Kinetics of Ring Closure Thiazole Cyclization Using 3-Chloroacetylacetone
with Thioamides
Authors: Zaware Bhaskar Hari , Sadavarte Prajakta Shamrao , Takate Sushama Jayawant 
Published: September 2022

Background:

Thiazoles are an important heterocycle which exhibits various bioactivities. Thiazole ring is found in core structure of various medicinally useful compounds. It shows biological activities like anti-inflammatory, antibacterial, antifungal, antioxidant, cytotoxicity, anticonvulsant, insecticidal, anticancer and antitumor. Thioamides are reported to show bioactivities like antibacterial, antileukemia, antifungal, anti-arthritic, antimalarial and cytotoxic. Hantzsch synthesis is one of the most efficient reactions for thiazole formation which is a cyclization reaction between thioamides and α-halo carbonyl compounds. A very few reports on kinetic investigation of thiazole formation are available. Previously we have studied thiazole formation using 3-chloroacetylacetone and substituted thioureas by pH metric study. The reaction between 3-chloroacetylacetone and Thioamides is not reported yet. The present work deals with kinetics and mechanistic study of ring closure of thiazole using thioamides and 3-chloroacetylacetone. The reaction has been carried out in water-ethanol system at 303K. The kinetic investigations are carried out pH metrically. Nature of reaction is explained on the basis of thermodynamic parameters. Reaction products are isolated and characterized on the basis of spectral data. The effect of temperature on reaction rate is studied at 30°C to 50°C. Thermodynamic parameters are evaluated.

Objective/s:

To determine the order of reaction. • To determine the rate of reaction. • To evaluate the rate of reaction at various temperatures. • To determine the rate of reaction in different media. • To study the effect of dielectric constant, ionic strength etc. • To observe calculation of energy of activation, enthalpy of activation, entropy of activation and free energy of activation. • To propose reaction mechanism considering various thermodynamic parameters.

Method:

Measuring the change in pH, the concentration of H+ ion will be determined and accordingly rate of reaction will be calculated.

Result:

Van’t Hoff’s differential method and the stoichiometric study suggested that one mole of Thioamides reacts with one mole of 3-chloroacetylacetone. The rates of reaction are measured at different concentration of Thioamides at constant concentration of 3-chloroacetylacetone. The plot of log (dc / dt) against log [3-chloroacetylacetone] and log [ Thioamides] is also straight line and slope of the plot is nearly one with respect to both. At five different temperatures second order rate constants are determined. The energy of activation (Ea) is determined by plotting graph of logk versus 1/T and other thermodynamic parameters are calculated. The negative entropy of activation (∆S*) of this reaction specifies rigid nature of the transition state. The entropy of activation (∆S*) is negative value and it specifies that less stable noncyclic reactants convert into stable cyclic product. Free energy of activation (∆G*) is calculated [Table 1], Graph 1. Reacting species are oppositely charged according to salt effect [Graph 2]. In water-isopropyl alcohol system reaction is fast than water-ethanol system [Graph 3].

Conclusion:

• Using Van’t Hoff’s differential method the rate of reaction between 3-chloroacetylacetone and Thioamides is found to be one with respect to both components. • The proposed rate law also shows that the order of reaction is two.
• Negative entropy (∆S*) shows that from open chain compound cyclic compound is formed. Nucleophilic addition and addition–elimination reaction take place.
• Oppositely charge species are present in reaction.
• Rate increases with increase in dielectric constant. Isopropyl alcohol-water system shows high-rate constant as compared to Ethanol-water system.