High-Throughput Experimentation in Practice: Hidden Bottlenecks and Digital Gaps

Abstract High-throughput experimentation (HTE) has become an increasingly important approach for reaction discovery, optimization, and AI-ready data generation in synthetic chemistry. However, despite rapid adoption, many practical limitations associated with implementing HTE workflows remain underreported, particularly outside industrial settings. In practice, experimental reliability is frequently constrained by factors such as solvent compatibility, evaporation, sealing performance, plate geometry, liquid handling limitations, and the physical constraints introduced through miniaturization. These effects can strongly influence reproducibility and data quality, yet are often treated as secondary implementation details rather than core considerations. Alongside these operational challenges, digital HTE workflows remain fragmented, with limited interoperability between software, hardware, analytical systems, and data structures. In this perspective, we discuss a range of practical and digital bottlenecks encountered during plate-based HTE, drawing on direct experimental experience, supporting experimental data, and recent developments across the field. In particular, we present new observations relating to solvent evaporation and sealing performance in common HTE formats, highlighting how seemingly minor physical effects can substantially influence experimental reliability and downstream interpretation. By making these practical considerations more explicit, we aim to support the development of more reproducible, interoperable, and scalable HTE workflows across academic and industrial chemistry.