Amide Synthesis via a Reactive Acid Chloride Intermediate

The use of acid chlorides and activated acids in organic synthesis is quite widespread due to the variety of structural motifs accessible when these functional groups undergo nucleophilic substitutions.  However, the inherent reactivity within these functional groups can also be problematic and can lead to unwanted to side-reactions, by-products and impurities.  Typical chromatographic conditions oftentimes decompose acid chlorides and activated acids.  Although derivitization is possible, it requires additional prep time and may introduce other uncertainty.  Other offline techniques pose challenges to timely and accurate analysis.  In addition, reactions of these functional groups are exothermic and therefore pose potential safety and scale-up concerns.  A thorough understanding of critical process parameters and their impact on the performance of these reactions is highly desirable for safe and efficient process development.