The molecule of trans-3,6-dimethoxy-1,2,4-trioxane has been studied by the semiempirical molecular orbital AM1 and PM3 methods. The numerical results of the structural study have been analyzed in terms of several stereoelectronic effects and compared with available experimental data. Theoretical predictions derived from both methods are in a good agreement with each other.Facultad de Ciencias Exacta

Cafferata, Lázaro F. R.

Castro, Eduardo Alberto

Gómez-Vara, M.

Jorge, Nelly

Russian Journal of General Chemistry

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1070-3632/01/7108-1314 $25.00C2001 MAIK [Nauka/Interperiodica]Russian Journal of General Chemistry, Vol. 71, No. 8, 2001, pp. 1314 !1317. Zhurnal Obshchei Khimii, Vol. 71, No. 8, 2001, pp. 1391!1395.Original English Text Copyright + 2001 by Jorge, Gomez-Vara, Cafferata, Castro.ÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍTheoretical Studyof the trans-3,6-Dimethoxy-1,2,4-trioxane Molecule1N. L. Jorge, M. Gomez-Vara, L. F. R. Cafferata, and E. A. CastroFacultad de Ciencias Exactas, Universidad Nacional del Nordeste, Corrientes, ArgentinaFacultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, ArgentinaReceived April 4, 2000Abstract-The molecule of trans-3,6-dimethoxy-1,2,4-trioxane has been studied by the semiempiricalmolecular orbital AM1 and PM3 methods. The numerical results of the structural study have been analyzedin terms of several stereoelectronic effects and compared with available experimental data. Theoreticalpredictions derived from both methods are in a good agreement with each other.The integral study of organic peroxides encom-passes a very large thematic field covering from bio-logical aspects, such as metabolic oxidation processes,up to important industrial applications, such as initia-tion of polymerization reactions, painting production,etc. [1!3]. Within the realm of biologically activecompounds, they have a significative relevance sincethey take part of cellular degradation transformationscaused by enzymatic self-oxidation due to inter-mediate peroxide species. An important peroxidebelonging to the 1,2,4-trioxane family is a naturalproduct obtained from Artemisia annua [4, 5], whichis a very potent antimalarial drug having a low humantoxicity effect [6]. This compound is denominatedQinghaosu (Artemisine or Arteannuin) and comesfrom research on the Chinese traditional medicinalpractice [7!10]. The antimalarial activity of the Arte-misia annua extract is associated with the presenceof the 1,2,4-trioxane ring in molecules forming thesecompounds. For that reason, several efforts were madeto synthesize some compounds having a 1,2,4-tri-oxane ring by means of different methods [11]. Sincethere is a real scarcity of structural information aboutthis class of molecules, we have deemed suitable andnecessary to perform a conformational study of both3,6-dimethoxy-1,2,4-trioxane isomers, resorting tothe semiempirical AM1 and PM3 methods.We have examined the diaxial (aa), diequatorial(ee), axial!equatorial (ae), and equatorial!axial (ea)isomers, analyzed their energetic stabilities, and dis-cussed the stereoelectronic (anomeric and exoano-meric) effects and their relevant role in the stabilityof the trans isomer where both methoxy groups areÄÄÄÄÄÄÄÄÄÄÄÄ1 This article was submitted by the authors in English.located at the axial positions. The results of theoreticalstudy by the two molecular orbital methods show thepreference of the trans-diaxial isomer over the cisisomer, in agreement with the experimental data.There exists a conformational equilibrium betweenthe synclinal and antiperiplanar forms for the firstisomer. Below are given the barriers for rotation ofthe methoxy groups, calculated by both methods, andthe stabilization preference of one isomer with respectto the other is discussed in terms of interactionsdepending on the orientation of free electron pairsbelonging to the exocyclic oxygen atom relative tothe CÄOendo bonds!antibonds.When the substituent has free electron pairs, theenergetic stability of the trans-diaxial isomer can beattributed to interactions involving free electron pairsof the substituent [12, 13], in addition to characteristicinteractions of free electron pairs of the ring oxygenatoms. The importance of stereoelectronic effect onthe substituent has not been taken into account before[12]. Table 1 lists the heats of formation of the trans-aa and cis-ae isomers of 3,6-dimethoxy-1,2,4-trioxanein the chair and twist conformations. The barriers toconversion of the diaxial isomer into diequatorial,(,H(aa!ee) are 8.61 (AM1) and 3.52 kcal/mol(PM3). This energy difference reveals the anomericeffect since it stabilizes the isomer with the axialmethoxy group. The chair-aa!chair-ee interconver-sion should pass through an intermediate twist con-formation, and the barrier to the chair!twist intercon-version is equal to 5.08 kcal/mol, according to theAM1 method (for comparison, the correspondingbarrier for the cyclohexane molecule is 5.5 kcal/mol).The value calculated with the PM3 method is4.05 kcal/mol. Analysis of the data in Table 1 showsRUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 8 2001THEORETICAL STUDY OF THE trans-3,6-DIMETHOXY-1,2,4-TRIOXANE MOLECULE 1315Fig. 1. Chair conformation of the trans-diaxial isomerof 3,6-dimethoxy-1,2,4-trioxane according to the AM1calculations.that the most stable is the trans-diaxial conformerin the chair form.The molecular geometries optimized by the AM1and PM3 molecular orbital methods are shown inFigs. 1 and 2. Table 2 contains the geometric param-eters obtained by the AM1 and PM3 methods: bondlengths, bond angles, and dihedral angles for thetrans-diaxial isomer of the title compound in the chairand twist conformations. The stability order of thismolecule has been analyzed taking into considerationfour main factors chosen in previous papers on thistopic [12!14] plus two additional stereoelectroniceffects:(1) The syn-axial effect arising from nonbondingrepulsions between free electron pairs located at thenonadjacent oxygen atoms. Assuming that the ringoxygen atom has a tetrahedral hybridization, therepulsion between the 1,5-syn!axial free electronpairs are weaker in the twist form than in the chairform due to the fact that free electron pair momentain the first of these are less parallel. This effect isenhanced as the OCO bond angle decreases and theXCX< bond angle increases (X = MeO, X< = H).Fig. 2. Chair conformation of the trans-diaxial isomerof 3,6-dimethoxy-1,2,4-trioxane according to the PM3calculations.(2) The torsion angle around the OÍO bond favorsthe twist form which is less strained. The results arepresented in Table 2.(3) Steric effect corresponding to the equatorial oraxial position of the methoxy group [8].(4) Anomeric effect produced by free electron pairsof the endocyclic oxygen atoms on the CÄOendoand CÄOexo bonds, when the methoxy group occupiesthe axial position.(5) Exoanomeric effect produced by free electronpairs of the substituent oxygen atom on the CÄOendoTable 1. Heats of formation (kcal/mol) of 3,6-dimethoxy-1,2,4-trioxane isomersÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÄIsomer³ Chair ³ TwistÃÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÂÄÄÄÄÄÄ³ AM1 ³ PM3 ³ AM1 ³ PM3ÄÄÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÅÄÄÄÄÄÄtrans-aa ³ !161.22 ³ !150.36 ³ !156.14 ³ !146.31cis-ae ³ !153.73 ³ !147.53 ³ !158.49 ³ !148.82trans-ee ³ !152.61 ³ !146.84 ³ !156.14 ³ !146.31ÄÄÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÁÄÄÄÄÄÄRUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 8 20011316 JORGE et al.Table 2. Geometric parameters of the trans-diaxialisomer of 3,6-dimethoxy-1,2,4-trioxane, calculated by theAM1a and PM3 methodsÄÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄParameter³ AM1 ³ PM3ÃÄÄÄÄÄÄÂÄÄÄÄÄÄÅÄÄÄÄÄÄÂÄÄÄÄÄÄ³ twist ³ chair ³ twist ³ chairÄÄÄÄÄÄÄÄÄÄÄÄÅÄÄÄÄÄÄÅÄÄÄÄÄÄÅÄÄÄÄÄÄÅÄÄÄÄÄÄBond lengths, )O1ÄO2 ³ 1.283 ³ 1.291 ³ 1.545 ³ 1.576C3ÄO2 ³ 1.443 ³ 1.428 ³ 1.396 ³ 1.373C3ÄO4 ³ 1.397 ³ 1.397 ³ 1.405 ³ 1.408C3ÄOexo ³ 1.404 ³ 1.401 ³ 1.403 ³ 1.403³ ³ ³ ³OexoÄC12 ³ 1.422 ³ 1.422 ³ 1.405 ³ 1.405³ ³ ³ ³C3ÄH10 ³ 1.117 ³ 1.120 ³ 1.114 ³ 1.112Bond angles, degC3O4C5 ³ 114.96³ 114.86³ 116.10³ 116.54O2C3O4 ³ 110.33³ 109.45³ 113.77³ 111.91O1C6C5 ³ 109.75³ 110.25³ 112.97³ 112.83O4C3Oexo ³ 104.87³ 105.28³ 108.15³ 110.59³ ³ ³ ³O4C3H10 ³ 109.62³ 109.07³ 105.34³ 105.99O2C3Oexo ³ 102.02³ 108.43³ 95.73³ 105.12³ ³ ³ ³O2C3H10 ³ 113.09³ 107.30³ 115.70³ 105.58C3OexoC12 ³ 113.78³ 113.92³ 115.49³ 115.30Torsion angle, degC6O1O2C3 ³ 65.09³ !58.85³ 63.68³ !54.86C6C5O4C3 ³ 59.39³ 48.62³ 57.21³ 47.60O2C3O4C5 ³ !30.63³ !53.80³ !27.01³ !55.52O2C3OexoC12 ³ !81.07³ !73.81³ !143.75³ !152.82³ ³ ³ ³O4C3OexoC12 ³ 163.84³ 169.13³ 98.91³ 86.21³ ³ ³ ³C5O4C3Oexo ³ 78.53³ 62.55³ 78.01³ 61.32³ ³ ³ ³O1O2C3Oexo ³ !143.67³ !55.63³ !145.21³ !64.57³ ³ ³ ³O1O2C3O4 ³ !32.65³ 58.71³ !32.49³ 55.42ÄÄÄÄÄÄÄÄÄÄÄÄÁÄÄÄÄÄÄÁÄÄÄÄÄÄÁÄÄÄÄÄÄÁÄÄÄÄÄÄa The AM1 method well describes stereoelectronic effects, butthe theoretical conformation differs appreciably from theexperimental one in bond lengths and bond angles. The theore-tical difference in the C3ÄO2 and C3ÄO4 bonds is 0.031 A;the corresponding experimental value is 0.011 A. The dif-ference between the O4C3Oexo and O2C3Oexo bond angles is3.15o (AM1) and 1.9o (experimental).bonds in the synclinal and antiperiplanar conforma-tions. As stated above, the barrier to rotation of themethoxy group about the C(ring)ÄO(MeO) bondmust be low (i.e., 1!3 kcal/mol [15]), and the exo-anomeric effect must increase the height of this barrierby about 2 kcal/mol [16].Below are given the energy minima (kcal/mol)found for rotation of the methoxy group around theCÄOexo bond according to both methods.trans Conformer synclinal antiperiplnarAM1 !161.22 !158.62RM3 !150.36 !147.92,H #(AM1)2 !158.55,H #(PM3)2 !146.72The AM1 results indicate that the synclinal con-former with two anomeric effects and one exoano-meric effect has the lowest energy, the energydifference between both conformers being equal to2.6 kcal/mol. The PM3 results coincide with thoseobtained by the AM1 method, but the energy differ-ence between these conformations is 2.3 kcal/mol.According to the AM1 calculations, the CÄCexo bondis shorter in the anti conformer than in the synclinalform, which supports the existence of the abovestereoelectronic interactions. The longer CÄOendobond corresponds to a structure in which the methoxygroup is located at the antiperiplanar position, i.e., tothe synclinal conformer shown in Fig. 3. The freeelectron pairs belonging to the oxygen atoms of themethoxy groups occupy antiperiplanar positions withrespect to each CÄOendo bond in the antiperiplanarconformer.Thus, the semiempirical PM3 method predicts thesame general results as AM1 does, but the differencesbetween the bond lengths of both conformers, cal-culated by the PM3 method, are lower than thoseobtained by the AM1 method. We can state that thesecondary stereoelectronic effect like n$I producedby free electron pairs of the peroxide oxygen atomson the CÄO antibonding orbital of the axial methoxygroup is responsible for significant stabilization of thetrans-diaxial isomer. Although the AM1 methodpoorly describes the OÄO bond distance, as comparedÄÄÄÄÄÄÄÄÄÄÄÄ2 Given are the enthalpies of activation for the conversion ofthe synclinal conformer to antiperiplanar. The barrier torotation of the methoxyl group about the CringÄCMeO bond,calculated by the AM1 method is 2.67 kcal/mol; the corre-sponding PM3 value is 3.64 kcal/mol.RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 8 2001THEORETICAL STUDY OF THE trans-3,6-DIMETHOXY-1,2,4-TRIOXANE MOLECULE 1317HMeCOFig. 3. Synclinal conformer of 3,6-dimethoxy-1,2,4-tri-oxane.to PM3, our results show that variations in theCÄOendo and CÄOexo bonds are better reproducedby the AM1 method, which is also the case of theother peroxide derivatives. Despite some experimentalevidences for similar compounds with five-memberedrings (i.e., the synclinal!antiperiplanar equilibriumof 2-methoxy-1,3-dioxolane in solution favors theantiperiplanar form), the synclinal conformer of 3,6-dimethoxy-1,2,4-trioxane is the most energeticallystable form.According to the calculations, the anti conformerof the title compound is electronically preferred dueto two exoanomeric effects of free electron pairs ofthe methoxy oxygen atoms on the CÄO antibonds ofthe ring. On the other hand, steric repulsion producedby the methyl group of the methoxy substituentlocated in the antiperiplanar position with respectTable 3. Geometric parameters of the trans-diaxial isomerof 3,6-dimethoxy-1,2,4-trioxane (chair conformation,synclinal and antiperiplanar), calculated by the AM1method and found experimentallyÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄParameter ³Experiment³ Synclinal ³AntiperiplanarÄÄÄÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÄÄÄÄBond lengths, )O1ÄO2 ³ 1.467 ³ 1.291 ³ 1.292C3ÄO2 ³ 1.412 ³ 1.422 ³ 1.425C3ÄO4 ³ 1.401 ³ 1.397 ³ 1.398Bond angles, degO2C3O4 ³ 110.10 ³ 109.45 ³ 111.79C5C6O1 ³ 107.90 ³ 110.25 ³ 109.21C5O4C3 ³ 115.00 ³ 114.83 ³ 118.14O2O1C6 ³ 107.31 ³ 114.10 ³ 113.31OexoC3O4 ³ 111.60 ³ 105.28 ³ 112.48OexoC3O2 ³ 109.91 ³ 108.43 ³ 111.49³ ³ ³C3OexoCMe ³ 110.20 ³ 113.92 ³ 120.00C6OexoCMe ³ ³ 114.05 ³ 114.05Torsion angles, degC6C5O4C3 ³ !45.90 ³ 48.62 ³ 37.58C6O1O2C3 ³ 71.50 ³ !58.85 ³ !60.65C5O4C3O2 ³ 54.80 ³ !53.80 ³ !39.38O2O1C6C5 ³ !62.31 ³ 50.63 ³ 54.25ÄÄÄÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÄÄÄÄto the CÄH bond makes the synclinal conformerthe most stable form. The most important conclusionof this study is as follows. When the substituent hasfree electron pairs, the stability of the trans-diaxialisomer can be attributed to the existence of stereoelec-tronic interactions involving those free pairs, in addi-tion to interactions of the free electron pairs of thering oxygen atoms.REFERENCES1. Adam, W. and Cilento, G., Chemical and BiologicalGeneration of Electronically Excited States, NewYork: Academic, 1982.2. Adam, W., Ullmann’s Encyclopedia of IndustrialChemistry, Weinheim: VCH, 1990, vol. A15, p. 548;Albrecht, S., Brandl, H., and Adam, W., Chem.Unserer Zeit, 1990, vol. 24, p. 227; Beck, S. andKoster, H., Anal. Chem., 1990, vol. 62, p. 2258;Adam, W., The Chemistry of Peroxides, Patai, S.,Ed., Chichester: Wiley, 1983, p. 829.3. Kohler, E.P., J. Am. Chem. Soc., 1906, vol. 36,p. 177.4. Casteel, D.A., Nat. Prod. Rep., 1992, p. 301.5. K’o Hsueh T’ung Pao, Chem. Abstr., 1977, vol. 87,no. 98 788 g.6. Dutta, D.G. and Vishwakarma, R.A., Indian J.Parasitol., 1987, vol. 11, p. 253.7. Acton, N. and Klayman, D.L., Planta Med., 1985,p. 441.8. Kinghorn, A.D., J. Nat. Prod., 1987, vol. 50,p. 1009.9. Klayman, D.L., Science, 1985, vol. 228, p. 1049.10. Xu, X.X., Zhu, J., Huang, D.Z., and Zhou, W.S.,Tetrahedron Lett., 1991, vol. 32, p. 5785.11. Payne, G.B. and Smith, C.W., J. Org. Chem., 1957,vol. 22, p. 1682; Adam, W. and Rios, A., J. Chem.Soc., Chem. Commun., 1971, p. 822; Subramanyan, V.,Brizuela, C.L., and Soloway, A.H., J. Chem. Soc.,Chem. Commun., 1976, p. 508; McCullough, K.J.and Kerr, B., J. Chem. Soc., Chem. Commun., 1985,p. 590.12. Jorge, N., Peruchena, N., Castro, E.A., and Caf-ferata, L.R.F., J. Mol. Struct. (Theochem), 1994,vol. 309, p. 315.13. De Thatcher, G.R.J., The Anomeric Effect andAssociated Stereoelectronic Effects. ACS SymposiumSeries 539, Washington: Am. Chem. Soc., 1993.14. Jorge, N., Peruchena, N., Cafferata, L.R.F., andCastro, E.A., J. Mol. Struct. (Theochem), 1994,vol. 433, pp. 311!317.15. Chin-Yun Chiang, Butler, W., and Kuczkowski, R.,J. Chem. Soc., Chem. Commun., 1988, pp. 465!466.16. Deslongchamps, P., Stereoelectronic Effects InOrganic Chemistry, London: Pergamon, 1983.

Theoretical Study of the trans-3,6-Dimethoxy-1,2,4-trioxane Molecule

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Theoretical Study of the trans-3,6-Dimethoxy-1,2,4-trioxane Molecule

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