Study of the Effect of Acidic and Basic Catalysts on the Acylation Reaction of 4-Aminoantipyrine
Abstract Generated abstract
This study examines the benzoylation of 4-aminoantipyrine with benzoyl chloride, a reaction relevant to the synthesis of biologically active acyl derivatives, and evaluates the influence of solvent, temperature, reaction time, and acid or base catalysts. Experiments compared benzene and p-xylene media and tested monochloroacetic acid, pyridine, sodium hydroxide, and potassium hydroxide, with reaction progress assessed by determination of unreacted amine and rate constants calculated for selected conditions. The results indicate that p-xylene at 138°C for 1 hour improves the uncatalyzed reaction, while all tested additives catalyze benzoylation, with alkaline aqueous conditions giving particularly high yields at room temperature. Potassium hydroxide was identified as the most effective catalyst, affording a high yield of the acyl derivative in a short reaction time.
Full Text
Proceedings
of the Tomsk Order of the October Revolution
and Order of the Red Banner of Labor
Polytechnic Institute named after S. M. Kirov
Vol. 233 1974
STUDY OF THE EFFECT OF ACID AND BASIC CATALYSTS ON THE ACYLATION REACTION OF 4-AMINOANTIPYRINE
G. M. STEPNOVA, G. A. TERENT’EVA, G. N. ZOTOVA, L. A. OVCHINNIKOVA
(Presented by the scientific-methodological seminar of the Department of Chemical Technology)
The acylation reaction of 4-aminoantipyrine with acid chlorides is widely used in the synthesis of new medicinal substances possessing anti-inflammatory, antipyretic, and analgesic activity [1, 2, 3]. Therefore, a comprehensive study of this reaction is of definite practical importance.
The aim of the present work is to determine the optimal reaction conditions and to clarify the possibility of the catalytic action of bases and carboxylic acids on the acylation process, using as an example the interaction of 4-aminoantipyrine with benzoyl chloride.
Experiments carried out in benzene showed that its use as a medium is impractical (Fig. 1).
Replacing low-boiling benzene with p-xylene leads to a considerable reduction in reaction time and an increase in product yield, especially in the temperature region close to the boiling point of the solvent. The optimal conditions for benzoylation of 4-aminoantipyrine are: solvent—p-xylene; time—1 h; temperature—138°C (Fig. 1).
As shown by the studies of Litvinenko and co-workers, carboxylic acids are effective catalysts for the acylation of aromatic amines [4, 5]. In the present work, the effect of additions of monochloroacetic acid on the benzoylation reaction of 4-aminoantipyrine was studied. It turned out that monochloroacetic acid is an effective catalyst for the acylation of a heterocyclic amine (Fig. 2).
Pyridine, potash, and caustic soda were used as basic catalysts for the acylation reaction of 4-aminoantipyrine with benzoyl chloride. The experimental results showed that pyridine catalyzes the benzoylation reaction of 4-aminoantipyrine (Fig. 3); however, it has no particular advantages over monochloroacetic acid. The catalytic effect of pyridine and monochloroacetic acid is more pronounced at low temperatures.
When caustic soda and potash were used in the form of 10% aqueous solutions, it was found that they are more effective catalysts, making it possible at room temperature, in an aqueous medium, within a short period of time (30 min), to achieve a high yield (97%) of the acyl derivative (Fig. 4).
Fig. 1. Dependence of the yield of the product of the acylation reaction of 4-aminoantipyrine with benzoic anhydride on the reaction temperature and time.
1 — medium: benzene, reaction time 3 h; 2 — medium: p-xylene, reaction time 2 h; 3 — medium: p-xylene, reaction time 1 h; 4 — medium: p-xylene, reaction time 0.5 h.
Fig. 2. Dependence of the yield of the acylated product on the temperature, reaction time, and amount of monochloroacetic acid.
Solid lines — reaction temperature 110°C. Dashed lines — reaction temperature 138°C.
Curves 1 — amine:catalyst ratio, g/mol:g/mol, 1:0; curves 2 — amine:catalyst ratio, g/mol:g/mol, 1:1; curves 3 — amine:catalyst ratio, g/mol:g/mol, 1:1.5.
Fig. 3. Dependence of the yield of the acylated product on the temperature, reaction time, and amount of pyridine.
Solid lines — reaction time 1 h. Dashed lines — reaction time 0.5 h.
Curves 1 — amine:catalyst ratio, g/mol:g/mol, 1:0; curves 2 — amine:catalyst ratio, g/mol:g/mol, 1:0.5; curves 3 — amine:catalyst ratio, g/mol:g/mol, 1:1.
Fig. 4. Dependence of the yield of the acyl derivative on the reaction time and on the amount of sodium hydroxide and potassium hydroxide.
— reaction time 60 min.
— — reaction time 115 min.
Curves 1 — potassium hydroxide catalyst. Curves 2 — sodium hydroxide catalyst.
On the basis of the experimental data, the rate constants of the acylation reaction of 4-aminoantipyrine hydrochloride under various conditions were calculated. The values of the constants are given in Table 1.
Experimental Part
The starting substances—benzene, p-xylene [6], benzoyl chloride [4], pyridine [7], and monochloroacetic acid [5]—were purified by known methods. 4-Aminoantipyrine hydrochloride was recrystallized from absolute alcohol to a constant melting point.
Table 1
| Reaction temperature, °C | Reaction time, h | Catalyst, g·mol per g·mol of amine | Reaction rate constants |
|---|---|---|---|
| 110 | 1 | — | \(7.03 \cdot 10^{-4}\) |
| 110 | 1 | monochloroacetic acid, 1:1 | \(6.0 \cdot 10^{-3}\) |
| 138 | 1 | — | \(9.62 \cdot 10^{-3}\) |
| 138 | 1 | monochloroacetic acid, 1:1 | \(3.15 \cdot 10^{-2}\) |
| 138 | 1 | pyridine, 1:1 | \(9.06 \cdot 10^{-2}\) |
| 20 | 0.5 | potassium hydroxide, 1:1 | \(1.12 \cdot 10^{-1}\) |
| 20 | 0.5 | sodium hydroxide, 2.3:1 | \(5.27 \cdot 10^{-2}\) |
Acylation in organic solvents was carried out by the following procedure. Into a round-bottom flask equipped with a stirrer, a reflux condenser, and a dropping funnel were charged 0.004 mole of 4-aminoantipyrine hydrochloride and 30 ml of solvent; the mixture was heated to the required temperature, and then benzoyl chloride was added in an equimolecular ratio. After the reaction time had elapsed, the reaction mass was cooled. The amount of unreacted amine was determined by titration with 0.1 N sodium nitrite solution. Acylation in the presence of catalysts was carried out by the same procedure. The catalyst was charged together with the amine,
In acylation in an aqueous medium, 0.004 mole of 4-aminoantipyrine hydrochloride was charged into a flask equipped with a stirrer, in the form of a 40% aqueous solution; an equimolecular amount of benzoyl chloride; and alkali or potash in the form of a 10% aqueous solution. The mixture was kept at room temperature with vigorous stirring. After the time had elapsed, the reaction mixture was cooled to \(+4^\circ\mathrm{C}\), and the amount of unreacted amine was determined.
Each experiment was repeated at least 3 times.
Conclusions
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The acylation reaction of 4-aminoantipyrine with benzoyl chloride in various solvents (benzene, \(p\)-xylene) was studied.
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The effect of additions of monochloroacetic acid, pyridine, caustic soda, and potash on the reaction under study was investigated.
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It was found that the indicated compounds are catalysts for the benzoylation of 4-aminoantipyrine.
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It was shown that potash is the best catalyst.
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