Example results obtained by 3rd year undergraduate students carrying out the reaction are summarized in Table 2. Students used a tubular reactor with volume 3.8 mL (192 cm length of 1/16th inch internal diameter PTFE tubing). A qualitative scan of the parameters was performed by the students to understand the important effects present that lead to varying conversions and selectivity.
The results shown in Table 2 indicate the effect of the various reaction parameters on product formation. The overall conversion of starting material ranges from 60 to 82% and selectivity for the mono-acetylated product from 63 to 80% for the parameter range investigated. It is important to note that, when using a tubular coil reactor, changing the residence time by changing the overall flow rate will impact on the interphase mass transfer; while changes in solution’s ratio will affect the slug’s size ratio, which can also affect the result. Although experimentally no effort was made to control those factors, they can be used to further expand the discussion about how changes in one parameter can have further implications in the reaction outcome.
As residence time increases, conversion also increases, but selectivity for the mono-substituted product decreases. With longer residence times the starting material has a longer time to react with the acetic anhydride, increasing overall conversion. However, it also means that once formed, the mono-acetylated product has time to react a second time forming the di-acetylated product. The kinetics of each step can be discussed with the students.
Ambient temperature was used as the default, and higher temperatures are achieved by immersing the tubing in a controlled water bath. The CSTRs sit on a hotplate-stirrer and a thermocouple can be inserted into one of the ports if required. With increasing temperature, a slight increase in conversion is seen, however, there is little change to the selectivity of the reaction. The temperature range investigated by students during this experiment is narrow (0, 20 and 28 °C) and we would recommend increasing the temperature further to observe more significant effects on product formation. We might expect an increase in conversion and decrease in selectivity for the mono-acetylated product to be observed at higher temperatures, due to increased reactivity of the starting diamine and more mono-acetylated product present, however the rate of acetic anhydride hydrolysis may compete in affecting the conversion.
As pH decreases, conversion and selectivity for the mono-substituted product increase. The increase in selectivity may be due to changes in the partitioning of reagents at different pH. Under acidic conditions, the diamine and indeed mono-acetylated product, once formed, would be protonated and would hence partition into the aqueous phase, leaving the organic phase containing acetic anhydride. This minimises over-reaction to the di-acetylated product. A model involving protonation of species and partitioning between each liquid phase can be discussed with the students. (Scheme 2).
Excess diamine is undesirable as it complicates the purification process due to the need to remove large quantities of starting material. A 1:1 ratio of diamine:acetic anhydride gave the highest conversion, and high selectivity for the mono-substituted product. Different stoichiometries can be used to access the order of the reaction.
Reactor & mixing
The extent of mixing within a reactor can have a significant effect on the conversion and selectivity of a reaction. For biphasic systems, the rate of mass transfer is limited by the interfacial area between the phases, which is low in conventional batch and tubular flow reactors. To overcome these limitations, a “plug-and-play” miniature CSTR cascade was utilised, which maximises the interfacial area by utilising a magnetic coupling design to provide active mixing within the reaction chamber.7
As the mixing speed (RPM) of the CSTRs increases, both the conversion and mono-selectivity increases (Fig. 2). Similarly, the CSTRs provide a higher conversion and mono-selectivity compared to both the batch and tubular reactors (Table 3). These results indicate that the active mixing provided by the CSTRs increases the rate of mass transfer and hence the rate of formation of the product.