 2. Analysis of the BO at the TSs corresponding to the [4+2] cycloadditions shows the synchronicity of the bond formation processes. In exoTS the BO values for the C2–C5 and C3–C8 forming bonds are 0.71 and 0.66, respectively. In endo-TS the

The molecular mechanism for the 1,3-DC reactions of C-phenyl-N-methylnitrone with ethylvinylether has been studied using density functional theory methods with the B3LYP functional and the 6-31G(d,p) basis set. The regioselectivity, the stereoselectivity and the molecular mechanism have been analyzed and discussed. The activation energy barriers favor the formation of endo-ortho cycloadduct due to the large secondary molecular orbital interactions of FMOs in this approach. The FMO analysis and DFT-based reactivity indices predicts the regioselectivity ortho. Charge transfer and Wiberg bond order analysis at transition states indicates that these1,3-DC reactions of C-phenyl-N-methynitrone with ethylvenylether occur via a synchronous- concerted mechanism.

Table 7: Wiberg Bond Orders at Transition Structures Bond

TS-3-exo

TS-3-endo

TS-4-exo

TS-4-endo

C1-O2

0.6364

0.6332

0.7253

0.7409

C3-C4

0.7916

0.7767

0.9561

0.7525



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Received on 14-05-2013

Accepted on 17-06-2013

09,

Revision

A.02;

Gaussian:

Published on 12-07-2013

DOI: http://dx.doi.org/10.14205/2309-4435.2013.01.01.4

© 2013 Nacereddine et al.; Licensee Pharma Professional Services. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.