A perturbational molecular orbital (PMO) treatment has been
developed for the title 1,3-cycloaddition reactions. Molecular orbitals
were computed by the CND0/2 method. The results obtained at
different levels of approximation of the PMO theory are presented.
The regiochemistry is also discussed on the basis of the charge
transfer model by using EA\u27s and IP\u27s

G. Zecchi

M. G. Cattania

P. L. Beltrame

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CROATICA CHEMICA ACTA CCA-1123 CCACAA 51 (4) 285-292 (1978) YU ISSN 0011-1643 541.124 :547 .72 :547.73 Original Scientific Paper PMO Calculations for the Regiochemistry of 1,3-Cycloadditions of 3,5-Dichloro-2,4,6-trimethylbenzonitrile Oxide to Thiophen, Furan, Benzothiophen, and Benzofuran P. L. Beltrame and M. G. Cattania Istituto di Chimica Fisica, Universi td e Centro del CNR, 20133 - Milano, Italy and G. Zecchi Istituto di Chimica Industriale, Universitd •e Centro del CNR, 20133 - Milano, Italy Received May 11, 1978 A perturbational molecular orbital (PMO) treatment has been developed for the title 1,3-cycloaddition reactions. Molecular orbitals were computed by the CND0/2 method. The results obtained at different levels of approximation of the PMO theory are presented. The regiochemistry is also discussed on the basis of the charge transfer model by using EA's and IP's. INTRODUCTION In spite of the extensive literature on 1,3-dipolar cycloadditions, regio-selectivity and reactivity phenomena in these reactions are still worthy of attention. In fact, classical electronic theories of organic chemistry appear to be inadequate to provide satisfactory general rules, and different opinions have been put forward on the nature of 1,3-dipolar cycloadditions1•2• In recent years, aiming at the rationalization of the experimental findings in this field, various authors have developed theoretical approaches according to the perturbational molecular orbital theory3•7• Because of the usual com-plexity of the systems which give rise to 1,3-dipolar cycloadditions, more accurate quantum-chemical methods could be adopted only in a few exceptio-nally simple cases, i.e. the 1,3-cycloaddition of diazomethane to ethylene8 and that of fulminic acid to acetylene9•10 and ethylene.10 We have recently reported11 that 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide (1) cycloadds to thiophen (2) and furan (3) in a regiospecific manner, at least within the experimental detection limits, to give the fused 2-isoxa-zolines (4) and (5), respectively. On the other hand, 1,3-cycloadditions of 1 to benzothiophen (6) and benzofuran (7) afford two possible orientational iso-mers in a similar proportion (8 : 9 = 70 : 30; 10 : 11 = 60 : 40) . The exceptionality of these dipolarophiles as well as their molecular geo-metry suitable for a perturbational treatmeent prompted us to seek a theore-tical support to the observed regioselectivities. Although part of the results obtained was communicated in a previous paper11 , a full description of our 286 P . L. BELTRAME ET AL. ArC=N-+O 1 3 ( 1) -Thiophen (2) Furan (3) Benzothiophen (6j Me Cl · Ar=_K_Me -X Benzofuran (7) _ u-(0~~ (.,)--!/..,N (4) 5 Ar r(o) l(_")4N (5) 0 Ar work seems to be advisable because it involves computations at different levels of approximation of the PMO theory. In the present paper we also discuss the regiochemistry on the basis of the charge-transfer model. COMPUTATIONS Within the framework of second-order perturbation theory, the treatment of Salem and Devaquet leads to three components of the interaction energy between two conjugated systems12• These are a repulsive term (Erep) and an attractive term (Emix), both of which depend on the overlap of interacting orbitals, as well as a polar term (EpoJ) representing the electrostatic interaction between net charges on the atoms: · Erep = - ~ (qr+ qr.) 'llrr' Srr' rr' occ vac (~ cjr ck'r' 'llrr->2 Emix =-2 ~ ~ rr' k' Ek'-Ei occ vac (~ ckr cj'r' 'llrr' )2 -2 ~ ~ rr' j' k E;;.-Ei' Epol = l: /'J.qs /'J.q5/Rss' ss' The symools r and r' indicate interacting atoms on two molecules ·(each atom contributes a 2pn: orbital) : qr and qr' are n: electron charges, 'Y]rr' and Srr' are resonance and overlap integrals, respectively; j and k are indices for the molecular orbitals of the first molecule, j' and k' refer analogously to the second molecule; Cjr is the coefficient of the 2pJi orbital of the atom r in the PMO CALCULATIONS OF 1,3-CYCLOADITIONS 287 j-th LCAO molecular orbital, the energy of which is Ei. In the polar term, /},. q. and /},. q.· are net electronic charges on the atoms s and s', which are at a distance Rss' from each other, the summation in this case runs over all pairs of atoms13. Resonance integrals were evaluated by the equations14 'llcc = - 21 Sec; 'llco = - 26 Seo where 'l']cc and 'l']co are in e V. We assumed that the two molecules remained planar during the approach. Energies were calculated for the reactions giving two regioisomers for several configurations of the approach; in each case, the centre (A) of the C1 • •• 0 3 dipole on the y-axis of 1 and the centre (B) of the CaC~ double bond* on the y'..:axis of the dipolarophile ,were on the z-axis perpendicular to the mole-cular plane of 1. The interacting four centres were on a vertical plane per-pendicular to both molecular planes. In symmetric configurations, the mole-cular planes were parallel and both incipient bond lenghts were equal; in unsymmetric configurations, the bond lengths were different. We varied the distances between the interacting atoy{is independently from 5 to 8 a. u. To take into account the deviations of the overlapping orbitals from the alignment required for pure a, a or :rt, :rt, overlapping we used equations of the type10: srr' = srr' (er, er) cos cp cos{} - srr' (it, it) sin cp sin{} In this equation we calculated the integrals Srr' (cr, cr) and Srr' (:rt, :rt) using the standard formulae16; cp and {} are the angles between the line joining atoms r and r' and the axes of the 2pn orbitals centred on r and on r' (see Figure 1). The difference {} - cp = 'ljJ represents the angle between the two molecular planes. r I I I I I I I I \ \ \ \ I \ \ \ \ \ \ I \ Figure 1. Geometry of a unsymmetric four-centre approach of the reactants. We named the two possible isomers C1 Ccx and C1C~, respectively. The mole-cular geometry for 1 was deduced as described previously.17 We used the geometries determined by Bak et al. for thiophen1s and furan19. Geometrically, * a and ~ relate to the heteroatom. 288 P . L . BELTRAME ET AL. we built benzothiophen and benzofuran from a benzene ring and the corre-sponding five-membered heterocyclic ring in which the appropriate C-C bond was opened to 1.397 A. To calculate orbital energies, coefficients, and net charges, we employed the CND0/2 method20 , using an spd basis set for chlo-rine and sulphur atoms. We considered only n-type molecular orbitals. For thiophen and benzothiophen, the highest occupied molecular orbital was cen-tred mostly on the sulphur atom: as HOMO, we chose the next occupied MO below the localized sulphur orbital. Figure 2 shows the energies and coefficients of the frontier orbitals of the five reactants. G 0 (1) -.367 .625 587 395 .480 .421 .571 .~70 . . .447 .182 <- "'> -<~ : .. ~ H-<-:<4.l ~=r;-~;,~H- <'•25>M- --Figure 2. Energies (in parentheses/hartrees) and coefficents for the frontie r molecular orbital~ of nitrile oxide (1), thiophen (2), furan (3) , benzothiophen (6), and benzofuran (7). Table I gives frontier interaction energies, while Table II collects the inter-action energies calculated using the complete PMO treatment for symmetrical approaches (R = R c1c = Ro3c ). Figure 3 shows the energy plots for the different approaches in thiophen and furan: for symmetric configurations and, in the case of the favoured orientation, for two unsymmetric configurations with 'ljJ = + 30° (C,C"' < 0 3 Cp) and 1jJ = - 30° (C1 C"' > 0 3 Cp) . TABLE I Calculated Frontier Energies (E/meV) 2 3 6 7 R = 7.0 a.u. cc.: -1.01 -1.17 -0.92 -0.90 CCi: -0.84 -0.88 -0.78 -0.70 R = 3.3 a .u . cc.: -705 -748 -666 -570 CCi : -742 -852 -693 -671 PMO CALCULATIONS OF 1,3-CYCLOADITIONS 289 TABLE II Calculated Energies (E/meV) as a Function of Distance R (a.u.) for Symmetrical Approach R Emix Erep Epol Etot Emix Erep Epol Etot Formation of C1 C"' Formation of C1 C~ 2 8 -0.51 1.08 -17.5 -16.9 -0.51 1.06 17.3 17.9 7 -5.01 10.0 -23.9 -18.9 -4.99 9.86 23.5 28.4 6 -42.3 80.9 -33.3 5.3 -42.1 79.5 32.5 69.9 5 -292.2 530.6 -47.7 190.7 -289.7 523.7 46.1 280.1 3 8 -0.52 1.10 -3.76 -3.18 -0.50 1.10 3.68 4.28 7 -5.02 10.3 -4.40 0.88 -4.90 10.3 4.59 9.99 6 -42.2 82.7 -4.59 35.9 -41.4 82.7 5.60 46.9 5 -289.2 543.3 -3.02 251.1 -285.8 543.6 6.37 264.2 6 8 -0.52 1.10 -21.2 -20.6 -0.52 1.10 21.0 21.6 7 -5.08 10.0 -28.8 -23.9 -5.07 9.8 28.5 33.2 6 -43.0 80.3 -40.0 -2.7 -42.8 79.4 39.3 75.9 5 -297.3 527.5 -56.9 173.3 -295.3 522.6 55.5 282.8 7 8 -0.53 1.10 -2.24 -1.67 -0.51 1.11 3.29 3.89 7 -5.10 10.0 -2.83 2.07 -5.00 10.3 4.17 9.47 6 -43.0 81.0 -3.03 35.0 -42.5 83.2 5.12 45.8 5 -294.6 533.6 -1.41 237.6 -294.5 545.3 5.62 256.4 Thiophen Fu ran ' +m E ' total C1 Cµ meV 111 =00 +40. ., ' +20. ·. \ c, ca -...._....-111=+300 0. \ 111= 0° I ·· ... · .. 11' =-30 I \ ~=-3~~"·· ···· \ ·. \ ··. ·· ........ \ ' ' ' 1jJ =+30 -20. ' --------c1ca 6 7 rA8/a.u. 6 7 rAB/a.u. Figure 3. Perturbation energy as a function of distance for different types of approach giving two possible regioisomers in thiophen and furan. (For definition of tjl, see text.) 290 P. L. BELTRAME ET AL. DISCUSSION In its simplest frontier-orbital approach, the perturbation theory states that the interaction between the HOMO of one reactant and the LUMO of the other governs the reaction pathway . This interaction occurs in the direction offering the maximum overlapping of the lobes. As shown in Figure 2, the two HOMO/LUMO interactions with the best overlapping give opposite effects: if the dipole LUMO is controlling, the larger coefficients lead to the four C1 C" isomers, if the dipole HOMO is controlling, the four C,C p isomers are predicted. On the other hand, the HOMO/LUMO pair possessing the nearest energy levels, responsible for the most effective interaction, favours the C1 Cp isomers for thiophen and benzothiophen and the C, Ca isomers for furan and benzofuran. Furthermore, the frontier-orbital approach, which takes into account both interactions as well as the resonance integrals, predicts for all dipolarophiles the formation of C1C" compounds at large distances, and of OyCp ones at short distances (Table I). Thus, these different frontier approaches are not able to rationalize the four experimental orientations at the same time. The results for the symmetric approaches using the complete PMO treatment (see E101a1 in Table II) indicate that the C1 C" isomers are preferred at ,various distances for all dipolarophiles. These predictions are in agreement with the experimental findings only for thiophen and furan. Tp.is may be accounted for on considering that the model of approach adopted does not consider mole-cular deformations of the reactants which probably intervene in the case of benzothiophen and benzofuran owing to the size of the molecules. Figure 3 shows a comparison between symmetrical and unsymmetrical approaches to the formation of the c, c" isomers in thiophen and furan, i. e. compounds 4 and 5, respectively. It is noteworthy that, particularly in the case of thiophen, PMO calculations suggest a non-synchronous mechanism of cycloaddition in which the bond formation is more advanced between the oxygen of 1 and the Cp atom of dipolarophile.* The above considerations are conditioned by the CNDO method employed to determine coefficients and orbital energies. As an alternative approach, the occupied orbital energies might be substituted by the negatives of the experi-mentally determined vertical IP's and the vacant orbital energies by the values of the EA's. So, a CI or charge-transfer model is implicitly assumed•. This pro-cedure has recently been followed for the 1,3 dipolar cycloadditions of benzoni-trile oxide to furan, 2,3-dihydrofuran, and cyclopentadiene21 • The available data are the ionization potential of furan (8 .88 eV)22 , benzofuran (8.66)23, thio-phen (8.87)24, benzothiophen (8.75)23 , benzonitrile oxide (8.96)20, and 2,4,6-tri-methylbenzonitrile oxide (8.35)25• In ref 21, the values - 1 and 2.1 eV are reported as estimated LUMO energies of benzonitrile oxide and furan, re-spectively, and -10 eV as an estimated HOMO energy of benzonitrile oxide. A value of 1.2 eV can be obtained for the LUMO of benzofuran by the same * Since thiophen and furan easily undergo electrophilic substitutions at the a position, the formation of 4 and 5 could prima facie be thought of as an electrophilic attack of the C atom of 1 to the a position of the heterocycle follo~ed by the cycli-zation of a zwitterionic intermediate. However, in addition to the previous evidence against a stepwise mechanism for 1,3-dipolar cycloadditions1•5•21, one should consider that such an intermediate, if formed, is expected to give the corresponding oxime, thus restoring the aromaticity of the heterocyclic ring. PMO CALCULATIONS OF 1,3-CYCLOADITIONS 291 considerations as employed for furan. The experimental values indicate: (a) a small gap between the HOMO energies of furan and benzofuran (and those of thiophen and benzothiophen), (b) a sensible raising of HOMO in going from benzonitrile oxide to 2,4,6-trimethylbenzonitrile oxide that suggests, an ana-logous displacement even if less marked, in going to 7. The estimated values indicate an energy gap between the LUMO's of furan and benzofuran that more than compensates the gap between the corresponding HOMO's. These obser-vations suggest that, in going from furan to benzofuran, the interaction dipole HOMO-dipolarophile LUMO might become competitive with the other one: as a result, a mixture of C1 C" and c;c~ products is obtained . ArCNO Fur an . Benzofuran / ----.--*<-An analogous mixture was found in the cycloaddition of benzonitrile oxicfe to benzofuran. In this mixture however, the C1C" type adduct was prevailing26 • The lesser extent of the intervention of the interaction dipole HOMO-dipo-larophile LUMO can be attributed to the lower HOMO of benzonitrile oxide when compared with 1. If the absolute estimated values of LUMO energies for furan and benzo-furan are also accepted, besides their more significant gap, a value in the range of 1-1.3 eV for LUMO of 1 may be provided. The corresponding reported value for benzonitrile oxide seems to be somewhat low as in the case of the estimated HOMO energy value when compared with the experimental one. So, the regiochemistry of all reactions under study seems to receive a satisfactory explanation by the above simple qualitative frontier approach, which uses the HO and LU orbital energies derived from experimental data. REFERENCES 1. R. Hui s gen, J. Org. Chem. 33 (1968) 2291 and 41 (1976) 403. 2. R. A. Firestone, J. Org. Chem. 33 (1968) 2285 and 37 (1972) 2181. 3. G. K 1 op man (Ed.), Chemical Reactivity and Reaction Path, Wiley, New York 1974 and references cited therein. 4. R. Sus t man n, Pure Appl. Chem. 40 (1974) 569. 5. K. N. Houk, Accounts Chem. Res. 8 (1975) 361. 6. J. Bast id e, N. E 1 Ghan dour, and 0. Henri - Rous sea u, Bull. Soc. Chim. Fr. (1973) 2890; J. Bast id e and 0. Henri - Rousseau, ibid. (1973) 2294 and (1974) 1037. . 7. R. Gree, F. Tonnar d, and R. Carrie, Tetrahedron Lett. (1974) 135 and Tetrahedron 32 (1976) 675. 8. G. Leroy and M. San a, Tetrahedron 31 (1975) 2091. 9. P. B e 1 tr am e, M. G. Catt an i a, and M. S i mo nett a, Phys. Chem. N. F. 91 (1974) 225. 10. D. Popping er, Austr. J. Chem. 29 (1976) 465. 11. P. L. Be 1 tram e, M. G. Catt an i a, V. Red a e 11 i, and G. Z e cc hi, J . Chem. Soc. Perkin II (1977) 706. 12. L. Sa 1 em, J. Amer. Chem. Soc. 90 (1968) 543, 553; A. Dev a q u et and L. S a 1 em, ibid. 91 (1969) 3793. 13. A. Dev a q u et, Mol. Phys. 18 (1970) 233. 292 P . L. BELTRAME ET AL. 14. K. N. Houk, J . Sims, C. R. Watts, and L. J. Lusk us, J . Amer. Chem. Soc. 95 (1973) 7301. 15. T. In u k a i, H. Sato, and T. Kojima, Bull. Chem. Soc. Jap. 45 (1972) 891. 16. R. S. Mulliken, C. A. Rieke, D. Orloff, and H. Orloff, J . Chem. Phys. 17 (1949) 1248. 17. P . Beltrame, P. L. Beltrame and M. G. Cattania, Gazz. Chim. Ital. 105 (1975) 59. 18. B. B a k, D. Christensen, L . Hans en - Ny g a a rd, and F . R. Ander-s en, J. Mol. Spectrosc. 7 (1961) 58. 19. B. Bak, D. Christensen, W. B. Dixon, L. Hansen-Nygaard, J. R. Anders en, and M. Shott 1 an de r, J . Mol. Spectrosc. 9 (1962) 124. 20. J. A. Pop 1 e and G. A. Se g a 1, J . Chem. Phys. 44 (1966) 3289; D. P. Sant r y and G. A. S e gal, ibid. 45 (1967) 158. 21. P . Car am e 11 a, G. Ce 11 er in o, A. Corsi co Cod a, A . Gamba In-v er n i z z i, P. Gr ii n anger, K . N. Houk, and F . M a r in on i A 1 bin i, J . Org. Chem. 41 (1976) 3349. 22. D. W. Turner, C. B a k er, A. D. B a k er, and C. R. Brund 1 e, Molecular Photoelectron Spectroscopy, Wiley-Interscience, New York 1970 p . 329. 23. M. H. Pa 1 mer and S. M. F. Kennedy, J . Chem. Soc. Perkin II (1974) 1893, 24. P. J . Derrick, L. As brink, 0. Ed q vis t, B-0. Joh s son, and E. Lind ho 1 m, Int. J . Mass. Spectrom. Ion. Phys. 6 (1971) 177. 25. J . B as tide, J. P. Mai er, and T. Kub o ta, J . Electron Spectrosc. Relat. Phenom. 9 (1976) 307. 26. P. Car a me 11 a, G. Ce 11 er in o, and F . Marino n e A 1 bin i, Fifth Inter-national Congress of Heterocyclic Chemistry, Ljubljana (1975). SAZETAK PMO-racuni regiokemije 1,3-cikloadicija oksida 3,5-diklor-2,4,6-trimetilbenzonitrila tiofena, furana, benzotiofena i benzofurana Pier Luigi Beltrame, Maria Grazia Cattania i Gaetano Zecchi Razvijen je PMO-formalizam za proucavanje regiokemije 1,3-cikloadicije oksida 3,5-diklor-2,4,6-trimetilbenzonitrila i tiofena, furana, benzotiofena i benzofurana. Mole-kularne orbitale upotrijebljene u PMO-racunima dobivene su s pomoeu CND0/2-- aproksimativne SCF MO metode. Regiokemija je takoder diskutirana na temelju modela prijenosa naboja, za koji su upotrijebljeni elektronski afiniteti i ionizaciJski potencijali molekula koje sudjeluju u spomenutim 1,3-cikloadicijsl{!im reakcijama. ISTITUTO DI CHIMICA FISICA, UNIVERSITA E CENTRO DEL CNR 20133-MILANO, ITALY AND ISTITUTO DI CHIMICA INDUSTRIALE, UNIVERSITA E CENTRO DEL CNR 20133-MILANO, ITALY P r ispjelo 11. svibnja 1978. 

PMO Calculations for the Regiochemistry of 1,3-Cycloadditions of 3,5-Dichloro-2,4,6-trimethylbenzonitrile Oxide to Thiophen, Furan, Benzothiophen, and Benzofuran

PMO Calculations for the Regiochemistry of 1,3-Cycloadditions of 3,5-Dichloro-2,4,6-trimethylbenzonitrile Oxide to Thiophen, Furan, Benzothiophen, and Benzofuran

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