Ryan L. Hartman

Deciding Whether To Go with the Flow: Evaluating the Merits of Flow Reactors for Synthesis

The fine chemicals and pharmaceutical industries are transforming how their products are manufactured, where economically favorable, from traditional batchwise processes to continuous flow. This evolution is impacting synthetic chemistry on all scales-from the laboratory to full production. This Review discusses the relative merits of batch and micro flow reactors for performing synthetic chemistry in the laboratory.

Microchemical systems for continuous-flow synthesis

Microchemical systems have evolved rapidly over the last decade with extensive chemistry applications. Such systems enable discovery and development of synthetic routes while simultaneously providing increased understanding of underlying pathways and kinetics. We review basic trends and aspects of microsystems as they relate to continuous-flow microchemical synthesis. Key literature reviews are summarized and principles governing different microchemical operations discussed. Current trends and limitations of microfabrication, micromixing, chemical synthesis in microreactors, continuous-flow separations, multi-step synthesis, and integration of analytics are delineated. We conclude by summarizing the major challenges and outlook related to these topics.

Palladium-catalyzed amination reactions in flow: overcoming the challenges of clogging via acoustic irradiation

A continuous-flow palladium-catalyzed amination reaction was made possible through efficient handling of solids via acoustic irradiation. Various diarylamines were obtained with reaction times ranging from 20 s to 10 min.

Distillation in microchemical systems using capillary forces and segmented flow

Distillation is a ubiquitous method of separating liquid mixtures based on differences in volatility. Performing such separations in microfluidic systems is difficult because interfacial forces dominate over gravitational forces. We describe distillation in microchemical systems and present an integrated silicon device capable of separating liquid mixtures based on boiling point differences. Microfluidic distillation is realized by establishing vapor-liquid equilibrium during segmented flow. Enriched vapor in equilibrium with liquid is then separated using capillary forces, and thus enabling a single-stage distillation operation. Design criteria for operation of on-chip distillation is set forth, and the working principle demonstrated by separation of binary mixtures of 50 : 50 mol% MeOH-toluene and 50 : 50 mol% DCM-toluene at 70.0 degrees C. Analysis of vapor condensate and liquid exiting a single-stage device gave MeOH mole fractions of 0.22 +/- 0.03 (liquid) and 0.79 +/- 0.06 (vapor). Similarly, DCM mole fractions were estimated to be 0.16 +/- 0.07 (liquid) and 0.63 +/- 0.05 (vapor). These experimental results were consistent with phase equilibrium predictions.

Teflon-Coated Silicon Microreactors: Impact on Segmented Liquid−Liquid Multiphase Flows

We describe fluoropolymer modification of silicon microreactors for control of wetting properties in chemical synthesis applications and characterize the impact of the coating on liquid-liquid multiphase flows of solvents and water. Annular flow of nitrogen gas and a Teflon AF (DuPont) dispersion enable controlled evaporation of fluoropolymer solvent, which in turn brings about three-dimensional polymer deposition on microchannel walls. Consequently, the wetting behavior is switched from hydrophilic to hydrophobic. Analysis of microreactors reveals that the polymer layer thickness increases down the length of the reactor from ∼1 to ∼13 μm with an average thickness of ∼7 μm. Similarly, we show that microreactor surfaces can be modified with poly(tetrafluoroethylene) (PTFE). These PTFE-coated microreactors are further characterized by measuring residence time distributions in segmented liquid-liquid multiphase flows, which display reduced axial dispersion for the coated microreactors. Applying particle image velocimetry, changes in segment shape and velocity fluctuations are observed resulting in reduced axial dispersion. Furthermore, the segment size distribution is narrowed for the hydrophobic microreactors, enabling further control of residence distributions for synthesis and screening applications.

Microfluidic investigation of the deposition of asphaltenes in porous media

The deposition of asphaltenes in porous media, an important problem in science and macromolecular engineering, was for the first time investigated in a transparent packed-bed microreactor (μPBR) with online analytics to generate high-throughput information. Residence time distributions of the μPBR before and after loading with ~29 μm quartz particles were measured using inline UV-Vis spectroscopy. Stable packings of quartz particles with porosity of ~40% and permeability of ~500 mD were obtained. The presence of the packing materials reduced dispersion under the same velocity via estimation of dispersion coefficients and the Bodenstein number. Reynolds number was observed to influence the asphaltene deposition mechanism. For larger Reynolds numbers, mechanical entrapment likely resulted in significant pressure drops for less pore volumes injected and less mass of asphaltenes being retained under the same maximum dimensionless pressure drop. The innovation of packed-bed microfluidics for investigations on asphaltene deposition mechanisms could contribute to society by bridging macromolecular science with microsystems.

Influence of water on the deprotonation and the ionic mechanisms of a Heck alkynylation and its resultant E-factors

The influence of water on deprotonation and ionic mechanisms of a Heck alkynylation and its resultant E-factors were investigated. Estimation of the Hatta modulus, MH < 0.02, in cationic deprotonation, anionic deprotonation, and the ionic mechanism each separately confirmed an infinitely slow rate of reaction with respect to the diffusive flux within the thin film of the immiscible aqueous–organic interface. As a consequence, intrinsic kinetic expressions for far-equilibrium conditions were derived from first principles for each mechanism. Analyses of Gibbs free energies revealed that water potentially switched the rate-determining steps of cationic and anionic deprotonation to any of oxidative addition of organohalide to form Pd-complex (ΔG++ = 97.6 kJ mol−1), coordination of the alkyne with the oxidative addition adduct (ΔG++ = 97.6 kJ mol−1), or ligand substitution to form the cationic Pd-complex (ΔG++ = 94.9 kJ mol−1). Hydrogen-bonding in the transfer mechanism might account for the switch. Water, in general, was found to influence which step governs each catalytic cycle and the magnitude of its Gibbs free energy. Transformation of the synthesis from batch to continuous-flow was also studied by analyses of E-factors within the thin film. The amount of waste generated, as indicted by estimations of E-factors, was less in continuous-flow operation than in batch when the fastest step of deprotonation (ligand substitution) was infinitely fast with respect to the diffusive flux. The concentration of hydrophilic phosphine ligand was observed to influence mass transport limitations and the E-factor. Increasing ligand concentrations beyond (10.5), (13.3), and (23.2) × 10−3 mol L−1 for reaction temperatures of 353, 343, and 323 K increased the E-factor above its minimum value of 4.7, and it also induced mass-transfer-limitations. The switch from intrinsic to mass-transport-limited kinetics by finite changes in the ligand concentration explains ambiguity when performing aqueous-phase catalyzed Heck alkynylations and possibly multiphase Pd-catalyzed C–C cross-couplings in general. The potential exists to inadvertently mask the reactivity of useful ligands during discovery and to force mass transport limitations during manufacture. Understanding why the E-factor can be minimized is vital to the sustainable discovery and manufacture of fine chemicals, materials, natural products, and pharmaceuticals.

When solids stop flow chemistry in commercial tubing

Flow chemistry has emerged as the enabling field of high-throughput, data-driven discovery, and process chemistry, yet solids handling remains its key challenge. Insoluble salt by-products can stop flow, fluctuate reagent concentrations in reactors, and cost unexpected time and materials consumptions. The clogging of perfluoroalkoxy (PFA) tubing, stainless steel (SS) tubing, and a silicon microreactor by NaCl during a Pd-catalyzed amination using XPhos ligand was each studied. Our goal of understanding the appropriate reactor design provides in-depth analyses of constriction and mechanical entrapment. Calculations of Stokes number (St)>1 revealed that NaCl particle depositions were independent of the reactor materials. Analyses of the clogging time’s dependence on the residence time (τ) and particle volume fraction (ϕ) discovered commercial tubing to be inadequate for the decoupling of the kinetics. The results prescribe why fabricated microreactors with on-chip analytics, particle formations and dissolutions, and without fluidic connections are solutions to discover and develop ubiquitous reactions that form inorganic salt by-products.

Microfluidic dispersion of mineral oil-seawater multiphase flows in the presence of dialkyl sulfonates, polysorbates, and glycols

Abstract The role of dispersants on hydrocarbon phase behavior in seawater is an important problem that influences marine environment ecology. Offshore petroleum and natural gas catastrophes, such as the Deepwater Horizon spill of 2010, motive the need to understand how to minimize the introduction of potentially invasive compounds while maximizing their efficacy during emergency remediation. The microfluidic stabilities of mineral oil-seawater multiphase flows in the presence of model dispersants were studied for We<1. Introducing dispersants at varying dimensionless volumetric injection rates, ranging from 0.001 to 0.01, transitions from stable slug flow to the bubbly regime. Dimensionless mass ratios of three model dispersants to the mineral oil necessary to establish emulsions were estimated from 2.6×10-3 to 7.7×10-3. Residence time distributions of seawater single-phase and mineral oil-seawater multiphase flows, laden with dispersants, were also investigated. Increasing the dimensionless dispersant injection rate from 0 to 0.01 was observed to increase convective dispersion, which was confirmed by estimations of the vessel dispersion number and the Bodenstein number. The observations undergird that microfluidics are useful laboratory techniques to identify the transition to bubbly flow where bacteria consumption rates could potentially be enhanced, while minimizing the dispersant mass introduced into calm-sea marine environments.

Microfluidics with in situ Raman spectroscopy for the characterization of non-polar/aqueous interfaces

The design of microfluidics with in situ Raman spectroscopy is reported in the present work for the investigation of immiscible non-polar/aqueous interactions. A dynamic aqueous phase in contact with a static hydrophobic phase (semi-flow) was engineered on-chip by performing a force balance, and it was validated using high-resolution in situ Raman spectroscopy. The semi-flow microfluidic device isolated non-polar solvents in a series of micro-reservoirs that communicated with aqueous laminar flows via molecular diffusion. As a consequence, the inspection of concentration and density profiles from the bulk-to-bulk of toluene–, diethyl ether–, and xylenes–water were made possible. The Schlieren pattern was observed for all solvent pairs, and the bulk-to-bulk region was characterized by water rarefaction (17.5 to 23.2 μm), mixing (3.4 to 6.4 μm), and hydrophobic shockwaves (34.9 to 38.8 μm). Understanding the position, thickness, and profiles of each zone revealed new insight on the chemistry at the interface, which could someday be used to validate molecular simulations, reduce the quantities of solvents wasted during separations/purifications of compounds, and improve kinetic models for mixed mass-transfer-reaction-rate-limited and mass-transfer-limited scenarios in continuous-flow processes.