Study of the Process of Obtaining 9-Fluorenone-4-carboxylic Acid Anilide by Statistical Methods of Experimental Design
Abstract Generated abstract
The study applies statistical experimental design to optimize the synthesis of 9-fluorenone-4-carboxylic acid anilide, a compound of potential interest for preparing biologically active substances. Using yield relative to reacted aniline as the optimization criterion, the authors examined the effects of reaction temperature and duration in a xylene medium after formation of the acid chloride with phosphorus pentachloride. A simplex design identified favorable conditions near 115°C and 95 min, giving a 95% yield, and a central composite rotatable design was then used to describe the stationary region with a second-order regression model. The response surface was characterized as an elliptic paraboloid, and the refined design produced a reported yield of 96.7%.
Full Text
STUDY OF THE PROCESS FOR PREPARING 9-FLUORENONE-4-CARBOXYLIC ACID ANILIDE BY STATISTICAL METHODS OF EXPERIMENTAL DESIGN
G. M. STEPNOVA, V. A. TRIGUBENKO
(Presented by the scientific-methodological seminar of the Faculty of Chemical Technology)
Previously [1] we described the development of optimal conditions for obtaining 9-fluorenone-4-carboxylic acid anilide, which may find application in the synthesis of biologically active compounds by the Wilson–Bock method [5].
To obtain more reliable data and to investigate the stationary region, in the present work, when determining the optimal conditions, we used a simplex design and rotatable uniform design [5].
The yield of 9-fluorenone-4-carboxylic acid anilide, calculated with respect to the aniline that had reacted, was chosen as the optimization criterion.
The influence of the following factors was studied: \(x_1\) — reaction temperature, °C; \(x_2\) — reaction duration, min.
These factors, their basic level, and the interval of variation were selected on the basis of literature data and preliminary experiments.
The experiments were carried out as follows: into a 100 ml flask equipped with a stirrer and a condenser were charged 0.005 mole (1.12 g) of 9-fluorenone-4-carboxylic acid, 0.005 mole (1.04 g) of phosphorus pentachloride, and 8 ml of xylene. The reaction mixture, with stirring, was heated to 70°C; the reaction continued for about two hours until the evolution of HCl ceased. The conditions for conducting the experiments and the results of their implementation are given in Table 1. After the required temperature had been reached, 0.005 mole (0.475 ml) of aniline was added to the reaction mixture, and from that moment the reaction time was counted. The yield of 9-fluorenone-4-carboxylic acid anilide was determined by the titration method.
Table 1
| Experiment No. | Conditions of execution, \(t,^\circ\mathrm{C}\) | Conditions of execution, min. | Yield, % |
|---|---|---|---|
| 1 | 110 | 30 | 76 |
| 2 | 125 | 50 | 80 |
| 3 | 110 | 70 | 86 |
| 4 | 125 | 90 | 92 |
| 5 | 110 | 110 | 85 |
| 6 | 115 | 95 | 95 |
| 7 | 144 | 70 | 77.5 |
The greatest value of \(y\) (95%) was obtained in experiment 6 under the following reaction conditions: temperature \(115^\circ\)C, time 95 min.
For a mathematical description of the process by a second-order equation around the point corresponding to experiment 6, carried out in the simplex—
Table 2
| No. | Factor levels | Value of \(t,^\circ\mathrm{C}\) | Time value, min |
|---|---|---|---|
| 1 | \(-1.414\) | 105 | 80 |
| 2 | \(-1\) | 110 | 90 |
| 3 | \(0\) | 115 | 95 |
| 4 | \(+1\) | 120 | 100 |
| 5 | \(+1.414\) | 125 | 110 |
design, we set up a series of experiments according to the scheme of a central composite rotatable uniform design [4].
The method of carrying out the experiments is analogous to the method indicated above. The planning conditions and experimental results are given in Tables 2 and 3.
Table 3
| Experiment No. | \(x_0\) | \(x_1\) | \(x_2\) | \(x_1x_2\) | \(x_1^2\) | \(x_2^2\) | \(y,\%\) |
|---|---|---|---|---|---|---|---|
| 1 | \(+1\) | \(-1\) | \(+1\) | \(-1\) | \(+1\) | \(+1\) | 85.2 |
| 2 | \(+1\) | \(-1\) | \(-1\) | \(+1\) | \(+1\) | \(+1\) | 90.1 |
| 3 | \(+1\) | \(+1\) | \(-1\) | \(-1\) | \(+1\) | \(+1\) | 94.2 |
| 4 | \(+1\) | \(+1\) | \(+1\) | \(+1\) | \(+1\) | \(+1\) | 94.4 |
| 5 | \(+1\) | \(+1.414\) | \(0\) | \(0\) | \(1.999\) | \(0\) | 96.7 |
| 6 | \(+1\) | \(0\) | \(+1.414\) | \(0\) | \(0\) | \(1.999\) | 94.1 |
| 7 | \(+1\) | \(-1.414\) | \(0\) | \(0\) | \(1.999\) | \(0\) | 92.7 |
| 8 | \(+1\) | \(0\) | \(-1.414\) | \(0\) | \(0\) | \(1.999\) | 93.6 |
| 9 | \(+1\) | \(0\) | \(0\) | \(0\) | \(0\) | \(0\) | 93.5 |
| 10 | \(+1\) | \(0\) | \(0\) | \(0\) | \(0\) | \(0\) | 94.0 |
| 11 | \(+1\) | \(0\) | \(0\) | \(0\) | \(0\) | \(0\) | 92.7 |
| 12 | \(+1\) | \(0\) | \(0\) | \(0\) | \(0\) | \(0\) | 93.7 |
| 13 | \(+1\) | \(0\) | \(0\) | \(0\) | \(0\) | \(0\) | 94.1 |
The regression equation obtained
\[ y=98.52+2.23x_1+0.48x_2+0.8x_1x_2+23.88x_1^2-4.76x_2^2 \tag{1} \]
adequately describes the second-order response surface.
\[ (F_{\mathrm{calc.}}=22.43;\quad F_{0.05}=4.95). \]
Equation (1) is reduced to canonical form
\[ y-99.1=-3.81x_1^2-5.01x_2^2. \]
The response surface is an elliptic paraboloid, and the contour curves are ellipses.
Thus, with the aid of the simplex design, the optimal conditions for the synthesis of 9-fluorenone-4-carboxylic acid anilide with a maximum yield of 95% were determined; using the rotatable uniform design, a yield of 96.7% was achieved.
REFERENCES
- G. M. Stepnova, V. A. Trigubenko, O. N. Martynenko, Khimiko-farmatsevticheskii zhurnal, 7, 1972.
- G. M. Stepnova, P. F. Tabinskaya, A. V. Kovalenok, ZhOKh, vol. I, issue 6, 1037, 1965.
- G. M. Stepnova, A. V. Kovalenok, A. P. Belyaeva, ZhOKh, vol. I, issue 8, 1425, 1965.
- L. P. Kulev, G. M. Stepnova, P. F. Tabinskaya, Proceedings of the Siberian Branch, Academy of Sciences of the USSR, 12, 137, 1962.
- V. V. Nalimov, N. N. Chernova, Statistical Methods for Planning Extreme Experiments. Moscow, “Nauka,” 1965.