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Charged-microdroplet (a, c) and microfluidic (b, d) reaction telescoping for the diphenhydramine synthesis in two solvents (ACN, toluene).
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Mass spectrometry (MS) is used to follow chemical reactions in droplets. In almost all cases, such reactions are accelerated relative to the corresponding reactions in bulk, even after correction for concentration effects, and they serve to predict the likely success of scaled up reactions performed in microfluidic flow systems. The particular chem...
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Citations
... Modified mass spectrometry ionization sources, including electrospray (ESI) 6,15,33,35,38,39 , electrosonic spray ionization (ESSI) 2,3 , nano-electrospray ionization (nESI) 1,3 , easy ambient sonic-spray ionization (EASI) 40 , as well as desorption electrospray ionization DESI 13,41 , have been used to generate microdroplets for acceleration. Paper spray ionization (PSI) sources have also been used for reaction acceleration through thin films 17,32,42 . ...
Confined volume systems, such as microdroplets, Leidenfrost droplets, or thin films, can accelerate chemical reactions. Acceleration occurs due to the evaporation of solvent, the increase in reactant concentration, and the higher surface-to-volume ratios amongst other phenomena. Performing reactions in confined volume systems derived from mass spectrometry ionization sources or Leidenfrost droplets allows for reaction conditions to be changed quickly for rapid screening in a time efficient and cost-saving manner. Compared to solution phase reactions, confined volume systems also reduce waste by screening reaction conditions in smaller volumes prior to scaling. Herein, the condensation of glyoxal with benzylamine (BA) to form hexabenzylhexaazaisowurtzitane (HBIW), an intermediate to the highly desired energetic compound 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20), was explored. Five confined volume systems were compared to evaluate which technique was ideal for forming this complex cage structure. Substituted amines were also explored as BA replacements to screen alternative cage structure intermediates and evaluate how these accelerated techniques could apply to novel reactions, discover alternative reagents to form the cage compound, and improve synthetic routes for the preparation of CL-20. Ultimately, reaction acceleration is ideal for predicting the success of novel reactions prior to scaling up and determining if the expected products form, all while saving time and reducing costs. Acceleration factors and conversion ratios for each reaction were assessed by comparing the amount of product formed to the traditional bulk solution phase synthesis.
... The thermal decomposition of RDX during mass spectrometric analysis cannot be neglected since the chemical reaction rate in microdroplets (formed, for example, during the electrospray ionization) sharply increase (by several orders of magnitude) in comparison with the same reaction in volume (Lee et al. 2015;Yan, Bain, and Cooks 2016). On the other hand, microdroplets can be used as micro-reactors to study the mechanisms and kinetics of reactions (Wleklinski et al. 2016), which seems to be important because of RDX modification for military and civilian use. Using the aerodynamic thermal breakup droplets ionization, ATBDI (we renamed the aerodynamic breakup droplets ionization, ABDI because of the key role of thermal processes) many compounds can be analyzed directly from the solution and without electric fields applied (Pervukhin and Sheven 2018;Pervukhin and Sheven 2016;Pervukhin, Sheven, and Kolomiets 2015). ...
... This approach is suitable for many relatively stable molecules; however, we encountered difficulties in the analysis of RDX most likely due to the specific features of RDX described above. When using the ATBDI method, the thermal decomposition of RDX molecules inside the aerosol droplets occurs (i.e., in a limited volume) which is expected to accelerate the thermal degradation of RDX (Wleklinski et al. 2016). Such investigation is of interest considering the wide use, storage, inevitable problem of pollution with RDX. ...
The thermal decomposition of RDX in microdroplets in the heated capillary was investigated by Aerodynamic Thermal Breakup Droplet Ionization (ATBDI) mass spectrometry. The kinetic parameters of the thermal decomposition of RDX in water droplets were estimated. The suction capillary of the ATBDI setup was considered as a flow reactor of ideal displacement. In water droplets, the activation energy of the reaction turns out to be 2-4 times smaller than in the gas and bulk solution, indicating the catalytic role of droplets.
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... reaction acceleration to inform continuous-flow syntheses 6,[21][22][23] . We have recently reported an extension of this approach to a high throughput format using desorption electrospray ionization mass spectrometry (DESI-MS) 27 . ...
We demonstrate the use of accelerated reactions with desorption electrospray ionization mass spectrometry (DESI-MS) as a tool for predicting the outcome of microfluidic reactions. DESI-MS was employed as a high throughput experimentation tool to provide qualitative predictions of reaction outcomes, so that vast regions of chemical reactivity space may be more rapidly explored and areas of optimal efficiency identified. This work is part of a larger effort to accelerate reaction optimization to enable the rapid development of continuous-flow syntheses of small molecules in high yield. In order to build confidence in this approach, however, it is necessary to establish a robust predictive connection between reactions performed under analogous DESI-MS, batch, and microfluidic reaction conditions. In the present work, we explore the potential of high throughput DESI-MS experiments to identify trends in reactivity based on chemical structure, solvent, temperature, and stoichiometry that are consistent across these platforms. N-alkylation reactions were used as the test case due to their ease of reactant and product detection by electrospray ionization mass spectrometry (ESI-MS) and their great importance in API synthesis. While DESI-MS narrowed the scope of possibilities for reaction selection among some parameters such as solvent, others like stoichiometry and temperature still required further optimization under continuous synthesis conditions. DESI-MS high throughput experimentation (HTE) reaction evaluation significantly reduced the search space for flow chemistry optimization, thus representing a significant savings in time and materials to achieve a desired transformation with high efficiency.
... Correlation of the distance, tip diameter, and surfactant effects on droplet size, as measured by splash microscopy, provided a picture of microdroplet size effects on reaction acceleration. Initial data on the use of ambient ion focusing on acceleration were taken also, in view of the potential value of such focusing in increasing the scale on which organic synthesis might be performed using nESI sprays [22]. ...
Phenylhydrazone formation from isatin is used to examine the effects on the reaction rate of (i) electrospray emitter distance from the mass spectrometer (MS) inlet, (ii) emitter tip diameter, and (iii) presence of surfactant. Reaction rates are characterized through measurement of conversion ratios. It is found that there is an increase in the conversion ratio as (i) the electrospray source is moved further from the inlet of the mass spectrometer, (ii) smaller sprayer diameters are used, and (iii) when surfactants are present. Each of these experimental operations is associated with an increase in reaction rate and with a decrease in average droplet sizes. The size measurements are made using super resolution microscopy from the “splash” on a collector surface produced by a fluorescent marker sprayed using conditions similar to those used for the reaction mixture. This measurement showed that droplets undergo significant evaporation as a function of distance of flight, thereby increasing their surface to volume ratios. Similarly, the effect of nanoelectrospray emitter size on conversion ratio is also found to be associated with changes in droplet size for which a 4 to 10 times increase in reaction rate is seen using tip diameters ranging from 20 μm down to 1 μm. Finally, the effects of surfactants in producing smaller droplets with corresponding large increases in reaction rate are demonstrated by splash microscopy. These findings point to reaction acceleration being strongly associated with reactions at the surfaces of microdroplets.
... To contribute to the emerging field of accelerated droplet reaction screening [19][20][21][22] , the current study applies a theory-guided photoreaction screening approach to investigate the underlying mechanistic difference between the reactivity of THQ and THiQ. The ultimate objective is to identify green catalytic conditions that are directly transferable to bulk solution-phase for large scale synthesis. ...
Visible-light mediated aerobic dehydrogenation of N-heterocyclic compounds is a reaction with enormous potential for application. Herein, we report the first complete aerobic dehydrogenation pathway to large-scale production of isoquinolines. The discovery of this visible light photoredox reaction was enabled through the combination of mathematical simulations and real-time quantitative mass spectrometry screening. The theoretical calculations showed that hyper-conjugation, the main underlying factor hindering the aerobic oxidation of tetrahydroisoquinolines, is relieved both by π- and σ-donating substituents. This mechanistic insight provided a novel photocatalytic route based on N-substituted auxiliaries that facilitated the conversion of tetrahydroisoquinolines into the corresponding isoquinolines in just three simple steps (yield 71.7% in bulk-solution phase), using unmodified Ru(bpy)3Cl2 photocatalyst, sun energy, atmospheric O2, and at ambient temperature.
... Reaction acceleration in droplets can be used to guide chemistry at scale, and it can also be leveraged to acquire chemical information in a high-throughput format, for example, using a DESI-MS high-throughput system [30,32]. This system utilizes DESI as an ambient ionization technique for analysis of the products formed in secondary microdroplets. ...
Suzuki cross-coupling is a widely performed reaction, typically using metal catalysts under heated conditions. Acceleration of the Suzuki cross-coupling reaction has been previously explored in microdroplets using desorption electrospray ionization mass spectrometry (DESI-MS). Building upon previous work, presented here is the use of a high-throughput DESI-MS screening system to identify optimal reaction conditions. Multiple reagents, bases, and stoichiometries were screened using the automated system at rates that approach 10,000 reaction mixture systems per hour. The DESI-MS system utilizes reaction acceleration in microdroplets to allow rapid screening. The results of screening of an array of reaction mixtures using this technique are presented as product ion images via standard MS imaging software, facilitating quick readout. Instructive comparisons are provided with another method of generating droplets for reaction acceleration—the Leidenfrost technique. Acceleration factors greater than 200 were measured for brominated substrates, paralleling the DESI-MS results. Acceleration factors dropped to near unity with highly substituted pyridines, attributable to a steric effect. The reaction proceeded in the absence of a base in Leidenfrost droplets although no product formation was seen without base in the bulk or in the DESI-MS screening experiments. These differences between Leidenfrost chemistry and the bulk and in droplets formed in high-throughput DESI are tentatively attributed to extremes of pH associated with the surfaces of Leidenfrost droplets.
... Droplet microfluidics is also a perfect tool to investigate the chemical communication of compartments comprising chemical oscillators such as the Belousov-Zhabotinsky reaction (Guzowski et al., 2016). An excellent overview of the various reactions performed in microdroplets can be found in a review by Elvira (Elvira et al., 2013) as well as in more recent publications (Guardingo et al., 2016;Wleklinski et al., 2016). ...
Emulsion—a liquid dispersed in another liquid—is in many respects very similar to granular matter. In the early 2000s a new technology—droplet microfluidics—began emerging from the wider field of microfluidics. Droplet microfluidics was quickly established as a discipline of science and engineering and has been used for the generation of highly uniform emulsions. The last few years have brought significant advances to the field, directed towards a wide range of applications in material sciences—from synthesis of nanoparticles in droplets to assembling complex droplets and using droplets as templates for ordered materials, with applications in food, cosmetic and diagnostic industries. Droplet microfluidic platforms are also successfully used as analytical tools in molecular biology and biochemistry, in e.g. high-throughput screening, digital assays, encapsulation of single cells, sequencing technologies, and in point-of-care diagnostic applications. This article provides an accessible overview of the physical phenomena observed in multiphase flow at the microscale and the techniques in droplet microfluidics systems. We also present the most interesting applications and potential further directions of research in this fascinating young field of science and engineering.
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... Recently, Wleklinski et al. developed a high throughput screening platform taking advantage of the accelerated reactions in microdroplets phenomenon (Yan et al., 2016), coupled with desorption electrospray ionization mass spectrometry (DESI-MS) (Wleklinski et al., 2016). DESI-MS is an ambient ionization technique originally applied to the analysis of samples on surfaces (Eberlin et al., 2011) whereby charged droplets are used to create a microfilm where analytes from a surface are desorbed and directed to the inlet of a mass spectrometer such as an ion-trap (Cooks et al., 2006). ...
... DESI-MS is an ambient ionization technique originally applied to the analysis of samples on surfaces (Eberlin et al., 2011) whereby charged droplets are used to create a microfilm where analytes from a surface are desorbed and directed to the inlet of a mass spectrometer such as an ion-trap (Cooks et al., 2006). This concept was employed in the analysis of organic reactions by depositing an array of up to 6144 spots containing reaction mixtures onto a polytetrafluoroethylene (PTFE) substrate, that were then desorbed rapidly for MS analysis at a rate of one second/spot (Wleklinski et al., 2016). Specifically, these ''spotted" reaction mixtures are sprayed with pneumatically accelerated (N 2 gas at 120 psi) and the charged solvent droplets such that the mixtures were desorbed at ambient temperature and pressure. ...
... Multistep organic synthesis involves a sequence of reactions from starting materials to product, frequently with use of column chromatography or other means to purify intermediates [1]. There are many possible reaction routes to any one desired product or intermediate, and cost, time, and yield are criteria in choosing the best synthetic route [2]. Throughout a multistep synthesis, functional groups may need to be conserved. ...
... We explore the use of a spray-based method to accelerate the deprotection of an amine in this laboratory exercise. Specifically, the deprotection of Boc-Ala-OH (1) by acid to produce free Ala-OH (2). The deprotection occurs by initial protonation of the tert-butyl carbamate and subsequent loss of the cationic butyl group as the carboxylic acid with production of the free amine. ...
... Reaction rate acceleration has been demonstrated using online mass spectrometric analysis of reaction mixtures ionized by electrospray ionization and other spray-based ionization methods [2,[18][19][20][22][23][24][25]. This phenomenon has been highlighted in recent reviews [21,26,27]. ...
... This limitation and the advantages of rapid synthesis development and the efficiency of a combined reactor and analytical system have been investigated and discussed. 47 In this study the question of whether the droplet reactor can be used to predict chemical reactivity in flow chemistry (microfluidic) systems has been discussed in detail and evaluated using several reactions. The authors clearly recognize that it may not be possible to transfer fully optimized reaction conditions from the droplet reactor to microfluidic scale. ...
The application of on-line mass spectrometry for direct analysis of chemical and other
types of process continues to grow in importance and impact. The ability of the
technique to characterize many aspects of a chemical reaction such as product and
impurity formation, along with reactant consumption in a single experiment is key to its
adoption and development. Innovations in ionization techniques and mass spectrometry
instrumentation are enabling this adoption. An increasing range of ambient
ionization techniques make on-line mass spectrometry applicable to a large range of
chemistries. The academic development and commercialization of small footprint
portable/transportable mass spectrometers is providing technology that can be
positioned with any process under investigation. These developments, coupled with
research into new ways of sampling representatively from both the condensed and
gaseous phases, are positioning mass spectrometry as an essential technology for online
process optimization, understanding and intelligent control. It is recognized that
quantitative capability of mass spectrometry in this application can cause some
resistance to its adoption, but research activities to tackle this limitation are on-going.
