## Services on Demand

## Journal

## Article

## Indicators

- Cited by SciELO
- Access statistics

## Related links

- Cited by Google
- Similars in SciELO
- Similars in Google

## Share

## Journal of the Chilean Chemical Society

##
*On-line version* ISSN 0717-9707

### J. Chil. Chem. Soc. vol.50 no.4 Concepción Dec. 2005

#### http://dx.doi.org/10.4067/S0717-97072005000400015

J. Chil. Chem. Soc., 50, N° 4 (2005), págs: 731-737
The application of the Principal Component of Analysis (PCA) over the theoretical data of a series of substituted 1,3-oxazines helps to determine the factors that rule the conformational equilibrium. Repulsive and intertribal syn-1,3-diaxial interactions have been used as determiners for the axial structures, whereas dipolar interactions are preferred in the equatorial conformation. Theoretical variables such as hardness, charges, nuclear repulsion energy and bond order in the different nuclear sectors have been used. PCA method has been successfully used in predicting the hyperconjugative interactions that play an important role in the conformational equilibrium between a given pair of conformers of 1,3-oxazines. The studied 1,3-oxazines belong to three different groups of structures having the heterocyclic ring as a common feature. The axial structures are stabilized by two-electron/two-orbital interactions, whereas the equatorial structures are believed to be stabilized by syn-1,3-diaxial and dipole-dipole interactions.
Since the decade of the 50's, oxazinic derivatives have drawn the attention because their antitumoral y antituberculostatic activities. Several analyses to determine the conformational preference have been carried out. Thus, Urbanski The later treats the interaction of the heteroatom lone pair with an antibonding s*-orbital of the ligand bond, stabilizing the axial orientation of the anomeric substituent The T matrix is the "score" matrix representing the positions of the compounds in the new coordinate system whereas the PCs are the axes. E is a residual matrix and L is the "loading" matrix. Using the singular values decomposition technique, SVD, that split
All structures were fully optimized at the HF/6-31G** level of theory using the Gaussian 03 series of programs
To visualize the interactions that govern the conformational equilibria and the stability of an allied of 1,3-oxazines, the geometry of the three groups of oxazines (see in figure1) were optimized. Frequencies and IR intensities were predicted at the equilibrium geometries (HF/6-31G**) yielding all real frequencies so that all calculated structures are local minima. The different optimized conformations were analyzed with NBO method in the aim to determine which conformations were forming a group. Accordingly, the set of conformers forming a group were introduced in the PCA data matrix. Variables representing intramolecular interactions were selected to ascribe each conformation (axial or equatorial) to the presence of a specific interaction or a combination of them. The following variables were employed: a)
b) c) d)
The data were scaled by subtracting column averages and dividing by column standard deviations. In this way, every variables were weighted in the same way in the principal component analysis. Data analysis was performed using the Pirouette software package
The analysis shows that for axial-equatorial classification, the variables NRE, PC1=-0.03NRE+0.28 PC2=-0.45NRE+0.25 PC3 separates group 1 from 2, but as the objective is not to visualize the differences between them, no further details will be given. In Figure 3, the notation 2-i-Pr(A) refers to an oxazine of group 2 that possesses an axial isopropyl group on N3, whereas 1-t-Bu(E) refers to an oxazine of group 1 having an equatorial terbuthyl group on N3. Table 2 shows that the most stable conformations, calculated at the HF/6-31G**// HF/6-31G** level, are the axial ones for R = methyl, ethyl, or propyl. When R=iPr or tBu, the preferred conformations are oxazines substituted in an equatorial position. Accordingly, we can conclude that the principal components analysis outlined above, not only allow the separation into groups to render the common characteristics of the axial and equatorial oxazines (information given by PC1), but also permits to establish the principal inherent characteristics of stability.
General speaking, we can think that the stability of the axial and equatorial structures posses opposite characteristics, i.e., they can be explained in rather different terms. In general, the equatorial structures are characterized by their hardness, to have a more positive charge on C2 and more negative charge on N3 and C5. The equatorial structures also present interactions that increase bonds 1 and 7 populations. PC2 provides information about the steric effects of the bulkier iPr and tBu substituents on N3. In fact, they increase the values of NRE, as can be expected. Moreover, these structures do not present larger differences between the interorbital interactions with respect to the rest of axial or equatorial oxazines. This implies that a low contribution of the bond orders in equation 2 is observed. In addition to the NRE, oxazines with bulky substituents show significant differences in the charges consistent with their larger hardness. This effect reflects the low trend in these conformers to experience intramolecular Homo-Lumo interactions. The better stability of the equatorial conformers over the axial ones can also be explained in terms of the electrostatic model. Keeping in mind that the ring dipole generated by the lone pairs of electrons and the approximately antiparallel polar bond or the substituent (N3-C(subst) or bond 7), is similar, thought the polarity of the bond N3-C(subst) is greater for the terbutil. In Table 3, the charges of the groups for the equatorial conformers are given in qualitative form to dimension the linkage dipole. In this way, a decrease of the electrostatic energy as a result of the less repulsive interactions (analysis carried out in gas phase) is observed. According to the information provided by PC1 and PC2 in the diagram of Scores ( fig.3) and equations 1 and 2, the variables of greater importance related to the axial conformation, as well as to the stability of them are BO3, PE2 and PE3, and thereby we can expect they will be involved in attractive interactions and interorbitals delocalizations increasing bonds 2 and 3 in populations. If an analysis is performed on the principal components of the axial oxazines, we will be able to correlate the principal delocalizations directly involved with the stability. Accordingly, we have used the interorbital interactions taken from the Natural Bond Orbital analysis (NBO) as variables. These interactions are related with both n A 10x34 matrix was constructed with the variables given in table 4. The data were autoscaled. The PCA results show the separation the axial more stable oxazines from the unstable ones in the first PCA collecting the 90.50% of the information. Equation 3 shows the weights of the selected variables: PC1=0.31A + 0.33B -0.30D +0.33E +0.33Q +0.33R -0.33S -0.33T -0.31AB -0.27AC ( The stable axial oxazines generate a compact group (see fig.4) in which the principal delocalizations are D, S, T, AB and AC; the last four are related with the delocalization from (S and T) and towards (AB and AC) bond 7., AB and AC are of larger magnitude implying a withdrawing character for the substituent. The most important is the D interaction, since it implies the presence of a clear anomeric center. It can also be expected the A interaction to be of great significance, though its importance is clearly diminished when one sees that is approximately equal in all structures. In other words, all oxazines belonging to group 1 and 2 with axial conformation, delocalize in a larger extent the lone pair on N3 towards the orbital
PC1=-0.07NRE+0.09 PC3=0.14NRE-0.02
The notation 3-C2C5-E refers to an equatorial oxazine of group 3 that also possesses substitutions on C2 (p-nitrophenyl) and C5 (dimethyl), whereas 3-E refers to an equatorial oxazine of group 3, having no substituents on C2 and C5. 3-C2-E and3-C5-E refer to equatorial oxazines of group 3 with substitutions on C2 and C5, respectively. Methyl groups on C5 stabilize equatorial position in group 3 oxazines. Accordingly, they show high negative charges on N3, demonstrating that electrons around such nucleus is preserved and so that delocalization of the lone pair will occur to a lesser extent. Low negative charge on C5 was also found and a high population in bond 1. It can also be observed, that variables related to the stability of the equatorial group 3 oxazines are represented by some characteristics attributable to charges and bonds interactions. When the alkyl groups are in equatorial positions, the minimization of the nuclear repulsions and the total energy would help in assigning the stability of a given conformer. However, from table 5 it can be inferred that DNRE is larger for 3-C5 compared with 3-C2C5, where its stabilization seems to involve simultaneously delocalization and charge transfer. Group 3 oxazines having no methyl groups on C5 are stabilized in axial positions. They display low negative charges on N3, high negative charges in C5 and high electronic population of bonds 2 and 3. One can assume that large delocalization of the N3 lone pair of electrons to the PC1=0.289A-0.291B+0.287D-0.288E+0.289S+0.285T-0.285U-0.287V+0.292AB+0.291AC-0.291AD-0.288AE ( PC2=0.328A+0.191B+0.304D+0.333E-0.283S-0.402T-0.413U-0.362V+0.013AB+0.059AC-0.053AD+0.321AE (
As it can be observe in the graphic of scores, that the variables employed to separate the axial from the equatorial conformation work reasonably well. Within the axial group the selected variables relates the stability of the oxazines very well, separating the stable group form the unstable one, as it can be observed in PC2. However, the equatorials are not so easily related, basically because the moving away of groups 3 (3-C5-E and 3-C2C5-E) equatorial stable oxazines from the equatorial stable oxazines of group 1 and 2. Accordingly, it is plausible to think that the stability of the axial structures is directly related to the delocalization process of the lone pair of electrons on nitrogen and to the delocalization of the bond from and towards the substituent group on nitrogen. Unfortunately, a similar argument for equatorial oxazines does not work and we need to introduce delocalizations in other molecular sectors. Analysing the charge on the oxygen atom (see table 5 a noticeable difference for the oxazines 3C2C5E and 3C5E and thereby if oxygen electron delocalizations would have been introduced in this analysis is likely that the separation of the equatorial structures would have been greatly improved
This work was partially supported by an operating grant (No 203.021.019-1.0) from Universidad de Concepcion, Chile. S.M.H thanks CONICYT for a scholarship.
REFERENCES 1.- (a) Gürne D. and Urbanski T., J. Chem.Soc. (1959) 1912. [ Links ] (b) Gürne D., Stefaniak L., Urbanski T. and Witanowski M., Tetrahedron supplement, 2.- Allingham Y., Cookson R.C., Crabb T.A., and Vary S. Tetrahedron 3.- (a) Lehn J.M. and Ridell F.G., J.Chem.Soc. (B) (1968) 1224 [ Links ](b) Lehn J.M., Ridell F.G. and Linscheid P. Bull. Soc. Chim. France N°3. (1968) 1172. [ Links ] 4.- Jones Richard A.Y., Katritzky A.R., Trepanier D.L. J. Chem. Soc(B) (1971) 1300. [ Links ] 5.- Edward,J.T., Chem. Ind.(London), (1955) 1102. [ Links ] 6.- Romers C.,Altona C., Buys H.R., Havinga E., Topics Stereochem, 7.- Beebe K.R. , Pell R.J., Seasholtz M.B., Chemometrics: A Practical Guide, Wiley, New York, 1998. [ Links ] 8.- Joliffe I.T., "Principal Component Analysis" , Springer Series in Statistics, Springer- Verlag, New York, 1986 [ Links ] 9.- Ferreira Marcia M.C., J. Braz. Chem. Soc. 13 (2002) 742 [ Links ] 10.- Gaussian 03, Revision B.03, Frisch M. J, Trucks G. W, Schlegel H. B., Scuseria G. E., Robb M.A., Cheeseman J. R.,. Montgomery, Jr. J. A,. Vreven T, Kudin K. N, Burant J. C., Millam J. M., Iyengar S. S.,. Tomasi J, Barone V., Mennucci B., Cossi M., Scalmani G., Rega N., Petersson G. A., Nakatsuji H., Hada M., Ehara M, Toyota K., Fukuda R., Hasegawa J., Ishida M., Nakajima T., Honda Y., Kitao O., Nakai H., Klene M., Li X, Knox J. E., Hratchian H. P., Cross J. B., Adamo C., Jaramillo J., Gomperts R., Stratmann R. E., Yazyev O., Austin A. J., Cammi R., Pomelli C., Ochterski J. W., Ayala P. Y., Morokuma K., Voth G. A., Salvador P., Dannenberg J. J., Zakrzewski V. G., Dapprich S., Daniels A. D., Strain M. C., Farkas O., Malick D. K., Rabuck A. D., Raghavachari K., Foresman J.B., Ortiz J. V., Cui Q., Baboul A. G., Clifford S., Cioslowski J., Stefanov B. B., Liu G., Liashenko A., Piskorz P., Komaromi I., Martin R. L., Fox D. J., Keith T., Al-Laham M. A., Peng C. Y, Nanayakkara A., Challacombe M., Gill P. M. W., Johnson B., Chen W., Wong M. W., Gonzalez C., and Pople J. A., Gaussian, Inc., Pittsburgh PA, 2003. [ Links ] 11.- Carpenter J.E., Weinhold F.T., Theoretical Chemistry Intitute, University of Wisconsin, Madison, WI , (1996) 12.- Pirouette, Infometrix , Washington, DC, (1996) [ Links ] 13.- Parr G.R., Pearson R.G., J. Am. Chem. Soc., 14.- a) AllinghamY., Cookson R.C., Crabb T.A., Tetrahedron All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License |