Annals of West University of Timisoara

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1 Annals of West University of Timisoara Series Chemistry 14 (2) (2005) CORRELATIONS BETWEEN HPLC CAPACITY FACTOR AND MOLECULAR DESCRIPTORS FOR PHOSPHORAMIDIC ACID DERIVATIVES Bianca Maranescu a, M. Glevitzky b, Mihaela Petric a, Luminiţ a Criş an a a Institute of Chemistry C. Dragulescu Timisoara, 24 Mihai Viteazul, , MANIA b "POLITEHNICA" University of Timişoara, Industrial Chemistry and Environmental Engineering Faculty, MANIA Received: 29 November 2005 Modified: 30 November 2005 Accepted: 8 December 2005 SUMMARY This paper is concerned with the problem of obtaining phosporamidic derivatives by an original synthesis, the compound separation by HPLC, founding molecular descriptors and their correlation for mathematical description of parameters that influence the capacity factor. Keywords: phosphoramidic derivatives, HPLC, molecular descriptors INTDUCTION Researching products obtained by original methods leads to the conclusion of oportunity to find a systematic investigation. The understanding of phenomenon leads to modeling of dependence equation between variables. In some situation a general model is needed, who could explain the liaison between the response variable and the independent variables [1]. 239

2 M ARANESCU B., G LEVITZKY M. ET AL. This work has two directions: the synthesis of phorphorimidic derivatives with general formula R 2 -P(O)-NH-R, (where R is C 2 H 5 O-, C 4 H 9 O-, C 6 H 5 O-, C 6 H 5 CH 2 O-, C 8 H 17 O-, C 10 H 21 O-, C 8 H 17 O -, and R is C 6 H 5, -C 6 H 4 NO 2 ) their separation by HPLC and analysis of experimental data [2]. Phosphoramidic acid derivatives gained importance because of their use as biological compounds, intermediates in organic synthesis [3,4]. The general procedure developed by Atherton and Todd [5,6] for the phosphorylation of amines uses as base an amine and the system phosphite/tetrahalometane (1). O O R 1 R 1 R 1 P H + CX NH P N + CHX 3 + NH. HX R (1) 2 R 2 R 2 Zwierzak [7,8] shown that the phosphorylation of amines can occurs in aqueous system in the presence of catalytic (about 5% mol) amounts of triethyl-benzyl-ammonium chloride. The title compounds are obtained by phosphorylation of aniline derivatives in liquid-solid systems, method not mentioned in the literature in synthesis of such compounds (2). O O H R 1 biphase system R 1 P H + H 2 N P N (2) SYNTHESIS A solution of dialkylphosphite and the corresponding amine in an appropriate solvent (dichloromethane when aniline was used and ethyl acetate when nitroanilines were used) was added dropwise to a stirred two-phase system consisting of dichloromethane, tetrachloromethane, otassium carbonate and a catalyst. The temperature was kept at C by external cooling. After the addition has been completed, stirring was continued for 1 hour at C and then for another 3 hour at room temperature. The potassium carbonate and potassium chloride were filtered and the organic layer was separated, washed with 3% hydrochloric acid and water, dried over anhydrous magnesium sulfate and the solvent evaporated. 240

3 PHOSPHOAMIDIC ACID DERIVATES MATERIALS AND METHODS The HPLC system used in this work includes a Jasco PU-1580 solvent delivery system and a MD-1510 UV/VIS detector with a 10 μl flow cell. A reversed-phase Nucleosil C18 column (25 cm x 0,4 mm, μparticle size) was used for separation, with 1ml/min flow rate methanol as mobile phase. A Reodyne 7725 injector with a 10 μl external loop was used for sample introduction. A Borwin chromatography workstation (system control version 1.5) was used to control the operation of HPLC, obtain the chromatogram, and perform data calculation. The non-retained component, used in calculation of capacity factor, was uracyl with t M = 1,04 min. The modeling of obtained molecules was done with HyperChem 5.11 software [9], using the AM1 hamiltonian in the geometry optimization phase. The convergence criteria SCF was fixed at 10-5, and the stop gradient for geometrical optimization was 0.01 (Polak Ribiere algorithm). RESULTS AND DISCUSSION As dependent variable we take the capacity facor (k ) in dependence with molecular descriptors obtained from HYPERCHEM program [9]: k ' = t R t M t M where: t R = retention time; t M = dead time (3) The compounds where quantified as follows: S 1 : R =C 2 H 2 O-, R =-C 6 H 5, S 2 : R =C 4 H 9 O-, R =-C 6 H 5, S 3 : R =C 6 H 5 O-, R =-C 6 H 5, S 4 : R =C 6 H 5 CH 2 O-, R =-C 6 H 5, S 5 : R =C 8 H 17 O-, R =-C 6 H 5, S 6 : R =C 10 H 21 O-, R =-C 6 H 5, S 7 : R =C8H17O-, R =C 6 H 4 NO 2, S 8 : R =C 2 H 5 O-,R =C 6 H 4 NO 2 S 9 : R =C 4 H 9 O-, R =C 6 H 4 NO 2, S 10 : R =C 6 H 5 O-, R =C 6 H 4 NO 2, S 11 =C 6 H 5 CH 2 O-, R =C 6 H 4 NO 2 Table I. The chromatography parameters and molecular descriptors obtained for the synthesized compounds Compound Capacity factor k Surface area Å 2 Volume Å 3 Hydration energy, kcal/mol Compound Capacity factor k Surface area Å 2 Volume Å 3 Hydration energy, kcal/mol S ,33 714,91-6,81 S , ,19-6,05 S ,55 928,17-3,82 S ,50 774,42-11,70 S ,49 924,92-9,89 S ,10 988,09-8,72 S , ,71-9,34 S ,23 990,60-13,67 S , ,08-1,12 S , ,85-14,24 S , ,53 0,14 241

4 M ARANESCU B., G LEVITZKY M. ET AL. 4,5 4,0 Capacity factor, k' 3,0 2,0 Figure 1. The dependency of the capacity factor on the surface area 1,0 0, Surface area, Å 2 Table II. The equation for the dependency of capacity factor on the surface area Coefficients Equation type r 2 r a b y = a + bx 0,80 0,89-0,9512 0,0048 4,5 4,0 Capacity factor, k' 3,0 2,0 1,0 Figure 2. The dependency of the capacity factor on the volume 0, Volume, Å 3 Table III. The equation for the dependency of capacity factor on the volume Coefficients E r 2 r a b y = a + bx 0,76 0,87-1,6551 0,

5 PHOSPHOAMIDIC ACID DERIVATES The correlation analysis shows that between the chromatographic parameters and the molecular descriptors appreciable correlation exists. The correlation coefficients between these parameters are 0.87 to The experimental data obtained for phosporamidic derivatives were analyzed with Statistica 6.0 program. In the Figure 3 were represented by an linear equation the capacity factor function of surface area and formation energy. The generated surface has an comportation suggested by equation from Table IV Figure 3. The dependency of the capacity factor on the surface area and formation energy A comparison between the model predictions and the data supplied by the real process is needed. As indicators of the model adequacy there have been used [10]: - the indicator of the precision of the model, r 2 : - the correlation coefficient of the capacity factor as a function of on surface area and formation energy. Table IV. The equation for the dependency of capacity factor on the surface area and formation energy Coefficients Equation tipe r 2 r a b c z = a + bx + cy 0,80 0,89-0,9474 0,0044-0,0015 In the same time, the model equation was verified by comparative representation of theoretical values (obtained for involved compounds data) versus experimental values. 243

6 M ARANESCU B., G LEVITZKY M. ET AL. 4,0 y=x 3,0 k' theoretic 2,0 1,0 Figure 4. The correlation between experimental data and the above model proposed 0,5 0,0 0,0 0,5 1,0 2,0 3,0 4,0 4,5 k' experimental The symmetrical disposition of data relative to y = x line (case in which the model correspond perfectly with experimental data) suggests the confirmation of the fiability of proposed model. CONCLUSION The aim of this paper was to obtain the optimal relationships between capacity factor and others molecular descriptors, even these correlations are linear. The calculation of the capacity factor according to the mentioned models leads to values close to the experimental ones. The correlation of structure with the capacity factor (k ) determined from chromatographic data are an argument for an unique retention mechanism in the analyzed compounds. The experimental research will be continued and applied in the non-linear multiple correlation. REFERENCES 1. Mihoc G., Urseanu V., Urseianu E., Modele de analiză statistică, Editura ştiinţifică şi enciclopedică, Bucureşti, R. Mihail, Introducere în strategia experimentării, cu aplicaţii din tehnologia chimică, Editura ştiinţifică şi enciclopedică, Bucureşti, Freel Meyers C.L. and Borch R. F., J. Med. Chem., 2000, 43(22), Tomoskozi I., Gacs-Baits E. and Otvos L., Tetrahedron, 1995, 51, Atherton F. R., Openshaw H. T. and Todd A. R., J. Chem. Soc., 1945, Atherton F. R. and Todd A. R., J. Chem. Soc., 1945, Zwierzak A., Synthesis, 1975, Weber W.P., Gokel G. W., Tetrahedron Lett., 1972, HyperChem 5.11 Pro and Chem Plus 1.6 are Hypercub Inc. Packages, Todinca T., Geantă M., Modelarea şi simularea proceselor chimice, Editura Politehnica - Timişoara, 1999, p