# Environmentally Friendly Green \(O\)-Alkylation Reaction for Ethenzamide Synthesis
## 3 Results
### Conventional Methods of Ethenzamide Synthesis  
The research was started with the synthesis by classical methods of ethenzamide, i.e., in the presence of sodium hydroxide in ethanol. The reactions were carried out under reflux, with progress monitored by TLC (Thin Layer Chromatography) until salicimide was no longer detected. The expected ethenzamide was obtained after 3 hours with a yield of 43% following crystallization from methanol (Table 1, no. 1). In the next stage of the study, \(O\)-alkylation of salicimide (**5**) was carried out in the presence of K\({}_{2}\)CO\({}_{3}\) and KI, in dimethylformamide (DMF) as a solvent, which allowed us to obtain ethenzamide (**6**) after 4 hours with a yield of 60% (Table 1, no. 2). Considering that, from an ecological point of view, it is necessary to \"minimize the use of toxic organic solvents, we also decided to carry out the synthesis in solvent-free conditions. The lack of a solvent in the reaction environment brings many benefits: for example, it reduces the risk of explosion, allows the elimination of toxic waste, often also has a positive effect on shortening the reaction time, improves the ease of isolating the product, and has a positive effect on the product efficiency. By eliminating expensive and toxic solvents, the synthesis process is made much cheaper and more ecological, which allows such reactions to be classified as \"green chemistry\" processes. This concept was first used by [PERSON] in 1991, who defined it as: \"Searching for, designing and implementing chemical products and processes that enable the reduction or elimination of the use and production of hazardous substances\" [31; 32; 33]. We began our research by evaluating the effect of temperature on the process, conducting the reaction at temperatures ranging from 20 \({}^{\circ}\)C to 80 \({}^{\circ}\)C. In these reactions, TBAB (tetrabbutylammonium bromide) was used as a catalyst, which is one of the most commonly used PTCs (Phase Transfer Catalysts) in the synthesis of bioactive compounds due to its non-toxicity, easy availability, and favorable low price. Due to the lack of reaction progress at lower temperatures, i.e., up to 60 \({}^{\circ}\)C, the reaction was stopped, despite the presence of salicamide in the reaction mixture. The \begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**No** & **Catalyst** & **Solvent** & **Base** & **Conditions** & \
\begin{tabular}{c} **Time** \\ **[h]** \\ \end{tabular} &
\begin{tabular}{c} **Yield * \\ **[\%]** \\ \end{tabular} \\ \hline
1 & - & ethanol & NaOH & reflux & 3 & 43 \\
2 & KI & DMF & K\({}_{2}\)CO\({}_{3}\) & reflux & 4 & 60 \\
3 & TBAB & - & K\({}_{2}\)CO\({}_{3}\) & 20 \({}^{\circ}\)C & 192 & 34 \\
4 & TBAB & - & K\({}_{2}\)CO\({}_{3}\) & 40 \({}^{\circ}\)C & 3.5 & 14 \\
5 & TBAB & - & K\({}_{2}\)CO\({}_{3}\) & 60 \({}^{\circ}\)C & 1.5 & 52 \\
6 & TBAB & - & K\({}_{2}\)CO\({}_{3}\) & 80 \({}^{\circ}\)C & 0.25 & 79 \\
7 & TEBA & - & K\({}_{2}\)CO\({}_{3}\) & 80 \({}^{\circ}\)C & 0.25 & 72 \\
8 & TEAC & - & K\({}_{2}\)CO\({}_{3}\) & 80 \({}^{\circ}\)C & 1 & 83 \\
9 & TEAI & - & K\({}_{2}\)CO\({}_{3}\) & 80 \({}^{\circ}\)C & 0.25 & 74 \\
10 & TEAB & - & K\({}_{2}\)CO\({}_{3}\) & 80 \({}^{\circ}\)C & 0.25 & 86 \\
11 & DABCO & - & K\({}_{2}\)CO\({}_{3}\) & 80 \({}^{\circ}\)C & 0.25 & 69 \\
12 & 18-CROWN-6 & - & K\({}_{2}\)CO\({}_{3}\) & 80 \({}^{\circ}\)C & 0.25 & 78 \\ \hline \hline \end{tabular}  
* Yields after crystallization from methanol.  
\end{table} 
Table 1: Synthesis of ethenzamide (**6**) under standard conditions. products isolated in these reactions were clearly contaminated with unreacted salicylamide (Table 1, no. 3-5). In the next stage of the research, the effectiveness of the catalysts on the rate and efficiency of the process was evaluated.