High-Throughput Experimentation and Continuous Flow Evaluation of Nucleophilic Aromatic Substitution Reactions

Abstract

Nucleophilic aromatic substitution (SNAr) reactions were optimized using high-throughput experimentation techniques for execution under flow conditions. A total of 3072 unique reactions were evaluated with an analysis time of ∼3.5 s per reaction using a system that combines a liquid handling robot for reaction mixture preparation with desorption electrospray ionization (DESI) mass spectrometry (MS) for analysis. The reactions were performed in bulk microtiter arrays with and without incubation. In-house developed software was used to process the data and generate heat maps of the results. This information was then used to select the most promising conditions for continuous synthesis under microfluidic reactor conditions. Our results show that this HTE approach provides robust guidance for narrowing the range of conditions needed for optimization of SNAr reactions.

Automated High-Throughput System Combining Small-Scale Synthesis with Bioassays and Reaction Screening

“…This agrees well with the expected trend that product formation in S N Ar is favored by amines with electron-donating groups and aryl halides with electron-withdrawing groups (compare the cases of the nitro substituted aryl halides with, for instance, 5-chloro-1,10-phenanthroline). 7 A further example of predictable structure–reactivity relationships is found in the N -arylation reactions, where fluorobenzene shows lower reactivity than bromobenzene, agreeing with previous reports, 94 as is the effect of the leaving group (e.g., fluorine vs bromine). A similar effect was observed in the Suzuki coupling reactions, where the oxidative addition is usually the rate-determining step of the mechanism.…”

“…The main output of these screening experiments is typically a yes/no answer to the question of whether or not a specific reaction generates an expected product under certain conditions, allowing for optimization of synthetic conditions and providing a starting point for scale-up. 6,7,63,70,71 Typically, no quantitative data are sought through organic reaction screening, although MS information can be readily utilized to assess compound purity.…”

“…are rapidly screened to locate optimal conditions. 6,7 The successful hits from reaction screening can then be used in bioactivity screening and further investigation. 8–13…”

“…The system has been successfully used to study multiple organic reactions through HTS campaigns. The reactions include N-alkylation, 70 N -acylation, 71 Sonogashira coupling, 12 nitrosation, 9 Suzuki cross-coupling, 63,72 aromatic nucleophilic substitution (S N Ar), 7 aldol reaction, 73 and reductive amination. 6 Capabilities have also been demonstrated for studies of enzymatic systems, such as acetylcholinesterase, which include the determination of Michaelis–Menten kinetic parameters, as well as the screening and characterization of both inhibitors and reactivators.…”

Advancement in Organic Synthesis Through High Throughput Experimentation

“…Thompson et al [43b] . evaluated 3072 unique reactions in NMP using DESI‐MS with an analysis time of 3.5 s per reaction in HTE where four different base conditions (DIPEA, NaO t Bu, TEA, no base) across eight amines and 12 electrophiles in multiple rounds of HTE.…”