Flow Chemistry

Design of dynamic trajectories for efficient and data-rich exploration of flow reaction design spaces

Batch and continuous reactors both enable exploration of a chemical design space. The former rely on transient experiments, thus experiencing a wide variety of operating conditions over time, whereas the latter are usually operated at steady state and are representative of only one set of conditions. Operating a continuous reactor under dynamic conditions allows more efficient exploration of the underlying reaction space for extraction of kinetics and optimization of performance. We present a methodology to efficiently explore a design space using a tubular flow reactor installed on an automatic platform (equipped with FTIR and HPLC analysis) operated in a transient regime using sinusoidal variations of the parameters. This data-dense method proves to be quicker with respect to steady-state operations because of the larger amount of information collected during a single experiment. A computational analysis provides a simple criterion for the design of dynamic experiments in order for them to be representative of steady-state conditions. The methodology is applied experimentally to the synthesis of a pharmaceutical intermediate via an esterification reaction in the presence of base. In the experiments, up to three parameters (reaction time, base equivalents, and temperature) are changed simultaneously. Proper design of the trajectories in the design space allows verification of the consistency of the results by exploiting the self-crossings within each trajectory and crossings between different trajectories. The experiments further validate the developed criterion for dynamic operations.

Continuous dimethyldioxirane generation for polymer epoxidation

Post-polymerization modification of commodity polymers yields new applications for materials already produced industrially. Incorporation of small amounts of epoxides into unsaturated polymers such as polybutadiene expands their use for grafting and compatibilization applications, but controlled epoxidation of these polymers in a safe, scalable manner presents a challenge. Here in we describe the development of a reactor for the continuous flow generation and use of dimethyldioxirane (DMDO) and its application to the low-level epoxidation of unsaturated polymers. A continuous stirred tank reactor (CSTR) prevents reactor clogging by allowing solid precipitates to settle, enabling the pumping of a homogeneous solution of oxidant. Modification of relative concentrations, flow rates, and temperatures achieves variable epoxidation levels. This method has been demonstrated on gram scale

Continuous-Flow Synthesis of Tramadol from Cyclohexanone

A multioperation, continuous-flow platform for the synthesis of tramadol, ranging from gram to decagram quantities, is described. The platform is segmented into two halves allowing for a single operator to modulate between preparation of the intermediate by Mannich addition or complete the fully concatenated synthesis. All purification operations are incorporated in-line for the Mannich reaction. ‘Flash’ reactivity between meta-methoxyphenyl magnesium bromide and the Mannich product was controlled with a static helical mixer and tested with a combination of flow and batch-based and factorial evaluations. These efforts culminated in a rapid production rate of tramadol (13.7 g°h–1) sustained over 56 reactor volumes. A comparison of process metrics including E-Factor, production rate, and space-time yield are used to contextualize the developed platform with respect to established engineering and synthetic methods for making tramadol.

Modular Continuous Flow Synthesis of Imatinib and Analogues

A modular continuous flow synthesis of imatinib and analogues is reported. Structurally diverse imatinib analogues are rapidly generated using three readily available building blocks via a flow hydration/chemoselective C–N coupling sequence. The newly developed continuous flow hydration and amidation modules each exhibit a broad scope with good to excellent yields. Overall, the method described does not require solvent switches, in-line purifications, or packed-bed apparatuses due to the judicious manipulation of flow setups and solvent mixtures.

Using Carbon Dioxide as a Building Block in Continuous Flow Synthesis

Carbon dioxide (CO2) is an attractive building block for organic synthesis that is environmentally friendly. Continuous flow technologies have enabled C−O and C−C bond forming reactions with CO2 that previously were either low-yielding or impossible in batch to afford value-added chemicals. This review describes recent advances in continuous flow as an enabling strategy in utilizing CO2 as a C1 building block in chemical synthesis.

Reconfigurable System for Automated Optimization of Diverse Chemical Reactions

Chemical synthesis generally requires labor-intensive, sometimes tedious trial-and-error optimization of reaction conditions. Here, we describe a plug-and-play, continuous-flow chemical synthesis system that mitigates this challenge with an integrated combination of hardware, software, and analytics. The system software controls the user-selected reagents and unit operations (reactors and separators), processes reaction analytics (high-performance liquid chromatography, mass spectrometry, vibrational spectroscopy), and conducts automated optimizations. The capabilities of this system are demonstrated in high-yielding implementations of C-C and C-N cross-coupling, olefination, reductive amination, nucleophilic aromatic substitution (SNAr), photoredox catalysis, and a multistep sequence. The graphical user interface enables users to initiate optimizations, monitor progress remotely, and analyze results. Subsequent users of an optimized procedure need only download an electronic file, comparable to a smartphone application, to implement the protocol on their own apparatus.