## 3 Results and Discussion  
In a typical fashion the ketone (2 mmol), ethylcyanoacetate (2 mmol), sulfur (2 mmol) and morpholine (2 mmol) were added to a custom made 1\(\
icefrac{{}_{2}}{{}^{\prime}}\times\) 2\({}^{\prime}\) screw-capped stainless steel vial and milled with a Spexcertiprep mixer/mill 8000 M for 24 h with a 1/8\({}^{\prime}\) inch stainless steel ball-bearing (Scheme 2). **Scheme 2. ** Representative solvent-free Gewald reaction via high speed ball milling (HSBM). At the conclusion of the reaction, the crude product was washed with water and products were isolated by column chromatography. \({}^{1}\)H NMR, \({}^{13}\)C NMR, GC-MS were obtained on the products and compared to literature values. The results are summarized in Table 1.  
Using our initial conditions we observed moderate yields of 2-aminothiophenes with aryl ketones. Similar to solution based Gewald reactions aryl groups substituted with electron-donating groups react slower than those with electron withdrawing groups. In order to improve the yield and reaction rate, we investigated various aspects of this reaction under ball milling conditions. A recent report by [PERSON] and results from our own lab suggest base reactivity is different under ball milling conditions than they are in solution [25]. In solution it was demonstrated that only morpholine gave high yields of thiophene product using the Gewald reaction. To that end, we examined the use of various bases to determine the effect it has on the reaction rate. Bases such as sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine, pyridine, piperidine and morpholine were analyzed under HSBM reaction conditions. Various amine bases (triethylamine, pyridine, piperidine) produced yields similar to what is reported in Table 1, however we observed no product formation when sodium bicarbonate, potassium carbonate or sodium hydroxide was used as the base. We next investigated the effect of reagent to vial ratio (_i.e._, the ratio of the amount of reagents that fill the volume of the vial) has on the rate and yield of our ball milled reaction. In our intial experiments we began using 1 mmol of all of the reagents. When these reagents were placed into our vial it covered roughly 10% of the vial capacity. The extent that the reagents fill the vial has been postulated as an important factor to consider in ball milled reactions. Unlike reactions that are conducted in a stirred solution, homogeneity in HSBM reactions is not achieved instantaneously. If the reagent to vial ratio is low, then it would take a longer time before all the components could react together. If the reagents to \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Starting** & **HSSM,** & **Oven, 120 °C,** & **HSBM, 0.5 h,** & **Oven, 120 °C,** \\
**Ketone** & **24 h** & **1 h** & **heat gun** & **1 h. cat. morpholine** \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Reactions of _p_-substituted acetophenones with malonitrile, sulfur and morpholine by high speed ball milling 1.  
vial ratio is too high then there is not enough voided space in the vial to be able to have the ball move throughout the reaction and provide the energy needed to cause the reaction to occur. We postulated that the reagent to vial ratio would be more essential for MCR's since these reactions rely on a series of bimolecular reactions before the final product is formed. Increasing the reagent to vial ratio would increase the reaction rate and give a higher yield of product. Using _p_-nitroacetophenone as the ketone (1 equivalent), ethylcyanoacetate (1 equivalent), sulfur (1 equivalent) and morpholine (1 equivalent) we conducted the ball milled Gewald reaction at ketone concentrations of 1 mmol, 3 mmol, 5 mmol, 7 mmol, and 9 mmol. ; this corresponds to approximately 10%, 25%, 50%, 75% and 95% vial capacity. Each experiment was done in duplicate and the products isolated by chromatography. Surprisingly we discovered that irrespective of the reagent to vial ratio each reaction gave similar yields.