Simultaneous solvent screening and reaction optimization in microliter slugs.

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.

[1]  M. Mrksich,et al.  Three-Component Reaction Discovery Enabled by Mass Spectrometry of Self-Assembled Monolayers , 2011, Nature Chemistry.

[2]  M. Berthelot,et al.  THE HYDROGEN-BOND BASICITY PKHB SCALE OF PEROXIDES AND ETHERS , 1998 .

[3]  J. Gal,et al.  Lewis Basicity and Affinity Scales: Data and Measurement , 2010 .

[4]  Kendall N Houk,et al.  Rapid catalyst identification for the synthesis of the pyrimidinone core of HIV integrase inhibitors. , 2012, Angewandte Chemie.

[5]  István T. Horváth,et al.  Handbook of fluorous chemistry , 2004 .

[6]  J. Legros,et al.  Selective monomethylation of primary amines with simple electrophiles. , 2014, Chemical Communications.

[7]  Helen Song,et al.  Experimental test of scaling of mixing by chaotic advection in droplets moving through microfluidic channels. , 2003, Applied physics letters.

[8]  Kenneth J. Beers Numerical Methods for Chemical Engineering: Applications in MATLAB , 2006 .

[9]  Dong‐Pyo Kim,et al.  Efficient and continuous monoacylation with superior selectivity of symmetrical diamines in microreactors. , 2012, Lab on a chip.

[10]  M. Gandelman,et al.  Design and Development of Bioinspired Guanine‐Based Organic Catalyst for Asymmetric Catalysis , 2012 .

[11]  Shun Su,et al.  Discovery of chemical reactions through multidimensional screening. , 2007, Journal of the American Chemical Society.

[12]  Klavs F. Jensen,et al.  Automated Multitrajectory Method for Reaction Optimization in a Microfluidic System using Online IR Analysis , 2012 .

[13]  Ryan L. Hartman,et al.  Deciding whether to go with the flow: evaluating the merits of flow reactors for synthesis. , 2011, Angewandte Chemie.

[14]  Klavs F Jensen,et al.  An integrated microreactor system for self-optimization of a Heck reaction: from micro- to mesoscale flow systems. , 2010, Angewandte Chemie.

[15]  N. Finney,et al.  An efficient method for the preparation of N,N-disubstituted 1,2-diamines , 2000 .

[16]  Helen Song,et al.  Formation of droplets and mixing in multiphase microfluidics at low values of the Reynolds and the capillary numbers , 2003 .

[17]  J. Gawroński,et al.  Facile monoprotection of trans-1,2-diaminocyclohexane , 2003 .

[18]  K. W. Jung,et al.  Cesium effect: high chemoselectivity in direct N-alkylation of amines. , 2002, The Journal of organic chemistry.

[19]  Tae Gyu Lee,et al.  Liquid–Liquid Equilibria for the Ternary Systems of Perfluorohexane or Perfluamine + Hydrofluoroether + Tetrahydrofuran at 298.15 K or 273.15 K , 2013 .

[20]  John R. Goodell,et al.  Development of an automated microfluidic reaction platform for multidimensional screening: reaction discovery employing bicyclo[3.2.1]octanoid scaffolds. , 2009, The Journal of organic chemistry.

[21]  A. Yudin,et al.  Chemoselectivity and the curious reactivity preferences of functional groups. , 2010, Angewandte Chemie.

[22]  Paul J van Maaren,et al.  Thermodynamics of hydrogen bonding in hydrophilic and hydrophobic media. , 2006, The journal of physical chemistry. B.

[23]  Jonathan P. McMullen,et al.  An Automated Microfluidic System for Online Optimization in Chemical Synthesis , 2010 .

[24]  Ian W Davies,et al.  Looking Forward in Pharmaceutical Process Chemistry , 2009, Science.

[25]  Srinivas Tummala,et al.  Emerging technologies supporting chemical process R&D and their increasing impact on productivity in the pharmaceutical industry. , 2006, Chemical reviews.

[26]  Delai L Chen,et al.  Microgram-scale testing of reaction conditions in solution using nanoliter plugs in microfluidics with detection by MALDI-MS. , 2006, Journal of the American Chemical Society.

[27]  M. Berthelot,et al.  HYDROGEN-BOND BASICITY OF ESTERS, LACTONES AND CARBONATES , 1994 .

[28]  M. Berthelot,et al.  Hydrogen-bond basicity of secondary and tertiary amides, carbamates, ureas and lactams , 1992 .

[29]  Christopher K Prier,et al.  Discovery of an α-Amino C–H Arylation Reaction Using the Strategy of Accelerated Serendipity , 2011, Science.

[30]  M. Berthelot,et al.  HYDROGEN-BOND BASICITY PKHB SCALE OF SIX-MEMBERED AROMATIC N-HETEROCYCLES , 1998 .

[31]  Jason E. Kreutz,et al.  Evolution of catalysts directed by genetic algorithms in a plug-based microfluidic device tested with oxidation of methane by oxygen. , 2010, Journal of the American Chemical Society.

[32]  Abigail G Doyle,et al.  Small-molecule H-bond donors in asymmetric catalysis. , 2007, Chemical reviews.

[33]  Biao Xu,et al.  A chiral primary-tertiary-1,2-diamine as an efficient catalyst in asymmetric aldehyde–ketone or ketone–ketone aldol reactions , 2013 .

[34]  M. Berthelot,et al.  The first basicity scale of fluoro-, chloro-, bromo- and iodo-alkanes: some cross-comparisons with simple alkyl derivatives of other elements , 1999 .

[35]  Brandon J. Reizman,et al.  An Automated Continuous-Flow Platform for the Estimation of Multistep Reaction Kinetics , 2012 .

[36]  M. Berthelot,et al.  The first measurement of the hydrogen bond basicity of monomeric water, phenols and weakly basic alcohols , 1989 .

[37]  John F. Hartwig,et al.  A Simple, Multidimensional Approach to High-Throughput Discovery of Catalytic Reactions , 2011, Science.

[38]  David R. Liu,et al.  Reaction discovery enabled by DNA-templated synthesis and in vitro selection , 2004, Nature.

[39]  David R. Liu,et al.  A Biomolecule-Compatible Visible Light-Induced Azide Reduction from a DNA-Encoded Reaction Discovery System , 2010, Nature chemistry.

[40]  Scot Mente,et al.  Measurement of atropisomer racemization kinetics using segmented flow technology. , 2012, ACS medicinal chemistry letters.

[41]  C. Laurence,et al.  Lewis Basicity and Affinity Scales , 2009 .

[42]  Ryan L Hartman,et al.  Microchemical systems for continuous-flow synthesis. , 2009, Lab on a chip.

[43]  Frank Glorius,et al.  A robustness screen for the rapid assessment of chemical reactions , 2013, Nature Chemistry.

[44]  Tae Gyu Lee,et al.  Liquid–Liquid Equilibria for the Ternary Systems of Perfluorohexane + Methyl Nonafluorobutyl Ether + Toluene, + 1,4-Dioxane, or + Dimethylformamide at 298.15 K , 2013 .

[45]  Axel Günther,et al.  Sample dispersion for segmented flow in microchannels with rectangular cross section. , 2008, Analytical chemistry.

[46]  C Scott Shultz,et al.  Unlocking the potential of asymmetric hydrogenation at Merck. , 2007, Accounts of chemical research.

[47]  David R. Liu,et al.  Development and initial application of a hybridization-independent, DNA-encoded reaction discovery system compatible with organic solvents. , 2007, Journal of the American Chemical Society.

[48]  A. deMello,et al.  Droplet microfluidics: recent developments and future applications. , 2011, Chemical communications.

[49]  Christian Laurence,et al.  Observations on the strength of hydrogen bonding , 2000 .