J. Chem. Sci. Vol. 126, No. 1, January 2014, pp. 283–292. c Indian Academy of Sciences. DFT study of the mechanism and stereoselectivity of the 1,3-dipolar cycloaddition between pyrroline-1-oxide and methyl crotonate KHADIJA MARAKCHIa,∗, RACHIDA GHAILANEb, OUM KALTOUM KABBAJa and NAJIA KOMIHAa aLaboratoire de Spectroscopie, Modélisation Moléculaire, Matériaux et Environnement (LS3ME) Université Mohammed V-Agdal Faculté des Sciences, BP 1014 Rabat, Maroc bLaboratoire de Synthèse Organique, Organométallique et Théorique. Faculté des Sciences, Université Ibn Tofail, BP 13314 Kénitra, Maroc e-mail: [email protected] MS received 22 May 2013; revised 8 October 2013; accepted 23 October 2013 Abstract. A theoretical study of the regio- and stereoselectivities of the 1,3-dipolar cycloaddition reaction between methyl crotonate and pyrroline-1-oxide has been carried out using density functional theory (DFT) at the B3LYP/6-31G(d) level of theory. The reaction has been followed by performing transition state opti- mization, calculations of intrinsic reaction coordinate and activation energies; the molecular mechanism of the reactions is concerted and asynchronous. The regio- and exo/endo-selectivity have been explained in terms of frontier molecular orbital interactions, local and global electrophilicity and nucleophilicity indices and an analysis of the Wiberg bond indices in the transition state. The FMO analysis and DFT-based reactivity indices showed that the regioselectivity of this reaction is controlled by the HOMOdipole–LUMOdipolarophile interaction. The activation parameters indicated favoured endo approach along the meta-pathway in agreement with the experimental results. Keywords. Pyrroline-1-oxide; dipolar cycloaddition; optimized structures; stereoselectivity; DFT-based reactivity indices. 1. Introduction levels together with the 6-31G* basis set. Activation energies and asynchronicity are dependent on the com- 1,3-Dipolar cycloaddition (1,3-DC) is one of the sim- putation level. Thus, while HF calculations gave large plest approaches for the construction of five-membered barriers, MP2 calculations tend to underestimate them. heterocyclic rings.1 Reactions between nitrones and DFT calculations gave reasonable values.8 Liu et al.9 alkenes leading to isoxazolidines are well-known have performed DFT calculations at B3LYP/6-31G* construction processes.1,2 Substituted isoxazolidines level on the 1,3-dipolar cycloaddition reaction of the are interesting biological active compounds3 and could simplest nitrone to dipolarophiles containing electron- be used as enzyme inhibitors.4,5 They are also fre- releasing substituents. Here, the endo approach is quently used as intermediates for the synthesis of a kinetically favoured because of stabilization of the variety of compounds after cleavage of the N–O bond.6 secondary orbital interactions. In another study, In the context of the cycloadditions of nitrones Cossó et al.10 have used B3LYP/6-31G* calculations to with several dipolarophiles, we have reported a den- study the 1,3-dipolar cycloaddition reaction of unsub- sity functional theory (DFT) study of 1,3-dipolar stituted nitrone with nitroethene. Asynchronicity in cycloaddition reaction between simple nitrone with the bond formation process in the two regioisomeric three-fluorinated dipolarophiles, analysis of the results approaches of the two reactants is found to be controlled on different reaction pathways shows that the reac- by the electron-deficient dipolarophile. Domingo tion occurs through a concerted process and proceed et al. have studied the 1,3-dipolar cycloaddition reac- more or less synchronously.7 We have also studied the tion of nitrones with several dipolarophiles using DFT molecular mechanism for the 1,3-dipolar cycloaddi- methods at the B3LYP/6-31G* and B3LYP/6-31+G* tion of nitrone with sulphonylethene chloride using ab levels.11,12 Their calculations predict an asynchronous initio and DFT methods at the HF, MP2 and B3LYP concerted mechanism and both stereo and regiose- lectivity were found dependent on the computational ∗For correspondence model and computational level. Nacereddine et al.13 283 284 Khadija Marakchi et al. have studied the regio- and stereoselectivities of the graphical interface GaussView3.08. The full geomet- 1,3-dipolar cycloaddition of C-diethoxyphosphoryl-N- rical optimization of all structures and transition states methylnitrone with substituted alkenes (allyl alcohol structures (TSs) were carried out with DFT by apply- and methyl acrylate) using DFT method. An ana- ing the Becke’s18 three-parameter hybrid functional lysis of potential energy surfaces (PESs) shows that and Lee-Yang-Parr’s19 correlation functional. The basis these 1,3-dipolar cycloaddition reactions favour the set 6-31G(d)20 has been employed for the prediction formation of the ortho-trans cycloadduct in agreement of activation energies of cycloaddition reactions and with experimental data. Stecko et al. have reported to provide geometries and electronic properties. The a DFT/B3LYP/6-31+G(d) study of the 1,3-dipolar stationary points were characterized by frequency cal- cycloaddition of cyclic nitrones with electron-poor and culations in order to check that the TSs had one and electron-rich cyclic dipolarophiles: α, β-unsaturated only one imaginary frequency with the corresponding lactones and vinyl ethers. Different reaction channels eigenvector involving the formation of the newly cre- and reactants approaches, effective in regio- and stereo- ated C–C and C–O bonds. Furthermore, the intrinsic chemical preferences are discussed; the results reaction coordinate (IRC)21,22 path was mapped to were compared to experimental data and found in authenticate the connection of a TS to the two asso- good agreement.14 Recently, Acharjee and Banerji15 ciated minima of the proposed mechanism. Electronic studied the 1,3-dipolar cycloaddition between C,N- structures of critical points were analysed by the natural diphenyl nitrone and an unsymmetrical disubstituted bond orbital (NBO) method.23 Global reactivity indices olefin at DFT/B3LYP/6-31G(d) level of theory. The were estimated according to the equations recom- analysis of FMO energies, reactivity indices and charge mended by Parr and Yang.24 In particular, the electronic transfer in the transition states indicates a normal chemical potentials (μ) and chemical hardness (η)of electron demand character for the reaction. the reactants studied were evaluated in terms of the The experimental investigations of Asrof et al.16 one-electron energies of the frontier molecular orbital implied that the cycloaddition between pyrroline-1- HOMO and LUMO, using the following equations: oxide 1 to dipolarophile 3b (methyl crotonate) gives μ = (E + E ) /2, (1) a mixture of substituted isoxazolidines 4b and 5b in HOMO LUMO a 93:7 ratio, respectively (scheme 1). In what follows, η = E − E . we present a DFT study on the cycloaddition reaction LUMO HOMO (2) involving cyclic 5-membered nitrone with methyl cro- The values of μ and η were then used for the calculation tonate. Our results are presented and discussed on the ω) basis of the generated trends in terms of detailed con- of global electrophilicity ( according to the formula: ceptual DFT-based reactivity indices and the analysis of ω = μ2/2η. (3) stationary points on the potential energy surfaces. This 25 analysis allows to elucidate the regio- and stereoselec- The global nucleophilicity (N) is referred to tetra- tivities of the 1,3-dipolar cycloaddition and to explain cyanoethylene (TCE) because it presents the lowest ω = the experimental observations. HOMO energy and a very large electrophilicity ( 5.95 eV) in a large series of molecules already investi- gated in the context of polar cycloadditions. The global nucleophilicity can then be expressed as: 2. Computational details N = EHOMO(nucleophile) − EHOMO(TCE). (4) 26 All calculations reported in this paper were performed The local electrophilicity (ωk) condensed to atom k using Gaussian 03 suite of programs17 along with the was calculated by projecting the indice ω onto any Scheme 1. 1,3-Dipolar cycloaddition of pyrroline-1-oxide with methylcrotonate. DFT study of the mechanism 285 where ρk(N+1), ρk(N) and ρk(N-1) are defined as the grosselectronic populations of the site k in the anionic, neutral and cationic species, respectively. 3. Results and discussions For this 1,3-DC reaction between cyclic nitrone: pyrroline-1-oxide and methyl crotonate, we first eva- luated the geometrical parameters and energies of all the stationary points (reactants, transition structures and cycloadducts) at DFT/B3LYP/6-31G(d). Popula- tion analysis at the transition structures in terms of bond orders and natural charges was performed, together with an analysis based on the global and local reac- tivity indices of the reactants involved during the cycloadditions. 3.1 Regiochemistry of 1,3-dipolar cycloaddition reaction based on FMOs and reactivity indices analysis Figure 1. Frontier molecular orbital (B3LYP/6-31G*)) 3.1a FMOs analysis: In this section, the frontier interaction in the 1,3-DC between pyrroline-1-oxide and molecular orbital theory30–39 was applied to explain the methyl crotonate. regioselectivity and reactivity in 1,3-dipolar cycloaddi- tion of methyl crotonate and the nitrone. reaction centre k of the molecule by using Fukui Analysis of the frontier molecular orbitals of the f + 27 function k . reactants show that in the nitrone, both HOMO and ω = ωf+. k k (5) LUMO are π molecular orbitals (MOs). However, in 28 the methyl crotonate, the HOMO is a nonbonding MO The local nucleophilicity (Nk) condensed to atom k was calculated using global nucleophilicity N and localized essentially on the oxygen of the carbonyl Fukui function f − according to the formula: group and, in consequence, it is expected that it will k not be directly involved in the 1,3-DC process. The N = Nf −. π k k (6) HOMO-1 of dipolarophile is a bonding molecular orbital with a large contribution of the atoms present For an atom k in a molecule, depending upon the type at the active sites, thus the relative reactivity can be of electron transfer, we have three different types of explained with analysis of this MO.