Co-reporter:Lu Yang, Nopphon Weeranoppanant, and Klavs F. Jensen
Industrial & Engineering Chemistry Research October 25, 2017 Volume 56(Issue 42) pp:12184-12184
Publication Date(Web):October 3, 2017
DOI:10.1021/acs.iecr.7b03207
The membrane microseparator is a milliliter-scale flow chemistry module that continuously separates a biphasic flow through a PTFE microporous membrane. It has found a wide range of applications in the continuous manufacturing of active pharmaceutical ingredients and fine chemicals, especially those involving multiple synthetic steps. Yet, the accurate prediction and control of the pressure balance needed for successful phase separations is technically challenging. In this article, we present systematic modeling of the operating ranges of the membrane microseparator. We characterize the retention and breakthrough phenomena of the device and develop two new analytic models for retention and breakthrough by taking into consideration the tortuosity factor and pore size distribution. The new models are shown to be better predictors of the experimental results than the original theoretical models based on the simple Young–Laplace equation and the straight-channel Hagen–Poiseuille equation.
Co-reporter:Víctor Sebastián, Nikolay Zaborenko, Lei Gu, and Klavs F. Jensen
Crystal Growth & Design May 3, 2017 Volume 17(Issue 5) pp:2700-2700
Publication Date(Web):March 30, 2017
DOI:10.1021/acs.cgd.7b00193
A sequential-addition microfluidic reactor and an ultrasonic integrated microfluidic reactor were designed to produce with high selectivity hybrid Au–Pd dumbbell-like nanostructures (Au–Pd DBNPs), consisting of a palladium segment tipped with gold heads. A single-stage synthesis was not able to synthesize hybrid nanostructures due to the high reactivity of gold. On the other hand, a two-step method was successful by first synthesizing Pd nanorod-like structures and subsequent growing of Au on the tips of those structures by the localized galvanic replacement reaction. The localized deposition of Au onto both tips of palladium rods was achieved by using two different microfluidic approaches: (i) by sequential injection of gold along the reaction channel at 100 °C and a 5 min residence time, and (ii) by ultrasonic radiation at room temperature and a 2 min residence time. The synthesized Au–Pd DBNPs had higher electrocatalytic activity in the ethanol oxidation reaction in alkaline media than the Pd nanorods.
Co-reporter:Connor W. Coley, Regina Barzilay, Tommi S. Jaakkola, William H. Green, and Klavs F. Jensen
ACS Central Science May 24, 2017 Volume 3(Issue 5) pp:434-434
Publication Date(Web):April 18, 2017
DOI:10.1021/acscentsci.7b00064
Computer assistance in synthesis design has existed for over 40 years, yet retrosynthesis planning software has struggled to achieve widespread adoption. One critical challenge in developing high-quality pathway suggestions is that proposed reaction steps often fail when attempted in the laboratory, despite initially seeming viable. The true measure of success for any synthesis program is whether the predicted outcome matches what is observed experimentally. We report a model framework for anticipating reaction outcomes that combines the traditional use of reaction templates with the flexibility in pattern recognition afforded by neural networks. Using 15 000 experimental reaction records from granted United States patents, a model is trained to select the major (recorded) product by ranking a self-generated list of candidates where one candidate is known to be the major product. Candidate reactions are represented using a unique edit-based representation that emphasizes the fundamental transformation from reactants to products, rather than the constituent molecules’ overall structures. In a 5-fold cross-validation, the trained model assigns the major product rank 1 in 71.8% of cases, rank ≤3 in 86.7% of cases, and rank ≤5 in 90.8% of cases.
Co-reporter:Seung-Kon Lee, Jinyoung Baek, and Klavs F. Jensen
Langmuir March 4, 2014 Volume 30(Issue 8) pp:2216-2222
Publication Date(Web):March 4, 2014
DOI:10.1021/la4041198
Uniform polymer microbeads with highly loaded quantum dots (QDs) are produced using high-throughput coherent jet breakup of a biocompatible poly(ethylene glycol) diacrylate (PEGDA) prepolymer resin, followed by in-line photopolymerization. A spiraling and gradually widening channel enables maximum absorption of radiated UV light for the in-line photopolymerization without coalescence and clogging issues. Although the dripping mode in general provides superior uniformity to the jet mode, our nozzle design with tapered geometry brings controlled jet breakup leading to 3% of uniform particle size distribution, comparable to dripping-mode performance. We achieve a maximum production rate of 2.32 kHz, 38 times faster than the dripping mode, at a same polymer flow rate. In addition, the jet-mode scheme provides better versatility with 3 times wider range of size control as well as the compatibility with viscous fluids that could cause pressure buildup in the microsystem. As a demonstration, a QD-doped prepolymer resin is introduced to create uniform biocompatible polymer beads with 10 wt % CdSe/ZnSe QD loading. In spite of this high loading, the resulting polymer beads exhibits narrow bandwidth of 28 nm to be used for the ultrasensitive bioimaging, optical coding, and sensing sufficiently with single bead.
Co-reporter:Connor W. Coley, Luke Rogers, William H. Green, and Klavs F. Jensen
ACS Central Science December 27, 2017 Volume 3(Issue 12) pp:1237-1237
Publication Date(Web):November 16, 2017
DOI:10.1021/acscentsci.7b00355
We demonstrate molecular similarity to be a surprisingly effective metric for proposing and ranking one-step retrosynthetic disconnections based on analogy to precedent reactions. The developed approach mimics the retrosynthetic strategy defined implicitly by a corpus of known reactions without the need to encode any chemical knowledge. Using 40 000 reactions from the patent literature as a knowledge base, the recorded reactants are among the top 10 proposed precursors in 74.1% of 5000 test reactions, providing strong quantitative support for our methodology. Extension of the one-step strategy to multistep pathway planning is demonstrated and discussed for two exemplary drug products.
Co-reporter:Jisong Zhang, Andrew R. Teixeira, Haomiao Zhang, and Klavs F. Jensen
Analytical Chemistry August 15, 2017 Volume 89(Issue 16) pp:8524-8524
Publication Date(Web):July 24, 2017
DOI:10.1021/acs.analchem.7b02264
Data on the solubilities of gases in liquids are foundational for assessing a variety of multiphase separations and gas–liquid reactions. Taking advantage of the tube-in-tube reactor design built with semipermeable Teflon AF-2400 tubes, liquids can be rapidly saturated without direct contacting of gas and liquid. The gas solubility can be determined by performing steady-state flux balances of both the gas and liquid flowing into the reactor system. Using this type of reactor, a fully automated strategy has been developed for the rapid in situ measurement of gas solubilities in liquids. The developed strategy enables precise gas solubility measurements within 2–5 min compared with 4–5 h using conventional methods. This technique can be extended to the discrete multipoint steady-state and continuous ramped-multipoint data acquisition methods. The accuracy of this method has been validated against several gas–liquid systems, showing less than 2% deviation from known values. Finally, this strategy has been extended to measure the temperature dependence of gas solubilities in situ and to estimate the local enthalpy of dissolution across a defined temperature range.
Co-reporter:Lu Yang, Maria Jose Nieves-Remacha, Klavs F. Jensen
Chemical Engineering Science 2017 Volume 169(Volume 169) pp:
Publication Date(Web):21 September 2017
DOI:10.1016/j.ces.2016.12.003
•Coupled simulations of fluid flow, transport and reactions in multiphase microreactors.•Simulations accurately capture mass transport features of the segmented flow.•Predicted mass transfer enhancement effect in the presence of reactions.•Developed new physical insights to enhance design of segmented flow microreactors.We present volume-of-fluid (VOF) based simulations of coupled transport and reaction processes in microscale segmented flow microreactors. The simulations implemented in OpenFOAM accurately capture the circulation patterns and micron-scale wetting film of the segmented flow. The accurate prediction of the interfacial concentration discontinuity is shown to depend on the local Peclet number. The integrated computational fluid dynamics (CFD) and mass transfer simulations provide complete spatial and temporal information about the concentration field within the reactor, which enable quantification of the mass transfer coefficient kLa as a function of time and operating condition. Mass transport in the segmented flow system is shown to be a two-regime process, dominated first by convection and then by diffusion. Scaling analysis provide a means for estimating mass transfer coefficients and give insights into how to select optimal operating conditions in segmented flow reactors. Finally, we predict mass transfer in segmented flow with reaction, specifically, the mass transfer enhancement as a function of the Damköhler number.Download high-res image (178KB)Download full-size image
Co-reporter:Kyoungmi Lee;Hongkun Lin
Reaction Chemistry & Engineering (2016-Present) 2017 vol. 2(Issue 5) pp:696-702
Publication Date(Web):2017/10/03
DOI:10.1039/C7RE00084G
Efficient ozonolysis of quinoline, electron deficient 8-nitroquinoline, and electron rich 6-methoxyquinoline is conducted in a Corning low flow reactor (Corning LFR) with recycling. The conversions of quinoline and 8-nitroquinoline from single-pass experiments were 75.6 and 52.4%, respectively. Upon successive oxidative work-up in a batch reactor, pyridine-2,3-dicarboxylic acid was obtained in 72.7 and 24.7% yields from the ozonolysis products of quinoline and 8-nitroquinoline, respectively. The recycling increased the overall conversions to 95.2 and 76.9%, respectively. For 6-methoxyquinoline, the conversion from the single-pass experiment, 45.2%, was increased to 73.5% with recycling under a higher liquid flow rate and substrate concentration for ozonolysis. Experimental results, conversions, residence time distribution (RTD), and the overall mass transfer coefficient are included in reactor models to determine the rate constants for ozonolysis. Predictions with the rate constants for quinoline, 8-nitroquinoline, and 6-methoxyquinoline show good agreement with the experimental results for different recycle ratios and concentrations of ozone and substrates.
Co-reporter:Yi Shen;Nopphon Weeranoppanant;Lisi Xie;Yue Chen;Marcella R. Lusardi;Joseph Imbrogno;Moungi G. Bawendi
Nanoscale (2009-Present) 2017 vol. 9(Issue 23) pp:7703-7707
Publication Date(Web):2017/06/14
DOI:10.1039/C7NR01826F
This paper presents a fully-continuous novel liquid–liquid-extraction (LLE) platform for the purification of nanoparticles. The use of multistage operation enhances the purity of the final stream without the expense of high solvent consumption. Two case studies, purification of CdSe quantum dots in organic solvent and that of gold nanoparticles in water, demonstrate that the LLE platform is versatile, non-destructive, and highly efficient.
Co-reporter:Ye-Jin Hwang;Connor W. Coley;Milad Abolhasani;Andreas L. Marzinzik;Guido Koch;Carsten Spanka;Hansjoerg Lehmann
Chemical Communications 2017 vol. 53(Issue 49) pp:6649-6652
Publication Date(Web):2017/06/16
DOI:10.1039/C7CC03584E
We report an automated flow chemistry platform that can efficiently perform a wide range of chemistries, including single/multi-phase and single/multi-step, with a reaction volume of just 14 μL. The breadth of compatible chemistries is successfully demonstrated and the desired products are characterized, isolated, and collected online by preparative HPLC/MS/ELSD.
Co-reporter:Stefano Lazzari;Milad Abolhasani
Reaction Chemistry & Engineering (2016-Present) 2017 vol. 2(Issue 4) pp:567-576
Publication Date(Web):2017/08/01
DOI:10.1039/C7RE00068E
A deterministic model based on population balance equations is developed to describe the formation of II–VI semiconductor nanocrystals. After deriving the necessary equations and reviewing the link between model predictions and experimental results, a parametric study is carried out to showcase the model's features. A comparison with literature experimental data shows how the present model can satisfactorily describe average properties of the colloidal semiconductor nanocrystals such as the average diameter or the distribution width. This model represents a first step towards the development of more refined models that would open up the possibility of improved optimization and control of the nanocrystal production process.
Co-reporter:Dr. Hongkun Lin;Dr. Chunhui Dai; Timothy F. Jamison; Klavs F. Jensen
Angewandte Chemie 2017 Volume 129(Issue 30) pp:8996-8999
Publication Date(Web):2017/07/17
DOI:10.1002/ange.201703812
AbstractWithin a total residence time of 9 min, the sodium salt of ciprofloxacin was prepared from simple building blocks via a linear sequence of six chemical reactions in five flow reactors. Sequential offline acidifications and filtrations afforded ciprofloxacin and ciprofloxacin hydrochloride. The overall yield of the eight-step sequence was 60 %. No separation of intermediates was required throughout the synthesis when a single acylation reaction was applied to remove the main byproduct, dimethylamine.
Co-reporter:Dr. Hongkun Lin;Dr. Chunhui Dai; Timothy F. Jamison; Klavs F. Jensen
Angewandte Chemie International Edition 2017 Volume 56(Issue 30) pp:8870-8873
Publication Date(Web):2017/07/17
DOI:10.1002/anie.201703812
AbstractWithin a total residence time of 9 min, the sodium salt of ciprofloxacin was prepared from simple building blocks via a linear sequence of six chemical reactions in five flow reactors. Sequential offline acidifications and filtrations afforded ciprofloxacin and ciprofloxacin hydrochloride. The overall yield of the eight-step sequence was 60 %. No separation of intermediates was required throughout the synthesis when a single acylation reaction was applied to remove the main byproduct, dimethylamine.
Co-reporter:Dr. Yi Shen; Dr. Milad Abolhasani;Yue Chen;Dr. Lisi Xie;Dr. Lu Yang;Connor W. Coley; Dr. Moungi G. Bawendi; Dr. Klavs F. Jensen
Angewandte Chemie International Edition 2017 Volume 56(Issue 51) pp:16333-16337
Publication Date(Web):2017/12/18
DOI:10.1002/anie.201710899
AbstractOscillatory flow reactors provide a surface energy-driven approach for automatically screening reaction conditions and studying reaction mechanisms of biphasic nanocrystal ligand-exchange reactions. Sulfide and cysteine ligand-exchange reactions with as-synthesized CdSe quantum dots (QDs) are chosen as two model reactions. Different reaction variables including the new-ligand-to-QD ratio, the size of the particles, and the original ligand type are examined systematically. Based on the in situ-obtained UV/Vis absorption spectra during the reaction, we propose two different exchange pathways for the sulfide exchange reaction.
Co-reporter:Connor W. Coley;Dr. Milad Abolhasani;Dr. Hongkun Lin; Klavs F. Jensen
Angewandte Chemie 2017 Volume 129(Issue 33) pp:9979-9982
Publication Date(Web):2017/08/07
DOI:10.1002/ange.201705148
AbstractWe present an automated microfluidic platform for in-flow studies of visible-light photoredox catalysis in liquid or gas–liquid reactions at the 15 μL scale. An oscillatory flow strategy enables a flexible residence time while preserving the mixing and heat transfer advantages of flow systems. The adjustable photon flux made possible with the platform is characterized using actinometry. Case studies of oxidative hydroxylation of phenylboronic acids and dimerization of thiophenol demonstrate the capabilities and advantages of the system. Reaction conditions identified through droplet screening translate directly to continuous synthesis with minor platform modifications.
Co-reporter:Dr. Yi Shen; Dr. Milad Abolhasani;Yue Chen;Dr. Lisi Xie;Dr. Lu Yang;Connor W. Coley; Dr. Moungi G. Bawendi; Dr. Klavs F. Jensen
Angewandte Chemie 2017 Volume 129(Issue 51) pp:16551-16555
Publication Date(Web):2017/12/18
DOI:10.1002/ange.201710899
AbstractOscillatory flow reactors provide a surface energy-driven approach for automatically screening reaction conditions and studying reaction mechanisms of biphasic nanocrystal ligand-exchange reactions. Sulfide and cysteine ligand-exchange reactions with as-synthesized CdSe quantum dots (QDs) are chosen as two model reactions. Different reaction variables including the new-ligand-to-QD ratio, the size of the particles, and the original ligand type are examined systematically. Based on the in situ-obtained UV/Vis absorption spectra during the reaction, we propose two different exchange pathways for the sulfide exchange reaction.
Co-reporter:Connor W. Coley;Dr. Milad Abolhasani;Dr. Hongkun Lin; Klavs F. Jensen
Angewandte Chemie International Edition 2017 Volume 56(Issue 33) pp:9847-9850
Publication Date(Web):2017/08/07
DOI:10.1002/anie.201705148
AbstractWe present an automated microfluidic platform for in-flow studies of visible-light photoredox catalysis in liquid or gas–liquid reactions at the 15 μL scale. An oscillatory flow strategy enables a flexible residence time while preserving the mixing and heat transfer advantages of flow systems. The adjustable photon flux made possible with the platform is characterized using actinometry. Case studies of oxidative hydroxylation of phenylboronic acids and dimerization of thiophenol demonstrate the capabilities and advantages of the system. Reaction conditions identified through droplet screening translate directly to continuous synthesis with minor platform modifications.
Co-reporter:Maryam Peer, Marcella Lusardi, and Klavs F. Jensen
Chemistry of Materials 2017 Volume 29(Issue 4) pp:
Publication Date(Web):January 26, 2017
DOI:10.1021/acs.chemmater.6b03570
Mesoporous carbon nitride is synthesized in a one-pot approach using different nonionic surfactants (Pluronic F-127, Pluronic P-123, and Triton X-100) and a melamine cyanurate hydrogen-bonded complex using just water as the solvent. We obtain three-dimensional assembled nanostructures from low-dimensional carbon nitride sheets by taking advantage of supramolecular assembly of melamine and cyanuric acid, moderate interactions between the surfactant and precursors, structure directing effects of the surfactants, and the good thermal stability of the melamine cyanurate sheets formed around the micelles. Different morphologies, including sheetlike, hollow spherical, and tubular or highly porous networks, result depending upon the synthesis approach and the surfactant/precursor ratio. Pseudoternary phase diagrams map the composition of the starting solution to the resultant carbon nitride morphology. Increasing the amount of surfactant leads to a higher carbon residue (C/N ∼ 1) and large BET surface areas (≤300 m2/g). Further tuning of the synthesis parameters as well as addition of HCl produces uniformly porous nanostructures with a high porosity (up to 0.8 cm3/g), a high surface area (>200 m2/g), and yet a stoichiometric C/N ratio (∼0.75). The synthesized high-surface area carbon nitrides show improved light absorption and enhanced photocatalytic activity in a rhodamine B dye degradation reaction under visible light irradiation compared to those of bulk melamine-derived carbon nitride.
Co-reporter:Brandon J. Reizman and Klavs F. Jensen
Accounts of Chemical Research 2016 Volume 49(Issue 9) pp:1786
Publication Date(Web):August 15, 2016
DOI:10.1021/acs.accounts.6b00261
The pharmaceutical industry is investing in continuous flow and high-throughput experimentation as tools for rapid process development accelerated scale-up. Coupled with automation, these technologies offer the potential for comprehensive reaction characterization and optimization, but with the cost of conducting exhaustive multifactor screens. Automated feedback in flow offers researchers an alternative strategy for efficient characterization of reactions based on the use of continuous technology to control chemical reaction conditions and optimize in lieu of screening. Optimization with feedback allows experiments to be conducted where the most information can be gained from the chemistry, enabling product yields to be maximized and kinetic models to be generated while the total number of experiments is minimized.This Account opens by reviewing select examples of feedback optimization in flow and applications to chemical research. Systems in the literature are classified into (i) deterministic “black box” optimization systems that do not model the reaction system and are therefore limited in the utility of results for scale-up, (ii) deterministic model-based optimization systems from which reaction kinetics and/or mechanisms can be automatically evaluated, and (iii) stochastic systems. Though diverse in application, flow feedback systems have predominantly focused upon the optimization of continuous variables, i.e., variables such as time, temperature, and concentration that can be ramped from one experiment to the next. Unfortunately, this implies that the screening of discrete variables such as catalyst, ligand, or solvent generally does not factor into automated flow optimization, resulting in incomplete process knowledge.Herein, we present a system and strategy developed for optimizing discrete and continuous variables of a chemical reaction simultaneously. The approach couples automated feedback with high-throughput reaction screening in droplet flow microfluidics. This Account details the system configuration for on-demand creation of sub-20 μL droplets with interchangeable reagents and catalysts. These droplets are reacted in a fully automated microfluidic system and analyzed online by LC/MS. Feeding back from the online analytical results, a design of experiments (DoE)-based adaptive response surface algorithm is employed that deductively removes candidate reagents from the optimization as optimal reaction conditions are refined, leading to rapid convergence.Using the automated optimization platform, case studies are presented for solvent selection in a competitive alkylation chemistry and for catalyst-ligand selection in heteroaromatic Suzuki–Miyaura cross-coupling chemistries. For the monoalkylation of trans-1,2-diaminocyclohexane, polar aprotic solvents at moderate temperatures are shown to be favorable, with optimality accurately identified with dimethyl sulfoxide as the solvent in 67 experiments. For Suzuki–Miyaura cross-couplings, the optimality of precatalysts and continuous variable conditions are observed to change in accordance with the coupling reagents, providing insights into catalyst behavior in the context of the reaction mechanism.Future opportunities in automated reaction development include the incorporation of chemoinformatics for faster analysis and machine-learning algorithms to guide and optimize the synthesis. Adoption of this technology stands to reduce graduate student and postdoc time on routine tasks in the laboratory, while feeding back knowledge used to guide new research directions. Moreover, the application of this technology in industry promises to lessen the cost and time associated with advancing pharmaceutical molecules through development and scale-up.
Co-reporter:Lisi Xie, Yi Shen, Daniel Franke, Víctor Sebastián, Moungi G. Bawendi, and Klavs F. Jensen
Journal of the American Chemical Society 2016 Volume 138(Issue 41) pp:13469-13472
Publication Date(Web):October 3, 2016
DOI:10.1021/jacs.6b06468
Clusters have been identified as important growth intermediates during group III–V quantum dot (QD) formation. Here we report a one-solvent protocol that integrates synthesis, purification, and mass characterization of indium phosphide (InP) QD growth mixtures. The use of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) successfully tracks the evolution of clusters and the formation of QDs throughout the synthesis. Similar clusters are observed during the formation of large particles, suggesting that these clusters serve as a reservoir for QD formation. Combining MALDI and NMR techniques further enables us to extract extinction coefficients and construct sizing curves for cluster-free InP QDs. The use of MALDI MS opens new opportunities for characterization and mechanistic studies of small-sized air-sensitive clusters or QDs.
Co-reporter:Víctor Sebastián and Klavs F. Jensen
Nanoscale 2016 vol. 8(Issue 33) pp:15288-15295
Publication Date(Web):08 Aug 2016
DOI:10.1039/C6NR04104C
Microfluidic synthesis in a microfabricated reactor enables fast and facile synthesis of a wide library of metallic nanostructures: monometallic, bimetallic, anisotropic growth and heterostructures. Specific nanostructures are realized by selection of flow pattern and synthesis parameters. The technique is shown to have advantages over conventional batch technologies. Not only does it allow faster scalable synthesis, but also realization of nanostructures hitherto not reported such as Pt–Ru, Pt–Ni and Pt–Co nanodendrites, Pt–Pd heterostructures, Ag–Pd core–shell NPs, Au–Pd nanodumbbells and Au–Pd nanosheets.
Co-reporter:Victor Sebastian, Christopher D. Smith and Klavs F. Jensen
Nanoscale 2016 vol. 8(Issue 14) pp:7534-7543
Publication Date(Web):01 Mar 2016
DOI:10.1039/C5NR08531D
A segmented flow-based microreactor is used for the continuous production of faceted nanocrystals. Flow segmentation is proposed as a versatile tool to manipulate the reduction kinetics and control the growth of faceted nanostructures; tuning the size and shape. Switching the gas from oxygen to carbon monoxide permits the adjustment in nanostructure growth from 1D (nanorods) to 2D (nanosheets). CO is a key factor in the formation of Pd nanosheets and Pt nanocubes; operating as a second phase, a reductant, and a capping agent. This combination confines the growth to specific structures. In addition, the segmented flow microfluidic reactor inherently has the ability to operate in a reproducible manner at elevated temperatures and pressures whilst confining potentially toxic reactants, such as CO, in nanoliter slugs. This continuous system successfully synthesised Pd nanorods with an aspect ratio of 6; thin palladium nanosheets with a thickness of 1.5 nm; and Pt nanocubes with a 5.6 nm edge length, all in a synthesis time as low as 150 s.
Co-reporter:Milad Abolhasani and Klavs F. Jensen
Lab on a Chip 2016 vol. 16(Issue 15) pp:2775-2784
Publication Date(Web):11 Jul 2016
DOI:10.1039/C6LC00728G
Continuous multiphase flow strategies are commonly employed for high-throughput parameter screening of physical, chemical, and biological processes as well as continuous preparation of a wide range of fine chemicals and micro/nano particles with processing times up to 10 min. The inter-dependency of mixing and residence times, and their direct correlation with reactor length have limited the adaptation of multiphase flow strategies for studies of processes with relatively long processing times (0.5–24 h). In this frontier article, we describe an oscillatory multiphase flow strategy to decouple mixing and residence times and enable investigation of longer timescale experiments than typically feasible with conventional continuous multiphase flow approaches. We review current oscillatory multiphase flow technologies, provide an overview of the advancements of this relatively new strategy in chemistry and biology, and close with a perspective on future opportunities.
Co-reporter:Tatyana A. Shatova, Shefali Lathwal, Marissa R. Engle, Hadley D. Sikes, and Klavs F. Jensen
Analytical Chemistry 2016 Volume 88(Issue 15) pp:7627
Publication Date(Web):July 1, 2016
DOI:10.1021/acs.analchem.6b01355
A portable, microfluidic blood plasma separation device is presented featuring a constriction–expansion design, which produces 100.0% purity for undiluted blood at 9% yield. This level of purity represents an improvement of at least 1 order of magnitude with increased yield compared to that achieved previously using passive separation. The system features high flow rates, 5–30 μL/min plasma collection, with minimal clogging and biofouling. The simple, portable blood plasma separation design is hand-driven and can easily be incorporated with microfluidic or laboratory scale diagnostic assays. The separation system was applied to a paper-based diagnostic test for malaria that produced an amplified color change in the presence of Plasmodium falciparum histidine-rich protein 2 at a concentration well below clinical relevancy for undiluted whole blood.
Co-reporter:Maryam Peer, Nopphon Weeranoppanant, Andrea Adamo, Yanjie Zhang, and Klavs F. Jensen
Organic Process Research & Development 2016 Volume 20(Issue 9) pp:1677-1685
Publication Date(Web):August 9, 2016
DOI:10.1021/acs.oprd.6b00234
We report continuous solvent-free biphasic alcohol oxidation with hydrogen peroxide and in-line separation of the tungsten polyoxometalate catalyst and phase transfer catalyst from the product. Zinc-substituted polyoxotungstate in combination with the selected phase transfer catalyst drives the oxidation reaction to completion within a short residence time (5–10 min) in a silicon Pyrex microreactor. This continuous and small-scale reactor allows for fast optimization of reaction conditions for each substrate and selection of the phase transfer catalyst. Scaling of the production rate (up to 650 times) is achieved with a Corning low flow reactor (LFR) and an advanced flow reactor (AFR). New scaled-up, in-line membrane-based liquid–liquid extraction units at the reactor outlet first separate the tungsten polyoxometalate catalyst with the aqueous waste stream from the organic product stream. A three-stage countercurrent liquid–liquid extraction then removes more than 90% of the phase transfer catalyst from the desired organic effluent stream while reducing the amount of extraction solvent required.
Co-reporter:Antony E. Fernandes, Olivier Riant, Alain M. Jonas and Klavs F. Jensen
RSC Advances 2016 vol. 6(Issue 43) pp:36602-36605
Publication Date(Web):07 Apr 2016
DOI:10.1039/C6RA05026C
A simple and reliable methodology is described for the preparation of heterogeneous bifunctional catalysts with a high control over surface composition. The strategy relies on the grafting of a mix of catalytic components from an azide-functionalized silica platform using the CuAAC reaction. The resulting finely engineered supported catalysts are employed in the model Cu/TEMPO-catalyzed aerobic oxidation of benzylic alcohol.
Co-reporter:Jean-Christophe M. Monbaliu, Torsten Stelzer, Eve Revalor, Nopphon Weeranoppanant, Klavs F. Jensen, and Allan S. Myerson
Organic Process Research & Development 2016 Volume 20(Issue 7) pp:1347-1353
Publication Date(Web):June 21, 2016
DOI:10.1021/acs.oprd.6b00165
A compact, fully integrated, and automated system is developed for end-to-end production, purification, and formulation of the active pharmaceutical ingredient (API) lidocaine hydrochloride, a widely used local anesthetic. The purification strategy includes appropriate combination of extraction, reactive crystallization, and antisolvent cooling crystallization that enables the production of lidocaine hydrochloride formulated solution, for topical application meeting US Pharmacopeia (USP) standards. On the basis of the optimal yield observed in each step, the system sustains a daily production of 810 doses (dosage strength = 20 mg mL–1, i.e., 2% formulation in commercial denomination).
Co-reporter:Jason S. Moore, Christopher D. Smith and Klavs F. Jensen
Reaction Chemistry & Engineering 2016 vol. 1(Issue 3) pp:272-279
Publication Date(Web):22 Feb 2016
DOI:10.1039/C6RE00007J
Temperature, pressure, gas stoichiometry, and residence time were varied to control the yield and product distribution of the palladium-catalyzed aminocarbonylation of aromatic bromides in both a silicon microreactor and a packed-bed tubular reactor. Automation of the system set points and product sampling enabled facile and repeatable reaction analysis with minimal operator supervision. It was observed that the reaction was divided into two temperature regimes. An automated system was used to screen steady-state conditions for offline analysis by gas chromatography to fit a reaction rate model. Additionally, a transient temperature ramp method utilizing online infrared analysis was used, leading to more rapid determination of the reaction activation energy of the lower temperature regimes. The entire reaction spanning both regimes was modeled in good agreement with the experimental data.
Co-reporter:Andrea Adamo;Rachel L. Beingessner;Eve M. Revalor;Torsten Stelzer;Jie Chen;Allan S. Myerson;Mohsen Behnam;Nopphon Weeranoppanant;Jean-Christophe M. Monbaliu;Timothy F. Jamison;David R. Snead;Shin Yee Wong;Ping Zhang
Science 2016 Volume 352(Issue 6281) pp:61-67
Publication Date(Web):01 Apr 2016
DOI:10.1126/science.aaf1337
Drug manufacturing in a fridge-sized box
Commodity chemicals tend to be manufactured in a continuous fashion. However, the preparation of pharmaceuticals still proceeds batch by batch, partly on account of the complexity of their molecular structures. Adamo et al. now present an apparatus roughly the size of a household refrigerator that can synthesize and purify pharmaceuticals under continuous-flow conditions (see the Perspective by Martin). The integrated set of modules can produce hundreds to thousands of accumulated doses in a day, delivered in aqueous solution.
Science, this issue p. 61; see also p. 44
Co-reporter:Lisi Xie, Daniel K. Harris, Moungi G. Bawendi, and Klavs F. Jensen
Chemistry of Materials 2015 Volume 27(Issue 14) pp:5058
Publication Date(Web):July 7, 2015
DOI:10.1021/acs.chemmater.5b01626
We report that trace amounts of water impurities in indium myristate precursors can negatively impact indium phosphide nanoparticle growth by limiting its size tunability. Without water, the growth can be effectively tuned by growth temperature and time with the first absorption peak reaching 620 nm; with water, the growth presents a “focused” behavior with the first absorption peak remaining around 550 nm. The results imply that water impurities, either from indium acetate derived indium precursors or generated in situ during nanoparticle growth, may be the cause of the currently observed inhibited growth behavior of indium phosphide quantum dots. We use multistage microfluidic reactors to show that this inhibiting effect occurs at the late stage of particle growth, following precursor depletion. We extend our study by showing that trace amounts of free hydroxide can also inhibit nanoparticle growth. We attribute the inhibited growth behavior to the hydroxylation effect of water or free hydroxide.
Co-reporter:Milad Abolhasani, Connor W. Coley, Lisi Xie, Ou Chen, Moungi G. Bawendi, and Klavs F. Jensen
Chemistry of Materials 2015 Volume 27(Issue 17) pp:6131
Publication Date(Web):August 13, 2015
DOI:10.1021/acs.chemmater.5b02821
An automated two-phase small scale platform based on controlled oscillatory motion of a droplet within a 12 cm long tubular Teflon reactor is designed and developed for high-throughput in situ studies of a solution-phase preparation of semiconductor nanocrystals. The unique oscillatory motion of the droplet within the heated region of the reactor enables temporal single-point spectral characterization of the same nanocrystals with a time resolution of 3 s over the course of the synthesis time without sampling while removing the residence time limitation associated with continuous flow-based strategies. The developed oscillatory microprocessor allows for direct comparison of the high temperature and room temperature spectral characteristics of nanocrystals. Utilizing this automated experimental strategy, we study the effect of temperature on the nucleation and growth of II–VI and III–V semiconductor nanocrystals. The automated droplet preparation and injection of the precursors combined with the oscillatory flow technique allows 7500 spectral data within a parameter space of 10 min reaction time at ten different temperatures and five different precursor ratios to be obtained automatically using only 250 μL of each precursor solution. The oscillatory microprocessor platform provides real-time in situ spectral information at the synthesis temperature, vital for fundamental studies of different mechanisms involved during the nucleation and growth stages of different types of nanomaterials.
Co-reporter:Everett J. O’Neal, Chang Ho Lee, Julian Brathwaite, and Klavs F. Jensen
ACS Catalysis 2015 Volume 5(Issue 4) pp:2615
Publication Date(Web):March 24, 2015
DOI:10.1021/acscatal.5b00149
The continuous nanofiltration and recycle of a ruthenium diphosphine/diamine catalyst for the asymmetric hydrogenation of α-tetralone is demonstrated in a small scale flow system. Batch experiments show that the catalyst can be recycled under hydrogen pressure. Subsequent transient packed bed experiments serve to characterize the reaction and inform the design of the recycle experiments. The total internal volume of the resulting system is ∼50 mL, making this pilot useful for testing catalyst recyclability via nanofiltration during the early stages of process development. The high-pressure catalyst recycle system is run with an automatic control system to respond to membrane flux decline during the course of operation and enable long duration runs. In 24 h, we achieved a turnover number approaching 5000 for ruthenium diphosphine/diamine catalyst used in the asymmetric hydrogenation of α-tetralone, demonstrating significant reuse of the catalyst since the substrate-to-catalyst ratio in the reactor approaches 250. During the 24 h period, the equivalent of 60 batch separation/recycle experiments is automatically performed. Ruthenium concentration in the product stream remains below 200 ppb. A slow decline in enantiomeric selectivity from 96% to 93% is observed during the run.Keywords: asymmetric hydrogenation; continuous flow; homogeneous catalyst; nanofiltration; recycle
Co-reporter:Brandon J. Reizman and Klavs F. Jensen
Chemical Communications 2015 vol. 51(Issue 68) pp:13290-13293
Publication Date(Web):22 Jul 2015
DOI:10.1039/C5CC03651H
An automated, continuous flow droplet screening system is presented, enabling real-time simultaneous solvent and continuous variable optimization. An optimal design of experiments strategy is applied to the alkylation of 1,2-diaminocyclohexane in 16 μL droplets, with scale-up demonstrated. Analysis of segmented flow results suggests correlation of yield with solvent hydrogen bond basicity.
Co-reporter:Milad Abolhasani, Nicholas C. Bruno and Klavs F. Jensen
Chemical Communications 2015 vol. 51(Issue 43) pp:8916-8919
Publication Date(Web):16 Apr 2015
DOI:10.1039/C5CC02051D
A multi-phase flow strategy, based on oscillatory motion of a bi-phasic slug within a fluorinated ethylene propylene (FEP) tubular reactor, under inert atmosphere, is designed and developed to address mixing and mass transfer limitations associated with continuous slug flow chemistry platforms for studies of bi-phasic catalytic reactions. The technique is exemplified with C–C and C–N Pd catalyzed coupling reactions.
Co-reporter:Milad Abolhasani, Connor W. Coley, and Klavs F. Jensen
Analytical Chemistry 2015 Volume 87(Issue 21) pp:11130
Publication Date(Web):October 5, 2015
DOI:10.1021/acs.analchem.5b03311
Taking advantage of the difference between the surface energies of aqueous and organic solvents on a Teflon substrate, a fully automated small-scale strategy is developed on the basis of gas-driven oscillatory motion of a biphasic slug for high-throughput in situ measurement and screening of partition coefficients of organic substances between aqueous and organic phases. The developed oscillatory flow strategy enables single partition coefficient data point measurement within 8 min (including the sample preparation time) which is 360 times faster than the conventional “shake-flask” method, while using less than a 30 μL volume of the two phases and 9 nmol of the target organic substance. The developed multiphase strategy is validated using a conventional shake-flask technique. Finally, the developed strategy is extended to include automated screening of partition coefficients at physiological temperature.
Co-reporter:Lu Yang, Yanxiang Shi, Milad Abolhasani and Klavs F. Jensen
Lab on a Chip 2015 vol. 15(Issue 15) pp:3232-3241
Publication Date(Web):01 Jul 2015
DOI:10.1039/C5LC00431D
We study microreactors with internal fields of posts as typical examples of structured microreactors to elucidate flow fields and their implications for mass transfer. Laser-induced fluorescence (LIF) visualization combined with image analysis is used to systematically quantify key features such as interfacial area, phase holdup and the characteristics of the post-wetting layer. The subsequent mass transport analysis yields insight into how the posts contribute to the overall enhanced mass transfer performance compared to open channels, and provides predictions of mass transfer performance under varying operating conditions. Computational fluid dynamic (CFD) simulations of multiphase flow using the volume-of-fluid (VOF) method are in good agreement with experimentally observed multiphase flows.
Co-reporter:Stephen G. Newman, Kyoungmi Lee, Jianghuai Cai, Lu Yang, William H. Green, and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2015 Volume 54(Issue 16) pp:4166-4173
Publication Date(Web):December 31, 2014
DOI:10.1021/ie504129e
The reaction of nitrous oxide with internal olefins is investigated in a flow reactor. When using a mixture of dodecene isomers, ketones are formed as the primary product with conversions up to 77% and yields up to 45%. The multiphase system is studied experimentally and computationally to gain understanding of the residence time distribution and phase composition. Significant volatility of the dodecenes and solubility of the nitrous oxide result in a system where reaction occurs in both the vapor and liquid at elevated temperatures. The rate constant for oxidation with nitrous oxide is determined by considering both phases and the material transfer between them using 16 different physical parameters through nonlinear optimization. The determined rate constant is in good agreement with parameters estimated by quantum chemistry calculations.
Co-reporter:María José Nieves-Remacha, Amol A. Kulkarni, and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2015 Volume 54(Issue 30) pp:7543-7553
Publication Date(Web):July 27, 2015
DOI:10.1021/acs.iecr.5b00232
Computational fluid dynamic (CFD) simulations are carried out for single-phase flow in an advanced-flow reactor (AFR) using the open source software OpenFOAM. Excellent agreement of simulations with experimental pressure drop and residence time distribution (RTD) is obtained. Streamlines, stagnant zones, velocity profiles, and pressure fields are obtained at different flow rates ranging from 5 to 100 mL/min. A change in the flow behavior with the presence of recirculation zones is observed with a 40 mL/min flow rate. The extent of the recirculation zones increases with increasing flow rate from 40 to 60 mL/min and is limited further by the presence of a second cylindrical post inside the heart cell, remaining almost constant in the flow rate range of 60–100 mL/min. The RTD is also determined for all flow rates, and a comparison between different reactor designs (two-post, single-post, and low-flow-reactor-like single-post) is presented. The AFR shows a plug-flow behavior with a small degree of dispersion, which broadens the RTD. Symmetric RTD curves are obtained for the single-post designs, whereas the Gen 1 AFR design experiences asymmetry in the RTD at flow rates in the range between 20 and 60 mL/min.
Co-reporter:María José Nieves-Remacha, Lu Yang, and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2015 Volume 54(Issue 26) pp:6649-6659
Publication Date(Web):June 23, 2015
DOI:10.1021/acs.iecr.5b00480
Advanced-flow reactor (AFR) technology is an alternative to scale-up continuous flow chemistries from micro to milli scales, while retaining mass and heat transfer performance. Here we conduct two-phase computational fluid dynamic (CFD) simulations using the open source software OpenFOAM in order to predict hydrodynamic parameters in the AFR for different operating conditions. After modification and validation of the interFoam solver based on the volume-of-fluid method to account for mass transfer across immiscible interfaces, it is applied to the AFR to predict specific interfacial areas (a) and individual mass transfer coefficients (kL) to yield overall mass transfer coefficients (kLa). The results are in good agreement with semiempirical values and the surface renewal theory of Danckwerts, except at the largest flow rates for which numerical coalescence is observed. A study of the influence of fluid properties yields the following conclusions. The contact angle is the variable that affects the flow patterns the most (and more specifically, the interfacial area); varying the contact angle can change the flow regime from bubbly to stratified flow. Decreasing surface tension decreases droplet size, but in order to achieve large specific interfacial areas and have a positive impact on the mass transfer process, a larger dispersed phase flow rate with increased holdup is also required. Viscosity of the continuous phase does not have a significant effect on mass transfer. The effect of reactor design was also seen to not be significant for the AFR designs and flow rates tested, with overall mass transfer coefficients varying within 17%.
Co-reporter:Stephen G. Newman, Lei Gu, Christoph Lesniak, Georg Victor, Frank Meschke, Lahbib Abahmane and Klavs F. Jensen
Green Chemistry 2014 vol. 16(Issue 1) pp:176-180
Publication Date(Web):12 Nov 2013
DOI:10.1039/C3GC41942H
Wolff–Kishner reductions are performed in a novel silicon carbide microreactor. Greatly reduced reaction times and safer operation are achieved, giving high yields without requiring a large excess of hydrazine. The corrosion resistance of silicon carbide avoids the problematic reactor compatibility issues that arise when Wolff–Kishner reductions are done in glass or stainless steel reactors. With only nitrogen gas and water as by-products, this opens the possibility of performing selective, large scale ketone reductions without the generation of hazardous waste streams.
Co-reporter:Klavs F. Jensen, Brandon J. Reizman and Stephen G. Newman
Lab on a Chip 2014 vol. 14(Issue 17) pp:3206-3212
Publication Date(Web):28 May 2014
DOI:10.1039/C4LC00330F
Chemical synthesis in microsystems has evolved from simple proof-of-principle examples to become a general technique in academia and industry. Numerous such “flow chemistry” applications are now found in pharmaceutical and fine chemical synthesis. Much of the development has been based on systems employing macroscopic flow components and tubes, rather than the integrated chip technology envisioned by the lab-on-a-chip community. We review the major developments in systems for flow chemistry and discuss limitations underlying the development of chip-scale integrated systems.
Co-reporter:Armon Sharei, Roberta Poceviciute, Emily L. Jackson, Nahyun Cho, Shirley Mao, George C. Hartoularos, Derek Y. Jang, Siddharth Jhunjhunwala, Alexandra Eyerman, Taylor Schoettle, Robert Langer and Klavs F. Jensen
Integrative Biology 2014 vol. 6(Issue 4) pp:470-475
Publication Date(Web):27 Jan 2014
DOI:10.1039/C3IB40215K
Intracellular delivery of materials is a challenge in research and therapeutic applications. Physical methods of plasma membrane disruption have recently emerged as an approach to facilitate the delivery of a variety of macromolecules to a range of cell types. We use the microfluidic CellSqueeze delivery platform to examine the kinetics of plasma membrane recovery after disruption and its dependence on the calcium content of the surrounding buffer (recovery time ∼5 min without calcium vs. ∼30 s with calcium). Moreover, we illustrate that manipulation of the membrane repair kinetics can yield up to 5× improvement in delivery efficiency without significantly impacting cell viability. Membrane repair characteristics initially observed in HeLa cells are shown to translate to primary naïve murine T cells. Subsequent manipulation of membrane repair kinetics also enables the delivery of larger materials, such as antibodies, to these difficult to manipulate cells. This work provides insight into the membrane repair process in response to mechanical delivery and could potentially enable the development of improved delivery methods.
Co-reporter:Norbert Heublein, Jason S. Moore, Christopher D. Smith and Klavs F. Jensen
RSC Advances 2014 vol. 4(Issue 109) pp:63627-63631
Publication Date(Web):27 Nov 2014
DOI:10.1039/C4RA13626H
Petasis and Ugi reactions are used successively without intermediate purification, effectively accomplishing a six-component reaction. The examined reactions are transferred from traditional batch reactors to an automated continuous flow microreactor setup, where optimization and kinetic analyses are performed, proposed mechanisms evaluated, and rate-limiting steps determined.
Co-reporter:Patrick L. Heider, Stephen C. Born, Soubir Basak, Brahim Benyahia, Richard Lakerveld, Haitao Zhang, Rachael Hogan, Louis Buchbinder, Aaron Wolfe, Salvatore Mascia, James M. B. Evans, Timothy F. Jamison, and Klavs F. Jensen
Organic Process Research & Development 2014 Volume 18(Issue 3) pp:402-409
Publication Date(Web):February 6, 2014
DOI:10.1021/op400294z
The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets. The entire process was run on several occasions, with the data presented herein corresponding to a 240 h run at a nominal throughput of 41 g h–1 of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temperature, achieving high yields (90%) and avoiding solid handling and a long residence time (due to higher concentrations compared to dilute conditions when run at lower temperatures in a solvent). The resulting stream was worked-up inline using liquid–liquid extraction with membrane-based separators that were scaled-up from microfluidic designs. The second reaction involved a Boc deprotection, using aqueous HCl that was rapidly quenched with aqueous NaOH using an inline pH measurement to control NaOH addition. The reaction maintained high yields (90–95%) under closed-loop control despite process disturbances.
Co-reporter:Yanjie Zhang, Stephen C. Born, and Klavs F. Jensen
Organic Process Research & Development 2014 Volume 18(Issue 11) pp:1476-1481
Publication Date(Web):September 30, 2014
DOI:10.1021/op500158h
The use of bleach to oxidize alcohols with the aid of a phase-transfer catalyst (PTC) offers several benefits over traditional oxidants: low material cost, mild reaction conditions, and no metallic waste. Mass transport limitations often dictate overall reaction rates of such PTC reactions, and continuous-flow reactors with superior mass and heat transport performance are consequently used to enhance their rates. Three PTC hypochlorite oxidation reactions are chosen to illustrate scaling of PTC reactions from microfluidic to mesoscale systems [Corning Low Flow Reactor (LFR) and Advanced Flow Reactor (AFR)]. The successful scaling from microliters per hour in microreactors to intermediate milliliters per minute without sacrificing mass transport performance leads to significant increases in production rate and constitutes an efficient flow reactor scaling approach. The production rate increases up to 700 times in the scaling process from a spiral microreactor to the LFR and then to the AFR.
Co-reporter:Spencer D. Schaber, Stephen C. Born, Klavs F. Jensen, and Paul I. Barton
Organic Process Research & Development 2014 Volume 18(Issue 11) pp:1461-1467
Publication Date(Web):September 8, 2014
DOI:10.1021/op500179r
Time-varying, or dynamic, experiments can produce richer data sets than sequences of steady-state experiments using less material and time. A case study demonstrating this concept for microreactor experiments is presented. Beginning with five kinetic model candidates for the reaction of phenylisocyanate with t-butanol, an initial dynamic experiment showed that two of the five models gave a similar quality of fit to the experimental data, whereas the remaining three gave significantly poorer fits. Next an optimal experiment was designed to discriminate between the remaining two models. This drove the two models to differ significantly in quality, leaving a single model and a set of kinetic parameter values that adequately described the data. This method can be applied to future kinetic studies to reduce material use and experimental time while validating a dynamic model of the physics and chemical kinetics.
Co-reporter:Ulrich Neuenschwander and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2014 Volume 53(Issue 2) pp:601-608
Publication Date(Web):January 2, 2014
DOI:10.1021/ie402736j
Handling hazardous multiphase reactions in flow brings not only safety advantages but also significantly improved performance, due to better mass transfer characteristics. In this paper, we present a continuous microreactor setup, capable of performing olefin autoxidations with O2, under solvent-free and catalyst-free conditions. Owing to the transparent reactor design, consumption of O2 can be visually followed and exhaustion of the gas bubbles marks a clear end point along the channel length coordinate. Tracking the position of this end point enables measuring effective rate constants. The developed system was calibrated using the well-studied β-pinene substrate, and was subsequently applied to the synthetically interesting transformation of (+)-valencene to (+)-nootkatone. For the latter, a space-time yield was obtained that is at least 3 orders of magnitude larger than that realized with established biotechnology approaches.
Co-reporter:Jason S. Moore; Klavs F. Jensen
Angewandte Chemie 2014 Volume 126( Issue 2) pp:480-483
Publication Date(Web):
DOI:10.1002/ange.201306468
Abstract
Currently, kinetic data is either collected under steady-state conditions in flow or by generating time-series data in batch. Batch experiments are generally considered to be more suitable for the generation of kinetic data because of the ability to collect data from many time points in a single experiment. Now, a method that rapidly generates time-series reaction data from flow reactors by continuously manipulating the flow rate and reaction temperature has been developed. This approach makes use of inline IR analysis and an automated microreactor system, which allowed for rapid and tight control of the operating conditions. The conversion/residence time profiles at several temperatures were used to fit parameters to a kinetic model. This method requires significantly less time and a smaller amount of starting material compared to one-at-a-time flow experiments, and thus allows for the rapid generation of kinetic data.
Co-reporter:Everett J. O'Neal ; Klavs F. Jensen
ChemCatChem 2014 Volume 6( Issue 10) pp:3004-3011
Publication Date(Web):
DOI:10.1002/cctc.201402368
Abstract
Continuous-flow nanofiltration and recycle of a metathesis catalyst is demonstrated in a small-scale continuous-flow system using less than 2 mg of catalyst in 50 h of operation. This length of time corresponds to an average of approximately 70 recycle experiments, where catalyst is partially removed and replaced during each cycle. The small-scale (2.9 mL total system volume) continuous-flow catalyst recycle system includes the first fully functional microfluidic organic solvent nanofiltration module using polyimide membranes, a stirred holding tank (<1 mL volume) with a liquid-level control system to respond to membrane-flux decline, a membrane reactor using Teflon AF for permeation of the ethylene byproduct, and automated sampling. A turnover number of 935 is obtained for the Hoveyda–Grubbs catalyst. Ruthenium contamination in the product remains less than 1 ppm throughout each experimental run.
Co-reporter:Jason S. Moore; Klavs F. Jensen
Angewandte Chemie International Edition 2014 Volume 53( Issue 2) pp:470-473
Publication Date(Web):
DOI:10.1002/anie.201306468
Abstract
Currently, kinetic data is either collected under steady-state conditions in flow or by generating time-series data in batch. Batch experiments are generally considered to be more suitable for the generation of kinetic data because of the ability to collect data from many time points in a single experiment. Now, a method that rapidly generates time-series reaction data from flow reactors by continuously manipulating the flow rate and reaction temperature has been developed. This approach makes use of inline IR analysis and an automated microreactor system, which allowed for rapid and tight control of the operating conditions. The conversion/residence time profiles at several temperatures were used to fit parameters to a kinetic model. This method requires significantly less time and a smaller amount of starting material compared to one-at-a-time flow experiments, and thus allows for the rapid generation of kinetic data.
Co-reporter:Seung-Kon Lee, Jinyoung Baek, and Klavs F. Jensen
Langmuir 2014 Volume 30(Issue 8) pp:2216-2222
Publication Date(Web):2017-2-22
DOI:10.1021/la4041198
Uniform polymer microbeads with highly loaded quantum dots (QDs) are produced using high-throughput coherent jet breakup of a biocompatible poly(ethylene glycol) diacrylate (PEGDA) prepolymer resin, followed by in-line photopolymerization. A spiraling and gradually widening channel enables maximum absorption of radiated UV light for the in-line photopolymerization without coalescence and clogging issues. Although the dripping mode in general provides superior uniformity to the jet mode, our nozzle design with tapered geometry brings controlled jet breakup leading to 3% of uniform particle size distribution, comparable to dripping-mode performance. We achieve a maximum production rate of 2.32 kHz, 38 times faster than the dripping mode, at a same polymer flow rate. In addition, the jet-mode scheme provides better versatility with 3 times wider range of size control as well as the compatibility with viscous fluids that could cause pressure buildup in the microsystem. As a demonstration, a QD-doped prepolymer resin is introduced to create uniform biocompatible polymer beads with 10 wt % CdSe/ZnSe QD loading. In spite of this high loading, the resulting polymer beads exhibits narrow bandwidth of 28 nm to be used for the ultrasensitive bioimaging, optical coding, and sensing sufficiently with single bead.
Co-reporter:Stephen G. Newman and Klavs F. Jensen
Green Chemistry 2013 vol. 15(Issue 6) pp:1456-1472
Publication Date(Web):26 Apr 2013
DOI:10.1039/C3GC40374B
Flow chemistry and continuous processing can offer many ways to make synthesis a more sustainable practice. These technologies help bridge the large gap between academic and industrial settings by often providing a more reproducible, scalable, safe and efficient option for performing chemical reactions. In this review, we use selected examples to demonstrate how continuous methods of synthesis can be greener than batch synthesis on a small and a large scale.
Co-reporter:Xiaoying Liu and Klavs F. Jensen
Green Chemistry 2013 vol. 15(Issue 6) pp:1538-1541
Publication Date(Web):02 Apr 2013
DOI:10.1039/C3GC40407B
By integrating a heterogeneous oxidation step, gas–liquid separation, and an oxidative amidation reaction to form a continuous system, a multistep synthetic protocol has been demonstrated to produce amides under mild conditions using alcohols and amines as the starting materials. The use of inexpensive oxygen and urea hydrogen peroxide as the only oxidants affords an economical and adaptable synthetic route for amides.
Co-reporter:Andrea Adamo, Alessandro Arione, Armon Sharei, and Klavs F. Jensen
Analytical Chemistry 2013 Volume 85(Issue 3) pp:1637
Publication Date(Web):December 21, 2012
DOI:10.1021/ac302887a
We present a microfluidic electroporation device with a comb electrode layout fabricated in polydimethylsiloxane (PMDS) and glass. Characterization experiments with HeLa cells and fluorescent dextran show efficient delivery (∼95%) with low toxicity (cell viability ∼85%) as well as rapid pore closure after electroporation. The activity of delivered molecules is also verified by silencing RNA (siRNA) studies that demonstrate gene knockdown in GFP expressing cells. This simple, scalable approach to microfluidic, flow-through electroporation could facilitate the integration of electroporation modules within cell analysis devices that perform multiple operations.
Co-reporter:María José Nieves-Remacha, Amol A. Kulkarni, and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2013 Volume 52(Issue 26) pp:8996
Publication Date(Web):May 30, 2013
DOI:10.1021/ie4011707
Hydrodynamics and mass transfer of gas–liquid flow are explored under ambient conditions in an Advanced-Flow Reactor (AFR), an emerging commercial system designed for continuous manufacture. Carbon dioxide/water is the model system used in this study for a range of flow rates for gas and liquid of 5.6–103 mL/min and 10–80 mL/min, respectively. Bubble size distribution, gas holdup, specific interfacial area, pressure drop, and mass transfer coefficients are determined from flow visualization experiments and compared with conventional gas–liquid contactors. These variables are mainly influenced by the inlet flow rates and inlet composition. Average bubble sizes () of 0.9–3.8 mm, gas holdup (εG) of 0.04–0.68, specific interfacial areas (a) of 160–1300 m2/m3, and overall mass transfer coefficients (kLa) of 0.2–3 s–1 were obtained for the vertical orientation of the AFR. Although effect of gravity is present for this system, no significant effect on the hydrodynamic properties was observed. The measured pressure drop for vertical orientation (3.6–53.4 kPa) was used to estimate power consumption, which is used as a metric to compare mass transfer efficiency among different gas–liquid contactors. A power law relationship was obtained for the overall mass transfer coefficients in terms of power input and gas holdup, given by kLa = 0.101Pw0.443εG0.459. The design of the AFR with a series of heart-shaped confined sections with obstacles enhances continuous breakup and coalescence of bubbles providing interfacial areas and mass transfer coefficients 1 order of magnitude larger than other gas–liquid contactors, such as bubble columns (50–600 m2/m3; 0.005–0.24 s–1) and spray columns (75–170 m2/m3; 0.015–0.022 s–1), and 1 order of magnitude smaller than gas–liquid microchannels (3400–9000 m2/m3; 0.3–21 s–1) or falling film reactors (20,000 m2/m3).
Co-reporter:Andrea Adamo, Patrick L. Heider, Nopphon Weeranoppanant, and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2013 Volume 52(Issue 31) pp:10802-10808
Publication Date(Web):July 3, 2013
DOI:10.1021/ie401180t
We describe the development and application of an improved, membrane-based, liquid–liquid separator. Membrane-based separation relies on the exploitation of surface forces and the use of a membrane wetted by one of the phases; however, successful separation requires accurate control of pressures, making the operation and implementation cumbersome. Here we present an improved separator design that integrates a pressure control element to ensure that adequate operating conditions are always maintained. Additionally, the integrated pressure control decouples the separator from downstream unit operations. A detailed examination of the controlling physical equations shows how to design the device to allow operation across a wide range of conditions. Easy to implement, multistage separations such as solvent swaps and countercurrent extractions are demonstrated. The presented design significantly simplifies applications ranging from multistep synthesis to complex multistage separations.
Co-reporter:Lu Yang and Klavs F. Jensen
Organic Process Research & Development 2013 Volume 17(Issue 6) pp:927-933
Publication Date(Web):May 12, 2013
DOI:10.1021/op400085a
The tube-in-tube reactor is a convenient method for implementing gas/liquid reactions on the microscale, in which pressurized gas permeates through a Teflon AF-2400 membrane and reacts with substrates in liquid phase. Here we present the first quantitative models for analytically and numerically computing gas and substrate concentration profiles within the tube-in-tube reactor. The model accurately predicts mass transfer performance in good agreement with experimental measurement. The scaling behavior and reaction limitations of the tube-in-tube reactor are predicted by modeling and compared with gas/liquid micro- and minireactors. The presented model yields new insights into the scalability and applicability of the tube-in-tube reactor.
Co-reporter:Dr. Pengfei Li;Dr. Jason S. Moore ;Dr. Klavs F. Jensen
ChemCatChem 2013 Volume 5( Issue 7) pp:1729-1733
Publication Date(Web):
DOI:10.1002/cctc.201300054
Co-reporter:Ulrich Neuenschwander, Arnaldo Negron, and Klavs F. Jensen
The Journal of Physical Chemistry A 2013 Volume 117(Issue 21) pp:4343-4351
Publication Date(Web):May 1, 2013
DOI:10.1021/jp400879d
Clock reactions are rare kinetic phenomena, so far limited mostly to systems with ionic oxoacids and oxoanions in water. We report a new clock reaction in cyclohexanol that forms molybdenum blue from a noncharged, yellow molybdenum complex as precursor, in the presence of hydrogen peroxide. Interestingly, the concomitant color change is reversible, enabling multiple clock cycles to be executed consecutively. The kinetics of the clock reaction were experimentally characterized, and by adding insights from quantum chemical calculations, a plausible reaction mechanism was postulated. Key elementary reaction steps comprise sigmatropic rearrangements with five-membered or bicyclo[3.1.0] transition states. Importantly, numerical kinetic modeling demonstrated the mechanism’s ability to reproduce the experimental findings. It also revealed that clock behavior is intimately connected to the sudden exhaustion of hydrogen peroxide. Due to the stoichiometric coproduction of ketone, the reaction bears potential for application in alcohol oxidation catalysis.
Co-reporter:Armon Sharei;Janet Zoldan;Woo Young Sim;Min-Joon Han;Nahyun Cho;Emily Jackson;Pamela A. Basto;Daniel A. Heller;Jeon Woong Kang;George C. Hartoularos;Kwang-Soo Kim;Robert Langer;Daniel G. Anderson;Andrea Adamo;Jungmin Lee;Shirley Mao;Sabine Schneider;Abigail Lytton-Jean;Siddharth Jhunjhunwala
PNAS 2013 Volume 110 (Issue 6 ) pp:2082-2087
Publication Date(Web):2013-02-05
DOI:10.1073/pnas.1218705110
Intracellular delivery of macromolecules is a challenge in research and therapeutic applications. Existing vector-based and
physical methods have limitations, including their reliance on exogenous materials or electrical fields, which can lead to
toxicity or off-target effects. We describe a microfluidic approach to delivery in which cells are mechanically deformed as
they pass through a constriction 30–80% smaller than the cell diameter. The resulting controlled application of compression
and shear forces results in the formation of transient holes that enable the diffusion of material from the surrounding buffer
into the cytosol. The method has demonstrated the ability to deliver a range of material, such as carbon nanotubes, proteins,
and siRNA, to 11 cell types, including embryonic stem cells and immune cells. When used for the delivery of transcription
factors, the microfluidic devices produced a 10-fold improvement in colony formation relative to electroporation and cell-penetrating
peptides. Indeed, its ability to deliver structurally diverse materials and its applicability to difficult-to-transfect primary
cells indicate that this method could potentially enable many research and clinical applications.
Co-reporter:Jungmin Lee, Armon Sharei, Woo Young Sim, Andrea Adamo, Robert Langer, Klavs F. Jensen, and Moungi G. Bawendi
Nano Letters 2012 Volume 12(Issue 12) pp:6322-6327
Publication Date(Web):November 12, 2012
DOI:10.1021/nl303421h
The ability to straightforwardly deliver engineered nanoparticles into the cell cytosol with high viability will vastly expand the range of biological applications. Nanoparticles could potentially be used as delivery vehicles or as fluorescent sensors to probe the cell. In particular, quantum dots (QDs) may be used to illuminate cytosolic proteins for long-term microscopy studies. Whereas recent advances have been successful in specifically labeling proteins with QDs on the cell membrane, cytosolic delivery of QDs into live cells has remained challenging. In this report, we demonstrate high throughput delivery of QDs into live cell cytoplasm using an uncomplicated microfluidic device while maintaining cell viabilities of 80–90%. We verify that the nanoparticle surface interacts with the cytosolic environment and that the QDs remain nonaggregated so that single QDs can be observed.
Co-reporter:Xiaoying Liu and Klavs F. Jensen
Green Chemistry 2012 vol. 14(Issue 5) pp:1471-1474
Publication Date(Web):13 Mar 2012
DOI:10.1039/C2GC35078E
A practical and economical protocol has been developed for the direct oxidative amidation of aromatic aldehydes with secondary amines to synthesize amides in a single operation under mild conditions within 15–40 min. The utilization of aqueous hydrogen peroxide affords a clean synthetic route. No catalysts or promoting reagents are required.
Co-reporter:Víctor Sebastián, Seung-Kon Lee, Chao Zhou, Martin F. Kraus, James G. Fujimoto and Klavs F. Jensen
Chemical Communications 2012 vol. 48(Issue 53) pp:6654-6656
Publication Date(Web):10 May 2012
DOI:10.1039/C2CC32969G
We present a novel one-step flow process to synthesize biocompatible gold nanorods with tunable absorption and biocompatible surface ligands. Photothermal optical coherence tomography (OCT) of human breast tissue is successfully demonstrated using tailored gold nanorods designed to have strong absorption in the near-infrared range.
Co-reporter:Andrea Adamo, Armon Sharei, Luigi Adamo, ByungKun Lee, Shirley Mao, and Klavs F. Jensen
Analytical Chemistry 2012 Volume 84(Issue 15) pp:6438
Publication Date(Web):June 20, 2012
DOI:10.1021/ac300264v
Mechanical properties of cells have been shown to have a significant role in disease, as in many instances cell stiffness changes when a cell is no longer healthy. We present a high-throughput microfluidics-based approach that exploits the connection between travel time of a cell through a narrow passage and cell stiffness. The system resolves both cell travel time and relative cell diameter while retaining information on the cell level. We show that stiffer cells have longer transit times than less stiff ones and that cell size significantly influences travel times. Experiments with untreated HeLa cells and cells made compliant with latrunculin A and cytochalasin B further demonstrate that travel time is influenced by cell stiffness, with the compliant cells having faster transit time.
Co-reporter:Seung-Kon Lee, Xiaoying Liu, Víctor Sebastián Cabeza and Klavs F. Jensen
Lab on a Chip 2012 vol. 12(Issue 20) pp:4080-4084
Publication Date(Web):14 Jun 2012
DOI:10.1039/C2LC40186J
We present a successive microfluidic approach to create and characterize hierarchical catalyst structures consisting of metal-decorated nanoparticles that are assembled into porous microparticles (“supraball” catalysts). First, using a silicon microreactor, platinum nanoparticles with a very narrow size distribution are grown and immobilized uniformly onto iron oxide/silica core–shell nanospheres. The Pt-decorated silica nanospheres are then assembled into uniform, spherical, micron-sized particles by using emulsion templates generated with a microfluidic drop generator. Finally, the assembled supraballs are loaded into a packed-bed microreactor for characterization of the catalytic reactivity. The prepared material showed excellent catalytic activity for the oxidation of aldehyde with only ∼1 mg of material (containing ∼50 μg of platinum nanoparticles). After the reactions, all the supraball catalysts are recovered by using the magnetic property of the underlying iron oxide/silica core–shell nanospheres.
Co-reporter:E. Victoria Dydek, Montana V. Petersen, Daniel G. Nocera and Klavs F. Jensen
Lab on a Chip 2012 vol. 12(Issue 8) pp:1431-1433
Publication Date(Web):07 Mar 2012
DOI:10.1039/C2LC21195E
We report on the design of a microfluidic electrochemical cell with a true Ag/AgCl reference electrode that does not rely on a physical barrier or salt bridge, but instead takes advantage of slow diffusion times in micro-channels. The device concept is demonstrated in PDMS using the Ir+IV/Ir+III redox couple as an example. A scaling analysis provides limits of operation for the device.
Co-reporter:Mahmooda Sultana and Klavs F. Jensen
Crystal Growth & Design 2012 Volume 12(Issue 12) pp:6260-6266
Publication Date(Web):November 5, 2012
DOI:10.1021/cg301538y
We describe a continuous microfluidic system for seeded crystallization of small organic molecules, such as active pharmaceuticals, and demonstrate integration with in situ detection tools for determining the size and polymorphic form of the crystals. This integrated device is used to extract growth kinetics, as a screening platform for process parameter effects and optimization, and to gain insight into the fundamentals of the crystallization process. In addition, the microfluidic system also allows studies of additive effects on the crystal habit. The method is demonstrated with growth kinetics for α-, β-, and γ-forms of glycine along with the effects upon the morphology of adding glutamic acid and methionine.
Co-reporter:Kevin D. Nagy, Bo Shen, Timothy F. Jamison, and Klavs F. Jensen
Organic Process Research & Development 2012 Volume 16(Issue 5) pp:976-981
Publication Date(Web):January 13, 2012
DOI:10.1021/op200349f
Continuous flow chemistry is being used increasingly; however, without detailed knowledge of reaction engineering, it can be difficult to judge whether dispersion and mixing are important factors on reaction outcome. Understanding these effects can result in improved choices of reactor dimensions and give insight for reactor scale-up. We provide an overview of both dispersive and mixing effects in flow systems and present simple relationships for determining whether mixing or dispersion is important for a given flow system. These results are summarized in convenient charts to enable the experimentalist to identify conditions with potential mixing or dispersion problems. The information also expedites design changes, such as inclusion or changes of mixers and changes in reaction tube diameters. As a case study, application of the principles to a glycosylation reaction results in increased throughput and cleaner product profiles compared to previously reported results.
Co-reporter:Jason S. Moore and Klavs F. Jensen
Organic Process Research & Development 2012 Volume 16(Issue 8) pp:1409-1415
Publication Date(Web):July 9, 2012
DOI:10.1021/op300099x
An automated multitrajectory optimization platform with continuous online infrared (IR) monitoring is presented. The production rate of a Paal–Knorr reaction is maximized within a constrained temperature and residence time design space. The automated platform utilizes a microreactor system to carry out optimizations with low material requirements and implements a micro IR flow cell for continuous online monitoring of reaction conversion. The approach to steady state at each set of reaction conditions is assessed continuously before the objective function is evaluated and reactor conditions move to the next set point. Several optimization algorithms are tested for their performance on a complex objective terrain. Each function comes to agreement on the optimal conditions but requires a significantly different number of experiments to reach the final conditions. Additionally, multiple objective functions are compared to analyze the trade-off between production rate and conversion.
Co-reporter:Brandon J. Reizman and Klavs F. Jensen
Organic Process Research & Development 2012 Volume 16(Issue 11) pp:1770-1782
Publication Date(Web):September 20, 2012
DOI:10.1021/op3001838
Automated continuous flow systems coupled with online analysis and feedback have been previously demonstrated to model and optimize chemical syntheses with little a priori reaction information. However, these methods have yet to address the challenge of modeling and optimizing for product yield or selectivity in a multistep reaction network, where low selectivity toward desired product formation can be encountered. Here we demonstrate an automated system capable of rapidly estimating accurate kinetic parameters for a given reaction network using maximum likelihood estimation and a D-optimal design of experiments. The network studied is the series–parallel nucleophilic aromatic substitution of morpholine onto 2,4-dichloropyrimidine. To improve the precision of the estimated parameters, we demonstrate the use of the automated platform first in optimization of the yield of the less kinetically favorable 2-substituted product. Then, upon isolation of the intermediates, we use the automated system with maximum a posteriori estimation to minimize uncertainties in the network parameters. From considering the steps of the reaction network in isolation, the kinetic parameter uncertainties are reduced by 50%, with less than 5 g of the dichloropyrimidine substrate consumed over all experiments. We conclude that isolating pathways in the multistep reaction network is important to minimizing uncertainty for low sensitivity rate parameters.
Co-reporter:María José Nieves-Remacha, Amol A. Kulkarni, and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2012 Volume 51(Issue 50) pp:16251
Publication Date(Web):November 9, 2012
DOI:10.1021/ie301821k
Hydrodynamics and mass transfer of immiscible liquid–liquid flows are explored in an Advanced-Flow Reactor (AFR). These systems are emerging as one of the major commercial systems for small scale continuous flow chemistry, and characterization of the transport phenomena is critical for reaction implementation. With hexane/water as a model system, we use flow visualization techniques to determine drop size distribution, hexane holdup, and specific interfacial areas for a phase flow rate range of 10–80 mL/min. The complex geometry of the AFR with its continuously changing cross section along the flow path and strategically placed obstacles creates pressure changes that cause drop breakup and enhance mass transfer. Observations show that a wide range of average drop size (0.33–1.3 mm) can be achieved in the AFR depending upon the inlet flow rates and inlet composition. Pressure drop measurements are performed to estimate the power consumption and are used to compare the efficiency of AFR with conventional liquid–liquid contactors. The analysis shows that, similar to microreactors, the AFR can provide specific interfacial areas (1000–10 000 m–1) and overall mass transfer coefficients (1.9–41 s–1) a few orders of magnitude larger than conventional stirred tank reactors and also the static mixers.
Co-reporter:Simon Kuhn and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2012 Volume 51(Issue 26) pp:8999-9006
Publication Date(Web):June 14, 2012
DOI:10.1021/ie300978n
We present a pH-sensitive laser-induced fluorescence (LIF) technique to investigate mass transfer in reactive flows. As a fluorescent dye, we used 5-(and-6)-carboxy SNARF-1, which, when excited with a pulsed Nd:YAG laser at 532 nm, provides good sensitivity in the range 4 ≤ pH ≤ 12. For validation, we first applied the dye to single-phase reactive flows by investigating the neutralization of sodium hydroxide with hydrochloric acid. Comparison to the classical passive mixing case showed that this dye was able to capture the reaction progress and to quantify the mass transport. Next, we investigated the absorption of CO2 in an alkaline solution using gas–liquid flow and found that the LIF technique is able to quantify the local mass-transfer rate in microfluidic systems. Results for different microchannel geometries highlight the strong connection between local mass transfer and secondary flow structures in gas–liquid Taylor flow.
Co-reporter:Victor Sebastian Cabeza, Simon Kuhn, Amol A. Kulkarni, and Klavs F. Jensen
Langmuir 2012 Volume 28(Issue 17) pp:7007-7013
Publication Date(Web):April 4, 2012
DOI:10.1021/la205131e
Segmented flow is often used in the synthesis of nanomaterials to achieve narrow particle size distribution. The narrowness of the distribution is commonly attributed to the reduced dispersion associated with segmented flows. On the basis of the analysis of flow fields and the resulting particle size distribution, we demonstrate that it is the slip velocity between the two fluids and internal mixing in the continuous-phase slugs that govern the nature of the particle size distribution. The reduction in the axial dispersion has less impact on particle growth and hence on the particle size distribution. Synthesis of gold nanoparticles from HAuCl4 with rapid reduction by NaBH4 serves as a model system. Rapid reduction yields gold nuclei, which grow by agglomeration, and it is controlled by the interaction of the nuclei with local flow. Thus, the difference in the physical properties of the two phases and the inlet flow rates ultimately control the particle growth. Hence, a careful choice of continuous and dispersed phases is necessary to control the nanoparticle size and size distribution.
Co-reporter:Timothy Noël, John R. Naber, Ryan L. Hartman, Jonathan P. McMullen, Klavs F. Jensen and Stephen L. Buchwald
Chemical Science 2011 vol. 2(Issue 2) pp:287-290
Publication Date(Web):03 Dec 2010
DOI:10.1039/C0SC00524J
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.
Co-reporter:Simon Kuhn, Timothy Noël, Lei Gu, Patrick L. Heider and Klavs F. Jensen
Lab on a Chip 2011 vol. 11(Issue 15) pp:2488-2492
Publication Date(Web):23 Jun 2011
DOI:10.1039/C1LC20337A
We present a general inexpensive method for realizing a Teflon stack microreactor with an integrated piezoelectric actuator for conducting chemical synthesis with solid products. The microreactors are demonstrated with palladium-catalyzed C–N cross-coupling reactions, which are prone to clogging microchannels by forming insoluble salts as by-products. Investigations of the ultrasonic waveform applied by the piezoelectric actuator reveal an optimal value of 50 kHz at a load power of 30 W. Operating the system at these conditions, the newly developed Teflon microreactor handles the insoluble solids formed and no clogging is observed. The investigated reactions reach full conversion in very short reaction times and high isolated yields are obtained (>95% yield).
Co-reporter:Nikolay Zaborenko, Matthew W. Bedore, Timothy F. Jamison, and Klavs F. Jensen
Organic Process Research & Development 2011 Volume 15(Issue 1) pp:131-139
Publication Date(Web):December 14, 2010
DOI:10.1021/op100252m
A continuous-flow microreactor is applied for a kinetic study of a model β-amino alcohol formation by epoxide aminolysis. A large number of experiments are performed in a short time with minimal reagent consumption. The kinetics of formation of secondary aminolysis between starting epoxide and product are decoupled from the primary synthesis, constructing a complete model for desired product formation. The activation energy for the formation of desired product is observed to be higher than those for regioisomer formation and for secondary aminolysis, indicating that increasing temperature improves selectivity in addition to accelerating the reaction. A set of optimized conditions is then selected for best reaction performance, and the process is scaled up to a 100-fold larger reactor volume with model predictions in good agreement with measured process performance.
Co-reporter:Jonathan P. McMullen and Klavs F. Jensen
Organic Process Research & Development 2011 Volume 15(Issue 2) pp:398-407
Publication Date(Web):March 4, 2011
DOI:10.1021/op100300p
Kinetic information is used to determine the optimal reaction conditions, to successfully scale up a reaction from the laboratory to the pilot plant, and to improve process control. Obtaining accurate kinetics using conventional benchtop equipment and techniques, however, requires numerous experiments and can be complicated by sluggish mixing and heat-transfer rates. To improve the speed and efficiency in gathering reaction kinetics, we present an automated, silicon microreactor system that uses a sequential experimentation framework driven by model-based optimization feedback for online reaction rate parameter determination. The method, based on Information Theory and Bayesian Statistics, first selects the appropriate global reaction rate expression. After determining the correct rate law, a D-optimal strategy precisely estimates the pre-exponential and activation energy of the rate constant. The approaches are validated experimentally with a model system, the Diels−Alder reaction of isoprene and maleic anhydride in DMF. The benefits of quickly obtaining this information with an automated microreactor system are further demonstrated by successfully scaling the Diels−Alder reaction by a factor of 500 from a microreactor to a Corning flow reactor.
Co-reporter:Christopher H. Marton, George S. Haldeman, and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2011 Volume 50(Issue 14) pp:8468-8475
Publication Date(Web):June 20, 2011
DOI:10.1021/ie200210d
A portable-scale thermoelectric power generator is designed, fabricated, and tested. The basis of the system is a mesoscale silicon reactor for the combustion of butane over an alumina-supported platinum catalyst. The system is integrated with commercial bismuth telluride thermoelectric modules to produce 5.8 W of electrical power with a chemical-to-electrical conversion efficiency of 2.5% (based on LHV). The energy and power densities of the demonstrated system are 321 W h kg–1 and 17 W kg–1, respectively. The pressure drop through the system is 130 Pa for the highest flow rate used, resulting in a parasitic power requirement for air-pressurization of ∼0.1 W. The demonstration represents an order-of-magnitude improvement in portable-scale electrical power from thermoelectrics and hydrocarbon fuels, and a notable increase in the conversion efficiency compared with previous studies.
Co-reporter:Jaroslav Keybl and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2011 Volume 50(Issue 19) pp:11013-11022
Publication Date(Web):September 14, 2011
DOI:10.1021/ie200936b
A high-pressure gas–liquid system is presented for determining homogeneous catalyst kinetic parameters. Microreactors enable segmented flow with very predictable gas–liquid contacting, reducing the effects of mass transfer as well as facilitating isothermal operation. The system is capable of studying homogeneous catalysis at high temperature and pressure (<350 °C and <100 bar) under continuous flow. By varying the pressure, temperature, and concentrations of both gas and liquid species, it is possible to determine kinetic parameters. Both inline and offline analyses are performed using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and gas chromatography (GC). The hydroformylation of 1-octene is studied to demonstrate the utility of this microreactor system as a laboratory tool for kinetic measurements. The system is capable of providing both parameter estimation and mechanistic insight. A discussion is also included that explores the types of chemical systems that can be studied practically in microreactors.
Co-reporter:Dr. Ryan L. Hartman;Jonathan P. McMullen; Klavs F. Jensen
Angewandte Chemie 2011 Volume 123( Issue 33) pp:7642-7661
Publication Date(Web):
DOI:10.1002/ange.201004637
Abstract
In der chemischen und pharmazeutischen Industrie gibt es Bestrebungen, Produktionsverfahren – wo immer möglich – vom Batchbetrieb auf kontinuierliche Verfahren umzustellen. Diese Entwicklung hat Auswirkungen auf die Synthesechemie jeglicher Größenskala, vom Labormaßstab bis hin zu großtechnischen Anlagen. Dieser Aufsatz diskutiert die Vor- und Nachteile von Batch-Reaktoren und Mikroströmungsreaktoren für die Durchführung chemischer Synthesen im Labor.
Co-reporter:Dr. Ryan L. Hartman;Jonathan P. McMullen; Klavs F. Jensen
Angewandte Chemie International Edition 2011 Volume 50( Issue 33) pp:7502-7519
Publication Date(Web):
DOI:10.1002/anie.201004637
Abstract
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.
Co-reporter:Jinyoung Baek;Dr. Peter M. Allen; Moungi G. Bawendi; Klavs F. Jensen
Angewandte Chemie International Edition 2011 Volume 50( Issue 3) pp:627-630
Publication Date(Web):
DOI:10.1002/anie.201006412
Co-reporter:Dr. Timothy Noël;Dr. Simon Kuhn;Andrew J. Musacchio;Dr. Klavs F. Jensen;Dr. Stephen L. Buchwald
Angewandte Chemie 2011 Volume 123( Issue 26) pp:6065-6068
Publication Date(Web):
DOI:10.1002/ange.201101480
Co-reporter:Simon Kuhn, Ryan L. Hartman, Mahmooda Sultana, Kevin D. Nagy, Samuel Marre, and Klavs F. Jensen
Langmuir 2011 Volume 27(Issue 10) pp:6519-6527
Publication Date(Web):April 21, 2011
DOI:10.1021/la2004744
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.
Co-reporter:Dr. Timothy Noël;Dr. Simon Kuhn;Andrew J. Musacchio;Dr. Klavs F. Jensen;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2011 Volume 50( Issue 26) pp:5943-5946
Publication Date(Web):
DOI:10.1002/anie.201101480
Co-reporter:Jian Wen, Erik W. Wilker, Michael B. Yaffe and Klavs F. Jensen
Analytical Chemistry 2010 Volume 82(Issue 4) pp:1253
Publication Date(Web):January 21, 2010
DOI:10.1021/ac902157e
Isoelectric focusing (IEF) is the first step for two-dimensional (2D) gel electrophoresis and plays an important role in sample purification for proteomics. However, biases in protein size and pI resolution, as well as limitations in sample volume, gel capacity, sample loss, and experimental time, remain challenges. In order to address some of the limitations of traditional IEF, we present a microfluidic free flow IEF (FF-IEF) device for continuous protein separation into 24 fractions. The device reproducibly establishes a nearly linear pH gradient from 4 to 10. Optimized dynamic coatings of 4% poly(vinyl alcohol) (PVA) minimize peak broadening by transverse electrokinetic flows. Even though the device operates at high electric fields (up to 370 V/cm), efficient cooling maintains solution temperature inside the separation channel controllably in the range 2−25 °C. Protein samples with a dynamic concentration range from μg/mL to mg/mL can be loaded into the microdevice at a flow rate of 1 mL/h and residence time of ∼12 min. By using a protein complex of nine proteins and 13 isoforms, we demonstrate improved separation with the FF-IEF system over traditional 2D gel electrophoresis. Device-to-device reproducibility is also illustrated through the efficient depletion of the albumin and hemoglobin assays. Postdevice sample concentrations result in a 10−20-fold increase, which allow for isolation and detection of low abundance proteins. The separation of specific proteins from a whole cell lysate is demonstrated as an example. The microdevice has the further benefits of retaining high molecular weight proteins, providing higher yield of protein that has a broader range in pI, and reducing experimental time compared to conventional IEF IGP gel strip approaches.
Co-reporter:Nikolay Zaborenko, Edward R. Murphy, Jason G. Kralj and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2010 Volume 49(Issue 9) pp:4132-4139
Publication Date(Web):March 29, 2010
DOI:10.1021/ie100263p
A modular silicon micromixer is designed and fabricated for high-flow rapid mixing at a wide range of reaction conditions. The mixer operates by splitting two inlet flows into a large number of channels, interdigitating them, and constricting the laminated flow to create submicrometer diffusion lengths. Mixing is quantified using the Villermaux−Dushman method, with UV−vis detection of the photoactive species, and compared against a commercial micromixer. Micromixers and tubing are then used to perform a quantitative kinetic study of the direct two-step synthesis of sodium nitrotetrazolate (NaNT) by a Sandmeyer type reaction via a reactive diazonium intermediate. Orders of reactions and temperature dependence of both steps, as well as pH and ionic strength dependence of the second step, are evaluated. Successful production of 4.4 g/h of NaNT in solution is ultimately achieved in a compact footprint using the kinetic data, verifying the potential for scaling to typical production amounts.
Co-reporter:Samuel Marre, Andrea Adamo, Soubir Basak, Cyril Aymonier, and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2010 Volume 49(Issue 22) pp:11310-11320
Publication Date(Web):October 19, 2010
DOI:10.1021/ie101346u
The development of chemically compatible microsystems that can operate across expanded process conditions, such as high pressures (HP) and high temperatures (HT), is of great interest for many applications, including high pressure chemistry and hydrothermal and supercritical fluid processes. We present a methodology for the successful design and use of HP/HT microsystems. Key parameters for the fabrication of microreactors and modular fluidic packaging able to withstand severe pressure and temperature conditions (30 MPa, 400 °C) are described. Applications of these HP/HT plug and play microsystems are illustrated with examples, including multiphase flow visualization through the transition of liquid−liquid immiscible hexane−water segmented flow to homogeneous supercritical flow, on chip supercritical water oxidation, and synthesis of iron oxide nanoparticles.
Co-reporter:Ryan L. Hartman, John R. Naber, Nikolay Zaborenko, Stephen L. Buchwald, and Klavs F. Jensen
Organic Process Research & Development 2010 Volume 14(Issue 6) pp:1347-1357
Publication Date(Web):September 10, 2010
DOI:10.1021/op100154d
We investigate the mechanisms that govern plugging in microreactors during Pd-catalyzed amination reactions. Both bridging and constriction were shown to be important mechanisms that lead to clogging in our system and greatly limited the utility of microsystems for this class of reactions. On the basis of these observations, several approaches were engineered to overcome the challenge of plugging and to enable the continuous-flow synthesis of a biarylamine. Bridging could be eliminated with acoustic irradiation while constriction was managed via fluid velocity and the prediction of growth rates.
Co-reporter:Matthew W. Bedore, Nikolay Zaborenko, Klavs F. Jensen and Timothy F. Jamison
Organic Process Research & Development 2010 Volume 14(Issue 2) pp:432-440
Publication Date(Web):January 26, 2010
DOI:10.1021/op9003136
The use of a continuous flow microreactor for β-amino alcohol formation by epoxide aminolysis is evaluated. Comparison to microwave batch reactions reveals that conditions obtainable in the microreactor can match or improve yields in many cases. By increasing the pressure of the system, maximum temperatures can also exceed those accessible using a microwave unit. The use of a microreactor for epoxide aminolysis reactions in the synthesis of two pharmaceutical relevant compounds is described.
Co-reporter:Jonathan P. McMullen and Klavs F. Jensen
Organic Process Research & Development 2010 Volume 14(Issue 5) pp:1169-1176
Publication Date(Web):August 19, 2010
DOI:10.1021/op100123e
An automated, continuous flow system for the online, multivariable optimization of a chemical reaction is presented. Time and material required for an optimization trial are minimized by performing reactions in an integrated silicon microreactor and incorporating an HPLC for inline monitoring of the reaction performance. We use the system to optimize two different reactions to describe the potential impact of this system for reaction development. First, we demonstrate the broad operation capabilities by incorporating several feedback algorithms to optimize a weighted objective function involving the yield and the throughput of a Knoevenagel condensation reaction. After illustrating how system operations can be adapted for individual reactions, we perform a multiparameter optimization to maximize the yield of benzaldehyde in the oxidation pathway of benzyl alcohol to benzaldehyde to benzoic acid. A significant feature of the automated system is the ability to perform “black-box” optimization where no a priori information of the reaction parameters is required.
Co-reporter:Ling Chao, Alice P. Gast, T. Alan Hatton and Klavs F. Jensen
Langmuir 2010 Volume 26(Issue 1) pp:344-356
Publication Date(Web):October 28, 2009
DOI:10.1021/la902084u
Sphingomyelinase (SMase) has been shown to be involved in a variety of cell regulation processes by reorganizing the cell membrane morphology. Here we report that SMase can induce a reaction-induced and a solvent-mediated phase transformation, causing switches of three stationary membrane morphologies and multiple-time-domain ceramide generation in model raft membranes. The reaction-induced phase transformation, triggered by the addition of SMase, transforms a pre-existing morphology to a long-lasting intermediate morphology with coexisting ceramide-enriched (Cer-enriched) and sphingomyelin-enriched (SM-enriched) domains. Solvent-mediated phase transformation ultimately transforms all of the SM-enriched domains of the intermediate morphology into Cer-enriched domains. Labeled SMase experiments suggest that the intermediate morphology results from physical trapping of SM in the SM-enriched domains, which are found to be relatively inaccessible to SMase. The characterization results from confocal fluorescence imaging show that the trigger of the solvent-mediated phase transformation is the formation of a 3-D feature rich in SMase, sphingomyelin, and ceramide. This 3-D feature is hypothesized as a slowly nucleating SMase-enriched phase, where SMase processes sphingomyelin more efficiently. The disparate time-scales of the formation of these SMase-features and the SM-enriched domains allow for the development of a significant duration of the middle intermediate morphology between the two transformations. The results show that SMase can be actively involved in the lipid membrane phase changes. The multistage morphology evolution is not only due to membrane-compositional changes caused by SMase, but also due to the selective binding of SMase, and the SMase’s special phase behavior during the solvent-mediated phase transformation.
Co-reporter:RyanL. Hartman;JohnR. Naber;StephenL. Buchwald ;KlavsF. Jensen
Angewandte Chemie International Edition 2010 Volume 49( Issue 5) pp:899-903
Publication Date(Web):
DOI:10.1002/anie.200904634
Co-reporter:Jonathan P. McMullen;Dr. Matthew T. Stone; Stephen L. Buchwald; Klavs F. Jensen
Angewandte Chemie International Edition 2010 Volume 49( Issue 39) pp:7076-7080
Publication Date(Web):
DOI:10.1002/anie.201002590
Co-reporter:Ryan L. Hartman and Klavs F. Jensen
Lab on a Chip 2009 vol. 9(Issue 17) pp:2495-2507
Publication Date(Web):28 May 2009
DOI:10.1039/B906343A
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.
Co-reporter:Ryan L. Hartman, Hemantkumar R. Sahoo, Bernard C. Yen and Klavs F. Jensen
Lab on a Chip 2009 vol. 9(Issue 13) pp:1843-1849
Publication Date(Web):07 Apr 2009
DOI:10.1039/B901790A
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 °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.
Co-reporter:Nuria de Mas, Axel Günther, Martin A. Schmidt and Klavs F. Jensen
Industrial & Engineering Chemistry Research 2009 Volume 48(Issue 3) pp:1428-1434
Publication Date(Web):December 30, 2008
DOI:10.1021/ie801232d
The throughput of a single-channel microreactor used for a fast gas−liquid reaction was increased by up to one order of magnitude relative to previously published results by simultaneously increasing the superficial gas and liquid velocities. Superficial gas and liquid velocities varied between 2.9−14.6 m/s and 0.012–0.061 m/s, respectively. The direct fluorination of toluene in acetonitrile, selected as a model reaction, was performed at room temperature in microchannels formed in a silicon substrate, coated with thermally grown silicon oxide and evaporated nickel, and capped by Pyrex. With faster velocities the toluene conversion increased from 63% to 76%, while the combined selectivity of ortho-, meta-, and para-fluorotoluene isomers remained constant at 26%. Operating at faster gas and liquid velocities appeared to enhance the contacting between the two phases, thus outweighing the reduced liquid residence time.
Co-reporter:S. A. Khan;K. F. Jensen
Advanced Materials 2007 Volume 19(Issue 18) pp:2556-2560
Publication Date(Web):14 AUG 2007
DOI:10.1002/adma.200700127
Multi-step addition microfluidic system for growth of well defined shell coatings without complications of secondary nucleation. Coating of colloidal silica core particles with titania layers of tunable thickness in a one-step, continuous flow process through controlled hydrolysis of titanium tetraethoxide.
Co-reporter:Jason G. Kralj, Hemantkumar R. Sahoo and Klavs F. Jensen
Lab on a Chip 2007 vol. 7(Issue 2) pp:256-263
Publication Date(Web):24 Oct 2006
DOI:10.1039/B610888A
We describe continuous flow liquid–liquid phase separation in microfluidic devices based on capillary forces and selective wetting surfaces. Effective liquid–liquid phase separation is achieved by using a thin porous fluoropolymer membrane that selectively wets non-aqueous solvents, has average pore sizes in the 0.1–1 µm range, and has a high pore density for high separation throughput. Pressure drops throughout the microfluidic network are modelled and operating regimes for the membrane phase separator are determined based on hydrodynamic pressure drops and capillary forces. A microfluidic extraction device integrating mixing and phase separation is realized by using silicon micromachining. Modeling of the phase separator establishes the operating limits. The device is capable of completely separating several organic–aqueous and fluorous–aqueous liquid–liquid systems, even with high fractions of partially miscible compounds. In each case, extraction is equivalent to one equilibrium extraction stage.
Co-reporter:Edward R. Murphy;Joseph R. Martinelli;Nikolay Zaborenko;Stephen L. Buchwald ;Klavs F. Jensen
Angewandte Chemie 2007 Volume 119(Issue 10) pp:
Publication Date(Web):19 JAN 2007
DOI:10.1002/ange.200604175
Schnelle Suche: Druckmikroreaktoren erweitern den Bereich der Reaktionsbedingungen erheblich und beschleunigen den Gas-flüssig-Massentransfer. Heck-Aminocarbonylierungen (siehe Schema) belegen das Potenzial für das schnelle und sichere Durchmustern von Reagentien und Reaktionsbedingungen. Die Amidausbeute steigt mit der Temperatur, und die Selektivität bezüglich der α-Ketoamidbildung (n=2) steigt mit abnehmender Temperatur und zunehmendem Druck.
Co-reporter:Hemantkumar R. Sahoo;Jason G. Kralj;Klavs F. Jensen
Angewandte Chemie International Edition 2007 Volume 46(Issue 30) pp:
Publication Date(Web):20 JUN 2007
DOI:10.1002/anie.200701434
All for one and one for all: A continuous-flow, multistep microchemical synthesis of carbamates starting from aqueous azide and organic azoyl chloride by using the Curtius rearrangement reaction is described. The procedure involves three reaction steps and two separation steps (one gas–liquid and one liquid–liquid). Formation of a microreactor network for parallel synthesis of analogous compounds is also demonstrated.
Co-reporter:Edward R. Murphy;Joseph R. Martinelli;Nikolay Zaborenko;Stephen L. Buchwald ;Klavs F. Jensen
Angewandte Chemie International Edition 2007 Volume 46(Issue 10) pp:
Publication Date(Web):19 JAN 2007
DOI:10.1002/anie.200604175
Squeeze play: Pressurized microreactor systems greatly expand the range of reaction conditions and accelerate gas–liquid mass transfer. Heck aminocarbonylation reactions (see scheme) exemplify the potential for the quick and safe scanning of reagents and reaction conditions. The yield of amide increases with an increase in temperature and the selectivity for α-ketoamide production (n=2) increases at lower temperature and higher pressure.
Co-reporter:Hemantkumar R. Sahoo;Jason G. Kralj;Klavs F. Jensen
Angewandte Chemie 2007 Volume 119(Issue 30) pp:
Publication Date(Web):20 JUN 2007
DOI:10.1002/ange.200701434
Einer für alle, alle für einen: Eine mehrstufige mikrochemische Durchflusssynthese von Carbamaten aus wässrigem Azid und einem organischen Azoylchlorid mithilfe der Curtius-Umlagerung wird beschrieben. Der Prozess umfasst drei Reaktionsstufen und zwei Trennschritte (eine Gas-flüssig- und eine Flüssig-flüssig-Trennung). Ein Mikroreaktornetzwerk für die Parallelsynthese analoger Verbindungen wird ebenfalls vorgestellt.
Co-reporter:B. A. Wilhite;S. E. Weiss;J. Y. Ying;M. A. Schmidt;K. F. Jensen
Advanced Materials 2006 Volume 18(Issue 13) pp:1701-1704
Publication Date(Web):8 JUN 2006
DOI:10.1002/adma.200502025
Micromembranes integrating nanometer-scale Pd films (see figure) with complex oxide methanol-reforming catalysts demonstrate high-purity hydrogen generation. Washcoating of an 8:1 LaNi0.95Co0.05O3/Al2O3 catalyst serves the dual purposes of preventing thin-film disintegration upon direct exposure to methanol while providing improved selectivity and conversion of methanol to hydrogen through partial oxidation.
Co-reporter:Zhiyu Zhang, Paolo Boccazzi, Hyun-Goo Choi, Gerardo Perozziello, Anthony J. Sinskey and Klavs F. Jensen
Lab on a Chip 2006 vol. 6(Issue 7) pp:906-913
Publication Date(Web):20 Apr 2006
DOI:10.1039/B518396K
In a chemostat, microbial cells reach a steady state condition at which cell biomass production, substrates and the product concentrations remain constant. These features make continuous culture a unique and powerful tool for biological and physiological research. We present a polymer-based microbioreactor system integrated with optical density (OD), pH, and dissolved oxygen (DO) real-time measurements for continuous cultivation of microbial cells. Escherichia coli (E. coli) cells are continuously cultured in a 150 µL, membrane-aerated, well-mixed microbioreactor fed by a pressure-driven flow of fresh medium through a microchannel. Chemotaxisial back growth of bacterial cells into the medium feed channel is prevented by local heating. Using poly(ethylene glycol) (PEG)-grafted poly(acrylic acid) (PAA) copolymer films, the inner surfaces of poly(methyl methacrylate) (PMMA) and poly(dimethylsiloxane) (PDMS) of the microbioreactor are modified to generate bio-inert surfaces resistant to non-specific protein adsorption and cell adhesion. The modified surfaces of microbioreactor effectively reduce wall growth of E. coli for a prolonged period of cultivation. Steady state conditions at different dilution rates are demonstrated and characterized by steady OD, pH, and DO levels.
Co-reporter:Thomas Gervais, Jamil El-Ali, Axel Günther and Klavs F. Jensen
Lab on a Chip 2006 vol. 6(Issue 4) pp:500-507
Publication Date(Web):03 Mar 2006
DOI:10.1039/B513524A
We study the elastic deformation of poly(dimethylsiloxane) (PDMS) microchannels under imposed flow rates and the effect of this deformation on the laminar flow profile and pressure distribution within the channels. Deformation is demonstrated to be an important consideration in low aspect ratio (height to width) channels and the effect becomes increasingly pronounced for very shallow channels. Bulging channels are imaged under varying flow conditions by confocal microscopy. The deformation is related to the pressure and is thus non-uniform throughout the channel, with tapering occuring along the stream-wise axis. The measured pressure drop is monitored as a function of the imposed flow rate. For a given pressure drop, the corresponding flow rate in a deforming channel is found to be several times higher than expected in a non-deforming channel. The experimental results are supported by scaling analysis and computational fluid dynamics simulations coupled to materials deformation models.
Co-reporter:Daniel M. Ratner, Edward R. Murphy, Manish Jhunjhunwala, Daniel A. Snyder, Klavs F. Jensen and Peter H. Seeberger
Chemical Communications 2005 (Issue 5) pp:578-580
Publication Date(Web):17 Dec 2004
DOI:10.1039/B414503H
Glycosylation reactions are performed rapidly over a wide range of conditions as an example of microreactor-based method optimization and process development in organic chemistry.
Co-reporter:Nicolas Szita, Paolo Boccazzi, Zhiyu Zhang, Patrick Boyle, Anthony J. Sinskey and Klavs F. Jensen
Lab on a Chip 2005 vol. 5(Issue 8) pp:819-826
Publication Date(Web):30 Jun 2005
DOI:10.1039/B504243G
A multiplexed microbioreactor system for parallel operation of multiple microbial fermentation is described. The system includes miniature motors for magnetic stirring of the microbioreactors and optics to monitor the fermentation parameters optical density (OD), dissolved oxygen (DO), and pH, in-situ and in real time. The microbioreactors are fabricated out of poly(methylmethacrylate)
(PMMA) and poly(dimethylsiloxane)
(PDMS), and have a working volume of 150 µl. Oxygenation of the cells occurs through a thin PDMS membrane at the top of the reactor chamber. Stirring is achieved with a magnetic spin bar in the reactor chamber. Parallel microbial fermentations with Escherichia coli are carried out in four stirred microbioreactors and demonstrate the reproducible performance of the multiplexed system. The profiles for OD, DO, and pH compare favourably to fermentations performed in bioreactor systems with multiple bench-scale reactors. Finally, the multiplexed system is used to compare two different reactor designs, demonstrating that the reproducibility of the system permits the quantification of microbioreactor performance.
Co-reporter:Jason G. Kralj, Martin A. Schmidt and Klavs F. Jensen
Lab on a Chip 2005 vol. 5(Issue 5) pp:531-535
Publication Date(Web):12 Apr 2005
DOI:10.1039/B418815B
Continuous microfluidic liquid–liquid extraction is realized in a microfluidic device by generating emulsions with large interfacial areas for mass transfer, and subsequently breaking these emulsions using electric fields into easily separated segments of immiscible liquids (plugs). The microfluidic device employs insulated electrodes in a potassium hydroxide-etched channel to create large electric fields (100 kV m−1) that drive coalescence of the emulsion phase. The result is a transition from disperse to slug flow that can then readily be separated by gravity. Extractions of phenol and p-nitrophenol from an aqueous to hexane–surfactant solution serve as model systems. In addition to the increased surface area in the emulsion, extraction efficiency is enhanced by reverse micelles resulting from the presence of surfactants. The surfactant concentration is varied ∼1–10 wt% and a general two-parameter model is developed to quantify the extraction behavior and demonstrate the effectiveness of reverse micelle enhanced extraction.
Co-reporter:Hang Lu, Martin A. Schmidt and Klavs F. Jensen
Lab on a Chip 2005 vol. 5(Issue 1) pp:23-29
Publication Date(Web):05 Nov 2004
DOI:10.1039/B406205A
We demonstrate a micro-electroporation device for cell lysis prior to subcellular analysis. Simple circuit models show that electrical lysis method is advantageous because it is selective towards plasma membrane while leaving organelle membrane undamaged. In addition, miniaturization of this concept leads to negligible heat generation and bubble formation. The designed microdevices were fabricated using a combination of photolithography, metal-film deposition, and electroplating. We demonstrate the electro-lysis of human carcinoma cells in these devices to release the subcellular materials.
Co-reporter:Brian K. H. Yen;Axel Günther;Martin A. Schmidt ;Moungi G. Bawendi
Angewandte Chemie International Edition 2005 Volume 44(Issue 34) pp:
Publication Date(Web):20 JUN 2005
DOI:10.1002/anie.200500792
Monodisperse CdSe quantum dots (QDs) with excellent optical properties can be prepared with a gas–liquid segmented flow microreactor with multiple temperature zones (see picture; red=heated; blue=cooled quench zone). The enhanced mixing and narrow residence time distributions of segmented flow produce QDs superior to those prepared in single-phase operations.
Co-reporter:Brian K. H. Yen;Axel Günther;Martin A. Schmidt ;Moungi G. Bawendi
Angewandte Chemie International Edition 2005 Volume 44(Issue 34) pp:
Publication Date(Web):22 AUG 2005
DOI:10.1002/anie.200590114
Co-reporter:Brian K. H. Yen;Axel Günther;Martin A. Schmidt ;Moungi G. Bawendi
Angewandte Chemie 2005 Volume 117(Issue 34) pp:
Publication Date(Web):20 JUN 2005
DOI:10.1002/ange.200500792
Monodisperse CdSe-Quantenpunkte (QDs) mit ausgezeichneten optischen Eigenschaften sind mit einem Gas-flüssig-segmentierten Fluss-Mikroreaktor erhältlich, der mehrere Temperaturzonen aufweist (siehe Bild; rot=beheizte, blau=gekühlte Quenching-Zone). Das bessere Mischen und die engen Verweilzeitverteilungen des segmentierten Flusses liefern QDs, die denen aus Einphasenoperationen überlegen sind.
Co-reporter:Brian K. H. Yen;Axel Günther;Martin A. Schmidt ;Moungi G. Bawendi
Angewandte Chemie 2005 Volume 117(Issue 34) pp:
Publication Date(Web):22 AUG 2005
DOI:10.1002/ange.200590113
Co-reporter:Chelsey D. Baertsch, Martin A. Schmidt and Klavs F. Jensen
Chemical Communications 2004 (Issue 22) pp:2610-2611
Publication Date(Web):04 Oct 2004
DOI:10.1039/B410078F
The metal dispersion of a Pt–Al2O3 catalyst was measured reproducibly using pulse CO chemisorption with 4 mg of sample in a silicon microfabricated packed-bed reactor, demonstrating the applicability of micoreactors for high-throughput catalyst characterization with quantitative comparison.
Co-reporter:Axel Günther, Saif A. Khan, Martina Thalmann, Franz Trachsel and Klavs F. Jensen
Lab on a Chip 2004 vol. 4(Issue 4) pp:278-286
Publication Date(Web):16 Jun 2004
DOI:10.1039/B403982C
We use micro particle image velocimetry (μPIV) and fluorescence microscopy techniques to characterize microscale segmented gas–liquid flow at low superficial velocities relevant for chemical reactions with residence times of up to several minutes. Different gas–liquid microfluidic channel networks of rectangular cross section are fabricated in poly(dimethylsiloxane) (PDMS) using soft lithography techniques. The recirculation motion in the liquid segments associated with gas–liquid flows as well as the symmetry characteristics of the recirculations are quantified for straight and meandering channel networks. Even minor surface roughness effects and the compressibility of the gas phase induce loss of symmetry and enhance mixing across the centerline in straight channels. Mixing is further accelerated in meandering channels by the periodic switching of recirculation patterns across the channel center. We demonstrate a new, piezoelectrically activated flow injection technique for determining residence time distributions (RTDs) of fluid elements in multiphase microfluidic systems. The results confirm a narrowed liquid phase RTD in segmented flows in comparison to their single-phase counterparts. The enhanced mixing and narrow RTD characteristics of segmented gas–liquid flows are applied to liquid mixing and in sol–gel synthesis of colloidal nanoparticles.
Co-reporter:Sameer K. Ajmera, Cyril Delattre, Martin A. Schmidt, Klavs F. Jensen
Sensors and Actuators B: Chemical 2002 Volume 82(2–3) pp:297-306
Publication Date(Web):28 February 2002
DOI:10.1016/S0925-4005(01)01012-7
A novel silicon microfabricated chemical reactor has been developed for testing catalyst particles relevant to chemical process applications. The reactor incorporates a cross-flow design with a short pass multiple flow-channel geometry enabled by microfabrication technology. The cross-flow geometry minimizes pressure drop though the particle bed and yields reaction conditions desirable for the extraction of chemical kinetics. Flow distribution is achieved through an array of 256 shallow pressure drop channels that minimize the influence of the catalyst packing on the flow in the reactor. Combined experiments and modeling confirm the even distribution of flow across the wide catalyst bed with a pressure drop ∼1600 times smaller than typical microfabricated packed-bed configurations. Coupled with the inherent heat and mass transfer advantages at the sub-millimeter length scales achievable through microfabrication, the cross-flow microreactor, with an isobaric catalyst bed free of transport limitations, is an advantageous design for catalyst testing. Kinetic studies with carbon monoxide oxidation as a model reaction demonstrate the usefulness of the microreactor for testing catalysts. When instrumented with sensors, the silicon cross-flow microreactor provides the opportunity for parallel, high-throughput testing of heterogeneous catalysts.
Co-reporter:Hang Lu, Martin A. Schmidt and Klavs F. Jensen
Lab on a Chip 2001 vol. 1(Issue 1) pp:22-28
Publication Date(Web):09 Aug 2001
DOI:10.1039/B104037P
This work presents an application of microfabricated reactors and detectors for photochemical reactions. Two fabrication schemes were demonstrated for the integration of the reaction and the detection modules: coupling individually packaged chips, and monolithic integration of the two functions. In the latter fabrication scheme, we have succeeded in bonding quartz wafers to patterned silicon wafers at low temperature using a Teflon-like polymer—CYTOP™. Using quartz substrates allows reaction and detection with UV light of lower wavelengths than Pyrex substrates permit. The pinacol formation reaction of benzophenone in isopropanol was the model reaction to demonstrate the performance of the microreactors. The extent of reaction was controlled by varying the flow rate and therefore the on-chip residence time. Crystallization of the product inside the microreactors was avoided by the continuous-flow design. Instead, crystallization was observed in the effluent storage
device. Off-chip analysis using HPLC confirms the results obtained from the on-line UV spectroscopy. The quantum yield estimated suggests that the reactor design is effective in improving the overall efficiency of the reactor unit.
Co-reporter:Brian G. Willis, Klavs F. Jensen
Surface Science 2001 Volume 488(Issue 3) pp:286-302
Publication Date(Web):10 August 2001
DOI:10.1016/S0039-6028(01)01068-8
An experimental study of the growth chemistry of dimethylaluminum hydride (DMAH) has been performed to elucidate the reaction pathways underlying the growth of aluminum by chemical vapor deposition. Results find that DMAH grows clean aluminum films through a surface disproportionation mechanism, which produces trimethylaluminum (TMA) and hydrogen as byproducts. Effusive beam scattering and temperature programmed desorption experiments provide evidence that the growth mechanism proceeds through the adsorption and decomposition of DMAH into Al(CH3)2, Al(CH3), and CH3 surface species. TMA is produced via recombination reactions involving freely diffusing surface methyl groups as primary intermediates. At high temperatures (>560–600 K), these methyl groups undergo dehydrogenation reactions which lead to irreversible carbon contamination. This latter reaction pathway is proposed to be accompanied by methyl radical ejection reactions.
Co-reporter:Istvan Lengyel, Klavs F Jensen
Thin Solid Films 2000 Volume 365(Issue 2) pp:231-241
Publication Date(Web):17 April 2000
DOI:10.1016/S0040-6090(00)00758-6
We present a systematic approach to formulating chemical mechanisms to chemical vapor deposition processes with the unusually large growth rate enhancement observed for in situ B doping of Si as a case study. The basic computational tools needed for mechanism development; quantum chemistry calculations, sensitivity analysis, and finite element simulations are combined to develop a mechanism for the process and to provide quantitative predictions of observed growth and dopant incorporation rates. Ab initio quantum chemistry computations of small molecules and clusters relevant to the H–B–Cl–Si system are used to determine thermodynamic and kinetics parameters. Particular emphasis is given to Cl–H exchange reactions between borane and chlorosilanes, which are shown to proceed with low reaction barriers. The reaction mechanism is incorporated into finite element simulation of reported deposition data. The developed mechanism is capable of representing quantitatively: (a) the silicon deposition from dichlorosilane; (b) etching of silicon by HCl; and (c) B-doped Si deposition in the SiC12H2/B2H6/H2 deposition system. The most important deposition processes are identified by sensitivity analysis, and gas-phase decomposition reactions of dichlorosilane are shown to be insignificant in the deposition process.
Co-reporter:Masaya Hamano, Kevin D. Nagy and Klavs F. Jensen
Chemical Communications 2012 - vol. 48(Issue 15) pp:NaN2088-2088
Publication Date(Web):2012/01/04
DOI:10.1039/C2CC17123F
The metal free, direct oxidation of 2-, 3-, and 4-picoline to the corresponding carboxylic acid using either oxygen or air has been developed under continuous flow conditions. Complete conversion for all three substrates was obtained at moderate temperatures and pressures within minutes.
Co-reporter:Ye-Jin Hwang, Connor W. Coley, Milad Abolhasani, Andreas L. Marzinzik, Guido Koch, Carsten Spanka, Hansjoerg Lehmann and Klavs F. Jensen
Chemical Communications 2017 - vol. 53(Issue 49) pp:NaN6652-6652
Publication Date(Web):2017/05/25
DOI:10.1039/C7CC03584E
We report an automated flow chemistry platform that can efficiently perform a wide range of chemistries, including single/multi-phase and single/multi-step, with a reaction volume of just 14 μL. The breadth of compatible chemistries is successfully demonstrated and the desired products are characterized, isolated, and collected online by preparative HPLC/MS/ELSD.
Co-reporter:Víctor Sebastián, Seung-Kon Lee, Chao Zhou, Martin F. Kraus, James G. Fujimoto and Klavs F. Jensen
Chemical Communications 2012 - vol. 48(Issue 53) pp:NaN6656-6656
Publication Date(Web):2012/05/10
DOI:10.1039/C2CC32969G
We present a novel one-step flow process to synthesize biocompatible gold nanorods with tunable absorption and biocompatible surface ligands. Photothermal optical coherence tomography (OCT) of human breast tissue is successfully demonstrated using tailored gold nanorods designed to have strong absorption in the near-infrared range.
Co-reporter:Milad Abolhasani, Nicholas C. Bruno and Klavs F. Jensen
Chemical Communications 2015 - vol. 51(Issue 43) pp:NaN8919-8919
Publication Date(Web):2015/04/16
DOI:10.1039/C5CC02051D
A multi-phase flow strategy, based on oscillatory motion of a bi-phasic slug within a fluorinated ethylene propylene (FEP) tubular reactor, under inert atmosphere, is designed and developed to address mixing and mass transfer limitations associated with continuous slug flow chemistry platforms for studies of bi-phasic catalytic reactions. The technique is exemplified with C–C and C–N Pd catalyzed coupling reactions.
Co-reporter:Brandon J. Reizman and Klavs F. Jensen
Chemical Communications 2015 - vol. 51(Issue 68) pp:NaN13293-13293
Publication Date(Web):2015/07/22
DOI:10.1039/C5CC03651H
An automated, continuous flow droplet screening system is presented, enabling real-time simultaneous solvent and continuous variable optimization. An optimal design of experiments strategy is applied to the alkylation of 1,2-diaminocyclohexane in 16 μL droplets, with scale-up demonstrated. Analysis of segmented flow results suggests correlation of yield with solvent hydrogen bond basicity.
Co-reporter:Timothy Noël, John R. Naber, Ryan L. Hartman, Jonathan P. McMullen, Klavs F. Jensen and Stephen L. Buchwald
Chemical Science (2010-Present) 2011 - vol. 2(Issue 2) pp:NaN290-290
Publication Date(Web):2010/12/03
DOI:10.1039/C0SC00524J
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.
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