Papers. Nivedita Acharjee & Avijit Banerji*

Indian Journal of Chemistry Vol. 49A, November 2010, pp. 1444-1452 Papers 1,3-dipolar cycloadditions. Part XX. DFT study of the configuration and conformation of C-aryl-N-phenyl nitrones and their reactivities as 1,3-dipoles to methyl and ethyl crotonates Nivedita Acharjee & Avijit Banerji* Centre of Advanced Studies on Natural Products including Organic Synthesis, Department of Chemistry, University College of Science, University of Calcutta, 92, Acharya Prafulla Chandra Road, Kolkata 700 009, India Email: ablabcu@yahoo.co.uk Received 3 August 2010; revised and accepted 27 October 2010 The preferred configurations and conformations of C-aryl-N-phenyl nitrones have been predicted theoretically by detailed comparison of DFT/B3LYP/6-311+G(2d,p) calculated gauge invariant atomic orbital nuclear magnetic shielding tensors and experimentally recorded chemical shift values. The frontier molecular orbital energies, electronic chemical potentials, chemical hardness, chemical softness and global electrophilicity indices of C-aryl-N-phenyl nitrones have been calculated at DFT/B3LYP/ 6-31+G(d,p) level of theory. Condensed Fukui functions and local electrophilicity indices have been computed to characterize the reactive sites and predict the preferred interactions of C-aryl-N-phenyl nitrones to methyl and ethyl crotonates. The softness matching indices have been evaluated to determine the regioselectivity of the cycloaddition reactions. The theoretical predictions were found to be in complete agreement with the experimental results implying that the DFT based reactivity indices correctly predict the regioselectivities of 1,3-dipolar cycloadditions of C-aryl-N-phenyl nitrones to methyl and ethyl crotonates. Keywords: Theoretical chemistry, Density functional calculations, Cycloadditions, Dipolar cycloadditions, Electrophilicity index, Chemical shifts, NMR shielding tensors, Regioselectivity, Nitrones, Aryl phenyl nitrones C-aryl-N-phenyl nitrones are known for their broad synthetic utility 1. Nitrone cycloadditions to olefins and acetylenes have emerged as versatile methods to generate five-membered heterocycles. Isoxazolidines generated from 1,3-dipolar cycloadditions (1,3DCs) of nitrones to olefins are used as starting compounds for synthesis of various natural products 1-3. The synthesis of N,O-psiconucleosides has been recently designed on the basis of 1,3DC of C-alkoxycarbonylnitrone to enol esters 4. Numerous experimental 2-6 and theoretical investigations 7-13 have been carried out to anticipate the mechanism and bonding nature of 1,3DCs of nitrones. Our interest to predict the configuration, conformation and reactivities of C-aryl-N-phenyl nitrones stems from their capability to act as potent 1,3-dipoles in cycloaddition reactions. The present study will be useful for prediction of the configurations and conformations of unknown C-aryl- N-phenyl nitrones and to predict the favored interactions involved in 1,3-dipolar cycloaddition reactions of C-aryl-N-phenyl nitrones to rationalize the experimentally observed regioselectivities. We have attempted to predict the preferred configuration (Z or E) and conformation of C-aryl-N-phenyl nitrones by a detailed comparison of gauge invariant atomic orbital (GIAO) nuclear magnetic shielding tensors at DFT/B3LYP/6-311+G(2d,p) level of theory and the experimentally recorded 1 NMR chemical shift values available in literature 14-16. In the present study, the frontier molecular orbital energies, electronic chemical potentials 17, chemical hardness and global electrophilicity indices 18-21 have been calculated at DFT/B3LYP/6-31+G(d,p) level of theory for C-aryl-N-phenyl nitrones (Fig. 1). R 1 R 2 3 4 5 2 6 1 N 6' 5' 1' 2' O 4' 3' R 1 = R 2 = (1) R 1 = Cl, R 2 = (2) R 1 = OC 3, R 2 = (3) R 1 =, R 2 =OC 3 (4) ROOC α β R = C 3 (5) R = C 2 C 3 (6) Fig. 1 C-aryl-N-phenyl nitrones (1-4) and the dipolarophiles (5, 6). C 3

ACARJEE & BANERJI: 1, 3 DIPOLAR CYCLOADDITIONS OF C-ARYL-N-PENYL NITRONES 1445 A theoretical rationalization of the reactivities of C-aryl-N-phenyl nitrones to unsymmetrically 1,2-disubstituted dipolarophiles with the functional groups involving varying electronic demands at the 1,2-olefinic positions is presented. Therefore, methyl (5) and ethyl crotonates (6) were selected for the present investigation. We had earlier reported the experimental findings for cycloaddition reactions of C-aryl-N-phenyl nitrones to ethyl crotonate 22. We have calculated the Condensed Fukui functions and local electrophilicity ndices to characterize the reactive sites in C-aryl-N-phenyl nitrones in the present study. Softness matching indices for the possible regioisomeric channels have been computed to rationalize the cycloaddition reactions by considering the case of a four center process. Computational Methods The geometries of the nitrones and the olefins have been optimized by density functional theory with Becke s 23 three-parameter hybrid exchange functional in combination with the gradientcorrected correlation functional of Lee, Yang, and Parr 24 (B3LYP) using 6-31+G(d,p) basis set. Theoretical calculations of NMR typically benefit from an accurate geometry and a large basis set. Cheeseman and coworkers 25 had suggested that B3LYP/6-31G(d) optimized structures are the minimum recommended models for predicting NMR properties. In our present study, GIAO/SCF 1 NMR calculations of the nitrones (geometry optimized at DFT/B3LYP level with a higher basis set 6-31+G(d,p) were carried out at B3LYP level using 6-311+G (2d,p) basis set. The electronic populations were computed from natural population analysis (NPA) at DFT/B3LYP/6-31+G(d,p) level of theory. All calculations were carried out using Gaussian 2003 26 set of programs along with the graphical interface Gauss View 2003. Results and Discussion NMR studies C-aryl and N-phenyl groups are in trans and cis relationships respectively in the Z- and E-isomers of C-aryl-N-phenyl nitrones ((1), (2), (3) and (4), Fig. 2). In Z-configuration, there is increased repulsion between the negative oxygen and the electron-rich aromatic ring favoring the formation of the E-isomer. This effect can be counteracted by the size of the N-substituent. We have computed that the DFT/B3LYP/6-31+G(d,p) calculated ground state energy of E-C,N-diphenyl nitrone is 31.01 kj mol -1 higher than that of its Z-configuration. We have shown earlier 27 that the preferred configuration (E- or Z-) of C, N-disubstituted aldonitrones (C-aryl-Nmethyl nitrones) can be predicted by comparing the GIAO nuclear magnetic shielding tensors of possible geometrical isomers with the experimentally recorded 1 NMR chemical shifts. The optimized geometries of C-aryl-N-phenyl nitrones have been provided in Fig. 3. Koyano and Suzuki 14,15 have reported that the nitrone group exerts an electron attracting effect while interacting mesomerically with the substituents. This is also verified theoretically for C, N-diphenyl nitrone [olefinic proton of trans-1,2-diphenylethylene and α proton of Z-C,N-diphenyl nitrone are computed to be δ 7.513 ppm and δ 8.139 ppm respectively]. The α proton signal in C-aryl-N-phenyl nitrones appears as a sharp singlet about 0.6 ppm downfield of the position in C-aryl-N-methyl nitrones 27. According to theoretical calculations, the nuclear magnetic shielding tensors of α protons in C-aryl-N-phenyl nitrones are 0.6-0.7 ppm higher than that in case of C-aryl-N-methyl nitrones 27. Our theoretical calculations indicate that the presence of p-methoxy group in C-aryl ring shields the nitrone proton signal by 0.11 ppm (Table 1). Two conformations are possible for the Z- and E- configurations of C-aryl-N-phenyl nitrones, (I) and (II) (Fig. 2). The proton nearer to oxygen is expected to be more deshielded due to oxygen bearing a total negative charge. owever, due to a low conformational barrier (of rotation around Cα-C1 bond), 2 and 6 interchange their positions very rapidly and thus the 1 NMR spectrum shows the same time-averaged chemical shift for these protons. This is true of the C-aryl (in 1, 2 and 3) where equal proportions of both conformers are present at equilibrium. 1 NMR chemical shifts of 2 and 6 of ring A are theoretically computed at δ 6.782 ppm and δ 7.396 ppm for E-C,N-diphenyl nitrone (Table 1) and at δ 7.474 ppm and δ 10.162 ppm respectively in the case of Z-C,N-diphenyl nitrone (1). The theoretically computed average values of chemical shift for orthohydrogens of ring A are δ 7.089 ppm and δ 8.818 ppm respectively for E- and Z-isomers of C,N-diphenyl nitrone (1) (Table 1). Experimentally, 2,6 (A) appears at δ 8.31-8.42 ppm 14. Therefore, it is evident that C,N-diphenyl nitrone (1) exists predominantly in

1446 INDIAN J CEM, SEC A, NOVEMBER 2010 Fig. 2 Possible configurations and conformations of C-aryl-N-phenyl nitrones. Z-configuration. Taylar and Sutton 28 have concluded from dipole moment measurements that C-aryl-Nphenyl nitrones exist predominantly in Z-configuration The 1 NMR spectrum shows a time-averaged chemical shift for the ortho-protons in C-phenyl nitrones (in (1)), as also in para-substituted phenyl rings (in (2) and (3)), where equal proportions of both conformers are present at equilibrium. owever, if an ortho-substituent, such as ortho-methoxy group is present (as in (4)), it imposes a larger conformational barrier between the alternative conformations (III) and (IV) (Fig. 2) and also affects the conformational equilibrium in favour of the less hindered conformation (III). As a result, the ortho proton of ring A nearer to oxygen appears at the downfield position of δ 9.40 ppm experimentally 16. It is possible to theoretically distinguish between the chemical shifts of the ortho-protons of ring A in the investigated nitrones by sticking to a particular geometrically optimized conformation. The proton nearer to oxygen is more deshielded due to the oxygen bearing a total negative charge and is computed at δ 10.234 ppm for conformation (III) of (4). owever, 6 of conformation (IV) is calculated to be δ 7.349 ppm. Experimentally, 6 of the C-aryl ring appears at δ 9.40 ppm. This indicates that (III) is the most preferred conformation of (4). A rough estimate about the approximate chemical shifts of 2 (1) (2) (3) (4) (III) Fig. 3 The DFT/B3LYP/6-31G+(d,p) calculated optimized geometries of C-aryl-N-phenyl nitrones.

ACARJEE & BANERJI: 1, 3 DIPOLAR CYCLOADDITIONS OF C-ARYL-N-PENYL NITRONES 1447 and 6 of ring A in (1) can be made from the experimental results. The chemical shift of 6 in (1) can be predicted as ~ δ 9.50 ppm, allowing for a slight shielding factor of ~ δ 0.1 ppm for the methoxy group in (4). Since the time-averaged value for the ortho-protons is δ 8.31-8.42 ppm in (1), the chemical shift for 2 is ~ δ 7.12-7.34 ppm. This is in good agreement to theoretically calculated chemical shift value δ 7.474 ppm of 2 of ring A in (1) (Table 1). Prediction of regioselectivities of 1,3-dipolar cycloaddition reactions of C-aryl-N-phenyl nitrones to methyl and ethyl crotonates The selectivities of 1,3-dipolar cycloaddition reactions of nitrones were recently analyzed in terms of DFT based reactivity indices. The regioselectivities of various 1,3-dipolar cycloaddition reactions of nitrones, such as that between C-(methoxycarbonyl)- N-methyl nitrones and methyl acrylate/vinyl acetate 8,12, C,N-diphenyl nitrone and acrolein 9 /maleimide 10, C-(hetaryl) nitrones and methyl acrylate/vinyl acetate 11, etc. have been reported to be in conformity with those predicted by the relative electrophilicity patterns. The approach has been found to be more reliable than the frontier molecular orbital theory 29. Chattaraj et al. 21 have recently reviewed the utility of the concept of electrophilicity index and its various extensions. Table 1 Comparison of experimentally recorded and DFT/B3LYP/6-311+G(2d,p) calculated GIAO nuclear magnetic shielding tensors of C-aryl-N-phenyl nitrones (relative to TMS in ppm) C,N-diphenyl nitrone a,d (1) =C 2,6 3,5 4 2,6 3 5 4 δ a 7.88 (s) 8.31-8.42 (m) 7.36-7.44 (m) 7.56-7.78 7.36-7.46 =C 2 6 3 5 4 2 6 3 5 4 δ b 8.139 7.474 10.162 7.599 7.757 7.651 8.553 7.763 7.725 7.558 7.630 δ c 8.130 6.782 7.396 7.117 7.533 7.286 7.991 7.330 7.806 7.455 7.635 C-(4-chlorophenyl)-N-phenyl nitrone d (2) =C 2,6 3,5 2,6 3 5 4 δ d 7.87 (s) 8.31(d) 7.41(d) 7.65-7.75 7.36-7.45 =C 2 6 3 5 2 6 3 5 4 δ b 8.113 7.369 10.116 7.586 7.724 8.531 7.736 7.730 7.561 7.646 C-(4-methoxyphenyl)-N-phenyl nitrone d (3) =C 2,6 3,5 2,6 3 5 4 δ d 7.83 (s) 8.39 (d) 6.95 (d) 7.74-7.67 7.33-7.39 =C 2 6 3 5 2 6 3 5 4 δ b 8.029 10.269 7.365 7.013 7.150 8.565 7.719 7.710 7.532 7.582 C-(2-methoxyphenyl)-N-phenyl nitrone e (4) =C 3 4 5 6 2,6 3,5 4 δ e 8.30 (s) 6.82 (d, J = 8.3 z) 7.37 (t, J = 5.5 z) 6.99 (t, J = 7.7z) 9.40 (d, J = 8.0z) 7.67 (dd, J = 7.4z, 3.0z) 7.35-7.37 (m) =C 3 4 5 6 2 6 3 5 4 δ f 8.815 6.847 7.584 7.291 10.234 8.580 7.739 7.694 7.596 7.627 δ g 8.173 6.989 7.551 7.125 7.349 8.466 7.764 7.684 7.527 7.640 a Ref. 14 & 15. b DFT/B3LYP/6-311+G (2d,p) calculated nuclear magnetic shielding tensors (relative to TMS) in ppm of Z configuration (Fig. 2). c DFT/B3LYP/6-311+G (2d,p) calculated nuclear magnetic shielding tensors (relative to TMS) in ppm of E configuration (Fig. 2). d Ref. 15. e Ref. 16. f DFT/B3LYP/6-311+G (2d,p) calculated nuclear magnetic shielding tensors (relative to TMS) in ppm of Z configuration with conformation (III) (Fig. 2). g DFT/B3LYP/6-311+G (2d,p) calculated nuclear magnetic shielding tensors (relative to TMS) in ppm of Z configuration with conformation (IV) (Fig. 2).

1448 INDIAN J CEM, SEC A, NOVEMBER 2010 Table 2 The DFT/B3LYP/6-31+G(d,p) computed optimized energies, frontier orbital energies, electronic chemical potential (µ), chemical hardness (η) and global electrophilicity indices (ω) of C-aryl- N-phenyl nitrones (1 4) and the olefins (5, 6) Comp. Optimized energies (au) OMO energy (ev) LUMO energy (ev) µ (au) η (au) ω (ev) S (au) (1) -631.959-5.850-2.041-3.946 3.809 2.04 3.571 (2) -1091.553-5.959-2.204-4.082 3.755 2.22 3.623 (3) -746.489-5.496-1.823-3.660 3.673 1.82 3.704 (4) -746.488-5.605-1.905-3.755 3.700 1.91 3.676 (5) -345.812-7.510-1.469-4.490 6.041 1.67 2.252 (6) -385.135-7.483-1.442-4.463 6.041 1.65 2.252 Table 3 The DFT/B3LYP/6-31+G(d,p) calculated OMO/LUMO energy gaps for the cycloaddition reactions of C-aryl-N-phenyl nitrones (1 4) and the olefins (5, 6) Reaction LUMO dipolarophile - OMO dipole (ev) LUMO dipole - OMO dipolarophile (ev) OMO LUMO Fig. 4 The DFT/B3LYP/6-31+G(d,p) calculated OMO and LUMO surfaces of C-(4-chlorophenyl)-N-phenyl nitrone (2). DFT/B3LYP/6-31+G(d,p) calculated optimized energies and the FMO energies of C-aryl-N-phenyl nitrones (1-4) have been provided in Table 2. The OMO and LUMO surfaces of C-(4-chlorophenyl)- N-phenyl nitrone (2) have been shown in Fig. 4. The OMO and LUMO energies of C-(4-chlorophenyl)- N-phenyl nitrone (2) are lowered by 0.109 ev and 0.163 ev respectively and that of C-(4-methoxyphenyl)-N-phenyl nitrone (3) are raised by 0.354 ev and 0.218 ev respectively compared to C,N-diphenyl nitrone (1). The OMO/LUMO energy gaps for the cycloaddition reactions of C-aryl-N-phenyl nitrones to methyl (5) and ethyl (6) crotonates have been listed in Table 3. The energy differences indicate that OMO dipole -LUMO dipolarophile interaction results in a lower energy gap than OMO dipolarophile -LUMO dipole interaction, and hence, the former is the predominant interaction involved in each case. This reveals a normal electron demand character of the cycloaddition reactions. The OMO dipole - LUMO dipolarophile energy gap is least along the series for the cycloaddition reactions of C-(4-methoxyphenyl)-N-phenyl nitrone (3) to methyl and ethyl crotonates and largest for the reactions involving C-(4-chlorophenyl)-N-phenyl nitrone (2). (1) + (5) 4.381 5.469 (1) + (6) 4.408 5.442 (2) + (5) 4.490 5.306 (2) + (6) 4.517 5.279 (3) + (5) 4.027 5.687 (3) + (6) 4.054 5.660 (4) + (5) 4.136 5.605 (4) + (6) 4.163 5.578 The electronic chemical potential 17, µ, is the negative of electronegativity and is the index pointing to the direction of the electronic flux during the cycloaddition, i. e., the charge transfer within the system in its ground state. Chemical hardness, η, specifies the resistance to the change transfer process. The chemical hardness is considered to be a measure of the stability of a system; the system having the maximum hardness being the most stable 18. Global softness S is related to global hardness and is given by the inverse of 2η (Ref. 18). The global electrophilicity index 18-21, ω, measures the stabilization in energy when the system acquires an additional electronic charge from the environment. The global electrophilicity index (ω) includes the propensity of the electrophile to acquire an additional electronic charge as well as the resistance to exchange the electronic charge with the environment simultaneously. It can be simply expressed in terms of electronic chemical potential µ and chemical hardness η as ω = µ 2 2η. DFT/B3LYP/6-31+G(d,p) calculated electronic chemical potentials, global hardness, global softness and global electrophilicities of C-aryl-N-phenyl nitrones have been listed in Table 2. The electronic chemical potentials of the nitrones (1), (2), (3) and (4) {-3.660 ev to -4.082 ev) are higher than that of the dipolarophiles (5) (-4.490 ev) and (6) (-4.463 ev). On

ACARJEE & BANERJI: 1, 3 DIPOLAR CYCLOADDITIONS OF C-ARYL-N-PENYL NITRONES 1449 the other hand, the global hardness of the dipolarophiles (5) and (6) (6.041 ev for both the dipolarophiles) are higher than that of the nitrones (1), (2), (3) and (4) (3.673 ev to 3.809 ev). This predicts that the net charge transfer will take place from the dipoles to the dipolarophiles in each case along the cycloaddition reactions, i. e., the normal electron demand character of the cycloaddition reactions. This is in complete agreement with the OMO/LUMO energy gap predictions. The global electrophilicity indices of the nitrones are higher than those of dipolarophiles. This indicates an inverse electron demand character (where charge transfer takes place from dipolarophile to the dipole) for cycloaddition reactions. This is in disagreement with FMO and electronic chemical potential calculations. Benchouk et al. 12 have recently reported a similar difference between the charge transfer directions predicted for 1,3DC of C-(methoxycarbonyl)-N-methyl nitrone to methyl acrylate by the global electrophilicities and electronic chemical potentials/fmo energies of the reactants. The authors have considered the electronic chemical potential and FMO predictions to comment on the direction of charge transfer along the cycloaddition pathway. The global electrophilicity differences between C-(4-methoxyphenyl)-N-phenyl nitrone (3) and the dipolarophiles ( ω = 0.15 for methyl crotonate (5) and ω = 0.17 for ethyl crotonate (6)) indicate the least polar character for the cycloaddition reactions of (3) to (5) and (6) along the series. The electrophilicity differences between C-(4-chlorophenyl)-N-phenyl nitrone (2) and the dipolarophiles ( ω = 0.55 for methyl crotonate (5) and ω = 0.57 for ethyl crotonate (6)) are the highest along the series. The natural charges and electronic populations computed from natural population analysis at DFT/B3LYP/6-31+G(d,p) level of theory at the reactive sites of C-aryl-N-phenyl nitrones [(1), (2), (3) and (4)] and the dipolarophiles (5) and (6) have been listed in Table 4. The charges obtained from natural population analysis 30 show less basis set dependence with respect to the Mulliken charges and are better descriptors of molecular density distribution 31,32. For the C-aryl-N-phenyl nitrones [(1), (2), (3) and (4)], the natural charge on the oxygen atom varies in the range -0.5371 to -0.5550 and that on the carbon atom in the range 0.0008-0.0101. The natural charges on C α of the dipolarophiles (5) and (6) are -0.3479 and -0.3462 and on C β are -0.1365 and -0.1389 respectively. Therefore, the major cycloadducts formed from the cycloaddition reactions of C-aryl-Nphenyl nitrones (1), (2), (3) and (4) to the dipolarophiles (5) and (6) are the isoxazolidines with the oxygen atom of the nitrones (most negative end of the dipole) attached to C β (less negative end of the olefins) of the dipolarophiles. This is in agreement with the experimental studies 22,33,34. It has been reported experimentally that the reactions of C,N-diphenyl nitrone to methyl crotonate 33,34 and ethyl crotonate 22 give rise to 4-carbomethoxy substituted and 4-carbethoxy substituted isoxazolidines respectively. We had earlier reported 22 that the 3,4-trans-4,5-trans-2-phenyl-3-aryl-4-carbethoxy-5-methylisoxazolidines are obtained regioand stereoselectively as the major products with the corresponding diastereomeric 3,4-cis-4,5-trans-isomers as minor cycloadducts from the cycloaddition reactions of C-aryl-N-phenyl nitrones to ethyl crotonate (6). Merino et al. 8 have also reported that the simplest analysis based upon the charges of the atoms directly involved in the formation of the two new sigma bonds in nitrone cycloaddition reactions can correctly predict the experimental findings. The electronic population at the oxygen atom of C-aryl-Nphenyl nitrones (neutral species of (1), (2), (3) and (4)) varies in the range 8.5372-8.5550 and that of the cationic species in the interval 8.2954-8.3363. The electronic population at the oxygen atom of the corresponding anionic species varies in the range 8.6408-8.6531. The electronic populations at the carbon atom of C-aryl-N-phenyl nitrones, (1), (2), (3) and (4) in the case of the cationic, neutral and anionic species vary in the range 5.8600 5.9021, 5.9899 5.9992 and 6.1250 6.1360 respectively. Domingo et al. 35 reported the theoretical study on the regioselectivity of 1,3-dipolar cycloaddition reactions using DFT-based reactivity indices. The report summarized that the regioselectivity can be consistently explained by the most favorable interactions between the highest nucleophilic and electrophilic sites of the reagents. The calculation of Fukui functions of an atom in a molecule proves to be a useful criterion to characterize the reactive sites within a chemical species. The Fukui functions can be written in terms of the respective electron populations of the cationic [q k (N-1)], neutral [q k (N)] and anionic [q k (N+1)] systems. For nucleophilic attack: f + k = q k (N+1) q k (N) and - for electrophilic attack: f k = q k (N) q k (N-1). The

1450 INDIAN J CEM, SEC A, NOVEMBER 2010 Table 4 The DFT/B3LYP/6-31+G(d,p) calculated natural population analysis of C-aryl-N-phenyl nitrones (1 4) and the olefins (5, 6). [k is the site at which the property is being evaluated according to Fig. 5] Comp. Species k Natural charge Natural population Core Valence Rydberg Total (1) Cationic O1-0.2953 1.9999 6.2791 0.0164 8.2954 C3 0.1401 1.9992 3.8424 0.0184 5.8600 Neutral O1-0.5398 1.9999 6.5207 0.0193 8.5399 C3 0.0042 1.9992 3.9781 0.0185 5.9958 Anionic O1-0.6434 1.9999 6.6219 0.0216 8.6434 C3-0.1292 1.9992 4.1045 0.0256 6.1293 (2) Cationic O1-0.3099 1.9999 6.2935 0.0165 8.3099 C3 0.1219 1.9992 3.8607 0.0183 5.8782 Neutral O1-0.5371 1.9999 6.5180 0.0193 8.5372 C3 0.0008 1.9992 3.9816 0.0184 5.9992 Anionic O1-0.6407 1.9999 6.6193 0.0216 8.6408 C3-0.1250 1.9992 4.1025 0.0233 6.1250 (3) Cationic O1-0.3363 1.9999 6.3200 0.0164 8.3363 C3 0.0979 1.9992 3.8846 0.0183 5.9021 Neutral O1-0.5550 1.9999 6.5357 0.0194 8.5550 C3 0.0101 1.9992 3.9723 0.0184 5.9899 Anionic O1-0.6530 1.9999 6.6316 0.0216 8.6531 C3-0.1321 1.9992 4.1067 0.0262 6.1321 (4) Cationic O1-0.3192 1.9999 6.3036 0.0157 8.3192 C3 0.1134 1.9992 3.8685 0.0190 5.8867 Neutral O1-0.5459 1.9999 6.5267 0.0193 8.5459 C3 0.0026 1.9992 3.9788 0.0194 5.9974 Anionic O1-0.6462 1.9999 6.6249 0.0214 8.6462 C3-0.1359 1.9992 4.1065 0.0303 6.1360 (5) Cationic C α -0.0441 1.9990 4.0295 0.0157 6.0442 C β 0.0898 1.9992 3.8962 0.0148 5.9102 Neutral C α -0.3479 1.9989 4.3329 0.0161 6.3479 C β -0.1365 1.9991 4.1227 0.0148 6.1366 Anionic C α -0.4937 1.9989 4.4498 0.0450 6.4937 C β -0.4170 1.9992 4.3712 0.0466 6.4170 (6) Cationic C α -0.0659 1.9990 4.0514 0.0154 6.0658 C β 0.0753 1.9992 3.9113 0.0142 5.9247 Neutral C α -0.3462 1.9989 4.3314 0.0159 6.3462 C β -0.1389 1.9991 4.1251 0.0147 6.1389 Anionic C α -0.4924 1.9989 4.4485 0.0450 6.4924 C β -0.4181 1.9991 4.3719 0.0471 6.4181 Table 5 The DFT/B3LYP/6-31+G(d,p) calculated local electrophilicity indices, electrophilic and nucleophilic Fukui functions and local softnesss of C-aryl-N-phenyl nitrones (1 4) and the olefins (5, 6). [k is the site at which the property is being evaluated according to Fig. 5] Comp. k + f k s + (au) + ω k (ev) - f k s - (au) (1) O1 C3 0.104 0.133 0.371 0.475 0.213 0.272 0.245 0.136 0.875 0.486 (2) O1 C3 0.104 0.126 0.377 0.456 0.231 0.280 0.227 0.121 0.822 0.438 (3) O1 C3 0.098 0.142 0.363 0.526 0.178 0.258 0.219 0.088 0.811 0.326 (4) O1 C3 0.100 0.139 0.368 0.511 0.191 0.265 0.227 0.111 0.831 0.408 (5) C α 0.146 0.329 0.244 0.304 0.685 C β (6) C α C β 0.280 0.146 0.279 0.631 0.329 0.628 0.467 0.241 0.460 0.226 0.280 0.214 0.509 0.631 0.482 local electrophilicity index ω k can be expressed as: ω k = ωf + k, where f + k is the Fukui function for a nucleophilic attack. Theoretical analysis of the regioselectivities of 1,3-dipolar cycloaddition reactions of nitrones have been reported 12,35 in terms of local electrophilicity index ω k and the condensed Fukui function for electrophilic attack f - k. We have recently rationalized 13 the experimentally observed regioselectivities of the cycloaddition reactions of 1-pyrroline-1-oxide to benzylidene acetophenone and methyl cinnamate by means of local electrophilicity indices and condensed Fukui functions of the reactants. The condensed Fukui functions f + - k, f k and the local electrophilicity indices ω k of C-aryl-N-phenyl

ACARJEE & BANERJI: 1, 3 DIPOLAR CYCLOADDITIONS OF C-ARYL-N-PENYL NITRONES 1451 nitrones, (1), (2), (3) and (4), and the dipolarophiles (5) and (6) have been collected in Table 5. In the case of the dipolarophiles (5) and (6), C β has the higher local electrophilicity index, ω k, than C α. Therefore, C β will be the preferred site for the nucleophilic attack by the dipoles. For the dipoles (1), (2), (3) and (4), - oxygen atom has higher f k compared to the carbon atom. Therefore, C β of the dipolarophiles will be linked to the oxygen atom of the dipoles following the favorable interaction between the highest nucleophilic and electrophilic sites of the reagents (Fig. 5). This predicts the generation of 4-carbomethoxy/carbethoxy substituted isoxazolidines from the cycloaddition reactions. This is in complete agreement with the experimental studies. The local softnesses s k + and s k - can be calculated + - from condensed Fukui functions f k and f k and the global softness S as s + k = S f + k, and, s - k = S f - k. The regioselectivity criteria of four center reactions is explained by Gazquez Mendez rule. Application of the rule to cycloaddition reactions reduces to the kl calculation of softness matching index ij for the possible regioisomeric channels along the kl cycloaddition pathway. ij can be expressed in terms kl of local softnesses as: ij = (s - i -s + k ) 2 + (s - j -s + l ) 2, where atoms i and j of the nucleophile interact with atoms k and l of the electrophile to give rise to the preferred regioisomer and s - i, s + k, s - j, and s + l are the respective local softnesses of the reactive sites. Calculation of softness matching index ensures the simultaneous fulfillment of local SAB concept at the two reacting termini. The reaction pathway involving lower value kl of ij will be the favored one. For the cycloaddition reactions of C-aryl-N-phenyl nitrones (1), (2), (3) and (4) to methyl (5)/ethyl crotonates (6), two possible regioisomeric channels leading to the generation of 4-carbomethoxy/ carbethoxy substituted and 5-carbomethoxy/ carbethoxy substituted isoxazolidines have been considered. The softness matching indices are given by Eqs(1) and (2). 4-carbomethoxy/carbethoxy substitution = (s - O1- s + Cβ) 2 + (s - C3 - s + Cα) 2 (1) 5-carbomethoxy/carbethoxy substitution = (s - C3 - s + Cβ) 2 + (s - O1 - s + Cα) 2 (2) The softness matching indices have been listed in Table 6. The 4-carbomethoxy/carbethoxy substitution in each case is smaller than 5-carbomethoxy/carbethoxy substitution. This suggests that 4-carbomethoxy/carbethoxy substituted isoxazolidines will be generated from the cycloaddition reactions of C-aryl-N-phenyl nitrones, Fig. 5 Prediction of the favored interactions using DFT-based indices. Table 6 DFT/B3LYP/6-31+G(d,p) calculated softness matching index (computed in au) for 1,3DCs of C-aryl- N- phenyl nitrones (1 4), and the olefins (5, 6) React. 4-carbomethoxy/carbethoxy subst 5-carbomethoxy/carbethoxy subst. [(s - C3 - s + C5) 2 + (s - O1 - s + C4) 2 ] [(s - O1- s + C5) 2 + (s - C3 - s + C4) 2 (1) + (5) 0.084 0.319 (1) + (6) 0.086 0.318 (2) + (5) 0.048 0.280 (2) + (6) 0.050 0.279 (3) + (5) 0.032 0.325 (3) + (6) 0.033 0.324 (4) + (5) 0.046 0.302 (4) + (6) 0.047 0.300

1452 INDIAN J CEM, SEC A, NOVEMBER 2010 (1), (2), (3) and (4), to the dipolarophiles (5) and (6), and hence, is in complete agreement with the experimental studies. Conclusions The preferred configuration and conformation of C-aryl-N-phenyl nitrones can be predicted by comparing DFT/B3LYP/6-311+G(2d,p) calculated GIAO nuclear magnetic shielding tensors with the experimentally recorded 1 NMR chemical shifts of the nitrones. The DFT based reactivity indices correctly predict the favorable interactions involved along the cycloaddition pathway of C-aryl-N-phenyl nitrones to methyl and ethyl crotonates and can be utilized to rationalize the experimentally observed regioselectivities of the cycloaddition reactions of C-aryl-N-phenyl nitrones. The frontier molecular orbital energies and electronic chemical potential calculations predict the net charge transfer from the dipoles to the dipolarophiles along the cycloaddition reactions C-aryl-N-phenyl nitrones to methyl and ethyl crotonates. The regioselectivity predictions based on softness matching indices are found to be in complete agreement with the experimental findings. The investigation will be informative for prediction of configuration and conformation of unknown C-aryl- N-phenyl nitrones and also to rationalize the experimentally observed regioselectivities of 1,3-dipolar cycloaddition reactions of C-aryl-Nphenyl nitrones to unsymmetrically 1,2-disubstituted olefins. Acknowledgement One of the authors (NA) is thankful to Council of Scientific and Industrial Research, New Delhi for financial support and University of Calcutta, Kolkata, for computational facilities. References 1 Merino P, Nitrones and Analogues in Science of Synthesis, Chap. 13, (Georg Thieme Verlag, Stuttgart, Germany) 2004, p 511. 2 Feuer & Torssell K B G, Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis, 2 nd Edn, (Wiley- International, New York) 2008. 3 Padwa A & Pearson W, Synthetic Applications of 1,3 Dipolar Cycloaddition Chemistry towards eterocycles and Natural Products, (John Wiley & Sons) New York, 2002. 4 Iannazzo D, Piperno A, Pistarà V, Rescifina A & Romeo R, Tetrahedron, 58 (2002) 581. 5 Banerji A, Biswas P K, Bandyopadhyay D, Gupta M, Prangé T & Neumann A, J eterocycl Chem, 44 (2007) 137. 6 Banerji A, Bandyopadhyay D, Sengupta P, Basak B; Prangé T & Neumann A, Tetrahedron Lett, 47 (2006) 3827. 7 Carda M, Portolés R, Murga J, Uriel S, Marco J A, Domingo L R, Zaragoźa R J & Röper, J Org Chem, 65 (2000) 7000. 8 Merino P, Revuelta J, Tejero T, Chiacchio U, Rescifina A & Romeo G, Tetrahedron, 59 (2003) 3581. 9 Domingo L R, Benchouk W & Mekelleche S M, Tetrahedron, 63 (2007) 4464. 10 Domingo L R, Aurell M J, Arno M & Sa ez J A, J Mol Struct: TEOCEM, 811 (2007) 125. 11 Merino P, Tejero T, Chiaccio U, Romeo G & Rescifina A, Tetrahedron, 63 (2007) 1448. 12 Benchouk W & Mekelleche S M, J Mol Struct: TEOCEM, 852 (2008) 46. 13 Acharjee N, Das T K, Banerji A, Banerjee M & Prangé T, J Phys Org Chem, (2010) doi: 10.1002/poc.1690. 14 Koyano K & Suzuki, Tetrahedron Lett, 15 (1968) 1859. 15 Koyano K & Suzuki, Bull Soc Chem Japan, 42 (1969) 3306. 16 Banerji A, Biswas P K, Gupta M, Saha R & Banerji J, J Indian Chem Soc, 84 (2007) 1004. 17 Parr R G & Yang W, Density Functional Theory of Atoms and Molecules, (Oxford University Press, NewYork) 1989. 18 Parr R G, Szentpaly L V & Liu S, J Am Chem Soc, 121 (1999) 1922. 19 Domingo L R, Aurell M J, Pe rez P & Contreras R, Tetrahedron, 58 (2002) 4417. 20 Pe rez P, Domingo L R, Aurell M J & Contreras R, Tetrahedron, 58 (2003) 3117. 21 Chattaraj P K, Sarkar U & Roy D R, Chem rev 106 (2006) 2065. 22 Banerji A, Dasgupta S, Sengupta P, Prangé T & Neuman A, Indian J Chem, 43B (2004) 1925. 23 Becke A D, J Chem Phys, 98 (1993) 5648. 24 Lee C, Yang W & Parr R G, Phys Rev B, 37(1988) 785. 25 Cheeseman J R, Trucks G W, Keith T A & Frisch M J, J Chem Phys, 104 (1996) 5497. 26 Gaussian 03, Rev. D.01 (Gaussian Inc, Wallingford CT) 2004. 27 Acharjee N, Banerji A, Banerjee M & Das T K, Indian J Chem, 48A (2009) 1627. 28 Taylar T W J & Sutton L E, J Chem Soc, (1931) 2190; Taylar T W J & Sutton L E, J Chem Soc, (1933) 63. 29 Corsaro A, Pistará V, Rescifina A, Piperno A, Chiacchio M A, & Romeo G, Tetrahedron, 60 (2004) 6443. 30 Mayo P, ecnar T & Tam W, Tetrahedron, 57 (2001) 5931. 31 Molder U, Burk P & Koppel I A, Int J Quant Chem, 82 (2001) 73. 32 Proft F D, Martin J M L & Geerlings P, Chem Phys Lett, 250 (1996) 393. 33 uisgen R, Grashey R, auck & Seidl, Chem Ber, 101 (1968) 2043, 2548, 2559, 2568; uisgen R, Grashey R, auck & Seidl, Chem Ber, 102 (1969) 736. 34 Joucla M, Grée D & amelin J, Tetrahedron 29 (1973) 2315. 35 Aurell M J, Domingo L R, Pe rez P & Contreras R, Tetrahedron, 60 (2004) 11503.