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Real time monitoring of chemical reactions has become a key step in industrial processes due to constantly increasing demands on product performance and environmental compatibility. In contrast to spectroscopic methods that usually require sample pretreatment, mass spectrometry (MS) has been proven as a robust method for multicomponent analysis. As an especially demanding reaction process, we here report successfully on the entirely contactless conduction and interrogation of a chemical reaction inside an acoustically levitated microliter droplet of reaction mixture. The approach represents a proof of concept study for fast reaction optimization approaches with minimal resource consumption. The sampling is done by repeated laser desorption of small fractions of the droplets volume spread over the timescale of the reaction process.
In many laser based ionization techniques with a subsequent drift time separation, the laser pulse generating the ions is considered as the start time t0. Therefore, an accurate temporal definition of this event is crucial for the resolution of the experiments. In this contribution, the laser induced plume dynamics of liquids evaporating into atmospheric pressure are visualized for two distinctively different laser pulse widths, Δt = 6 nanoseconds and Δτ = 280 microseconds. For ns-pulses the expansion of the generated vapour against atmospheric pressure is found to lead to turbulences inside the gas phase. This results in spatial and temporal broadening of the nascent clouds. A more equilibrated expansion, without artificial smearing of the temporal resolution can, in contrast, be observed to follow μs-pulse excitation. This leads to the counterintuitive finding that longer laser pulses results in an increased temporal vapour formation definition. To examine if this fume expansion also eventually results in a better definition of ion formation, the nascent vapour plumes were expanded into a linear drift tube ion mobility spectrometer (IMS). This time resolved detection of ion formation corroborates the temporal broadening caused by collisional impeding of the supersonic expansion at atmospheric pressure and the overall better defined ion formation by evaporation with long laser pulses. A direct comparison of the observed results strongly suggests the coexistence of two individual ion formation mechanisms that can be specifically addressed by the use of appropriate laser sources.
The upscaling from small scale academic reactors to large industrial processes typically suffers from a large change in surface-to-volume ratio. A promising approach is the general avoidance of surfaces as in levitated droplet techniques. However, up to now, no mass spectrometric interface for online reaction monitoring in levitated droplets has been provided.
As model reaction the photoinitiated thiol-ene coupling between N-boc cysteine methyl ester and allyl alcohol was studied. A droplet of 5 µL reactand solution was provisioned into an acoustic trap aligned lateral to the MS inlet. Contactless sampling by laser ablation (LA) is followed by dielectric barrier discharge (DBD) postionization. The latter is needed to address non polar reaction partners.
Matrix assisted laser desorption/ionization using liquid matrices and infrared laser irradiation (liquid IR-MALDI) is an attractive detection scheme since it enables a direct coupling to liquid chromatographic separation techniques.1 Albeit extensive studies have been targeted to achieve a more general understanding of the underlying ionization mechanism, the exact role of individual contributions, such as thermal vaporization, phase explosion or photoablation, could not be exhaustively identified.2 This contribution will present a direct comparison of ion mobility (IM) spectra obtained by utilizing an optical parametric oscillator and an Er:YAG laser, both operating at a central wavelength of = 2.94 µm, but with temporal pulse widths of 7 ns or several hundred µs, respectively. Thus, the resulting peak power of the Er:YAG laser is three orders of magnitude smaller than that of the OPO, however supplies a tenfold higher energy per pulse. In addition to the mere detection efficiencies, analysis of the IM spectrometric results gives insights into the initial solvation state of the formed ions. Accompanying high speed shadowgraphy imaging experiments contribute towards a better understanding of the involved liquid-gas phase transition dynamics.
Introduction
The list of applications for ion mobility spectrometry (IMS) is steadily growing quickened by advances in instrumental design, experimental methods and accompanying theory. The performance of IMS is greatly influenced by the ionization source and the introduction of the analyte, hence new ionization schemes and sampling strategies recently received particular interest.[1] An overall new approach is the coupling of IMS to an acoustically levitated droplet and combined sample desorption/ionization by a laser. In this setup the acoustically levitated droplet works as a wall-less micro reactor.[2] The latter opens the way towards quality control of fast reactions. Generally, the combination of acoustically levitated droplet and IMS bears a wide range of applications from routine analysis to microfluidic optimization of chemical reactions.
Experimental part
A novel coupling of an acoustically levitated droplet with a homebuilt drift tube ion mobility spectrometry is presented. A new prototype of inlet was customized according to design constrains yielding in maximum ion transmission. Moreover, the commonly used plate repeller was replaced with a point electrode to form a concentric electric field between the droplet and the IMS, geometrically allowing space for the acoustically levitated droplet. The desorption/ionization out of the droplet was performed with an optical parametric oscillator at 2,94 µm wavelength with pulse duration of FWHM = 7 ns. Primary evaluation of the setup was achieved using tetra-n-butylammonium bromide, promazine, perphenazine and L-arginine in direct comparison with the results obtained with a µdroplet IR-MALDI IMS.
Results and discussion
The coupling of acoustically levitated droplet with IMS was successfully realized giving further possibilities to utilize it as detection method to interrogate the fast kinetics of reactions preformed directly in the droplet. The presented modifications simplify the assembly of the setup and allow for a sufficient isolation between the high voltage, applied on the individual electrodes of the IMS, and the acoustic field sonotrode. The implemented point electrode produces a concentric steep potential field around the acoustically levitated droplet forcing the flow of nascent ions towards the drift tube inlet region. Additionally, it minimizes spatial restrictions giving space for a better accessibility for the sampling laser beam. The recorded ion mobility spectra confirm that the entire arrangement results in an efficient desorption, ionization and ion transfer of the sample liquid. First results show a sensitivity of the IMS comparable to that of the previously introduced µdroplet IR-MALDI. However the main advantage of acoustically levitated droplet is the reduction of long memory effect typically observed for the µdroplet source. These memory effects are attributed to wash-out times of the sample volume and to contamination of surfaces that get into contact with the sample. The contribution can therefore positively demonstrate that by avoiding sample-surface interfaces, the instrument response function can be drastically shortened. This not only significantly decreases the time necessary to clean the system between subsequent measurements but mostly opens the path towards fast kinetic monitoring of chemical reactions within the microdroplet reactors.
New aspects
The combination of acoustically levitated droplets and ion mobility separation provides a tool for direct online detection of reaction kinetics.
The carbon-sulfur bond is frequently occurring in natural products and pharmaceuticals. In a wide range of industrial applications such as polymers and bioorganic functionalization, biomaterials and nanostructured networks formation and microdevice fabrication the targeted construction of C-S bonds is being synthetically important.
The synthesis of thioethers is mainly conducted by radical thiol-ene click reactions typically initiated by thermal or UV activation of a radical initiator or direct radical formation via UV irradiation. The reported conversion yields are high after relatively short irradiation times, thus, a fast reaction monitoring is necessary to optimize reaction conditions in terms of total yield and occurrence of undesired by-products.
Especially for fast reactions, rapid response is the key feature for online monitoring. The latter gets increasingly important in process analytical approaches for quality assurance and to better control the conversion rate by feedback control. For a headspace analysis, gas detection methods like ion mobility spectrometry (IMS) and mass spectrometry (MS) are especially suitable to this aim since they provide response times in the ms - s range. Moreover, as complementary methods they provide comprehensive information about the molecule and it's structure. The aim of the work is to qualitatively interrogate the sample composition of a photocatalytically initiated thiol-ene coupling in real time. This contribution presents primary results of direct analysis of the photoinitiated synthesis of methyl 2-((tert-butoxycarbonyl)amino)-3-((3-hydroxypropyl)thio) propanoate by IMS and MS utilizing different ionization sources. The thiol-ene reaction is performed between N-Boc-cysteine methyl ester and allyl alcohol utilizing Ru(bpz)3(PF6)2 catalyst as a photoinitiator and p-toluidine as a redox mediator, irradiated at 450 nm according to the procedure presented in [2]. The obtained results were validated by NMR analysis unambiguously indicating the formation of the newly formed C-S bond and additionally providing total reaction yield calibration curves for a quantitative analysis.
Acoustically levitated droplets have been suggested as compartmentalized, yet wall-less microreactors for high-throughput reaction optimization purposes. The absence of walls is envisioned to simplify up-scaling of the optimized reaction conditions found in the microliter volumes. A consequent pursuance of high-throughput chemistry calls for a fast, robust and sensitive analysis suited for online interrogation. For reaction optimization, targeted Analysis with relatively low sensitivity suffices, while a fast, robust and automated sampling is paramount. To follow this approach, in this contribution, a direct coupling of levitated droplets to a homebuilt ion mobility spectrometer (IMS) is presented. The sampling, Transfer to the gas phase, as well as the ionization are all performed by a single exposure of the sampling volume to the resonant output of a mid-IR laser. Once formed, the nascent spatially and temporally evolving analyte ion cloud needs to be guided out of the acoustically confined trap into the inlet of the ion mobility spectrometer. Since the IMS is operated at ambient pressure, no fluid dynamic along a pressure Gradient can be employed. Instead, the transfer is achieved by the electrostatic potential gradient inside a dual ring electrode ion optics, guiding the analyte ion cloud into the first stage of the IMS linear drift tube accelerator. The design of the appropriate atmospheric pressure ion optics is based on the original vacuum ion optics design of Wiley and McLaren. The obtained experimental results nicely coincide with ion trajectory calculations based on a collisional model.
Driven mostly by the search for chemical syntheses under biocompatible conditions, so called "click" chemistry rapidly became a growing field of research. The resulting simple one-pot reactions are so far only scarcely accompanied by an adequate optimization via comparably straightforward and robust analysis techniques possessing short set-up times. Here, we report on a fast and reliable calibration-free online NMR monitoring approach for technical mixtures. It combines a versatile fluidic system, continuous-flow measurement of 1H spectra with a time interval of 20 s per spectrum, and a robust, fully automated algorithm to interpret the obtained data. As a proof-of-concept, the thiol-ene coupling between N-boc cysteine methyl ester and allyl alcohol was conducted in a variety of non-deuterated solvents while its time-resolved behaviour was characterized with step tracer experiments. Overlapping signals in online spectra during thiol-ene coupling could be deconvoluted with a spectral model using indirect hard modeling and were subsequently converted to either molar ratios (using a calibrationfree approach) or absolute concentrations (using 1-point calibration). For various solvents the kinetic constant k for pseudo-first order reaction was estimated to be 3.9 h-1 at 25 °C. The obtained results were compared with direct integration of non-overlapping signals and showed good agreement with the implemented mass balance.
Currently research in chemical manufacturing moves towards flexible plug-and-play approaches focusing on modular plants, capable of producing small scales on-demand with short down-times between individual cam-paigns. This approach allows for efficient use of hardware, a faster optimization of the process conditions, and thus, an accelerated introduction of new products to the market. Driven mostly by the search for chemical syntheses under biocompatible conditions, so-called “click” chemistry rapidly became a growing field of research. The re-sulting simple one-pot reactions are so far only scarcely accompanied by an adequate optimization via compara-bly straightforward and robust analysis techniques. Here we report on a fast and reliable calibration-free online high field NMR monitoring approach for technical mixtures. It combines a versatile fluidic system, continuous-flow measurement with a time interval of 20 s per spectrum, and a robust, automated algo-rithm to interpret the ob-tained data. All spectra were acquired using a 500 MHz NMR spectrometer (Varian) with a dual band flow probe having a 1/16 inch polymer tubing working as a flow cell. Single scan 1H spectra were recorded with an acquisition time of 5 s, relaxation delay of 15 s.
Currently, research in chemical manufacturing moves towards flexible plug-and-play approaches focusing on modular plants, capable of producing small scales on-demand with short down-times between individual campaigns. This approach allows for efficient use of hardware, a faster optimization of the process conditions, and thus, an accelerated introduction of new products to the market. Driven mostly by the search for chemical syntheses under biocompatible conditions, so-called “click” chemistry rapidly became a growing field of research. The resulting simple one-pot reactions are so far only scarcely accompanied by an adequate optimization via comparably straightforward and robust analysis techniques.
Here we report on a fast and reliable calibration-free online high field NMR monitoring approach for technical mixtures. It combines a versatile fluidic system, continuous-flow measurement with a time interval of 20 s per spectrum, and a robust, automated algorithm to interpret the obtained data. All spectra were acquired using a 500 MHz NMR spectrometer (Varian) with a dual band flow probe having a 1/16-inch polymer tubing working as a flow cell. Single scan 1H NMR spectra were recorded with an acquisition time of 5 s, relaxation delay of 15 s. As a proof-of-concept, the thiol-ene coupling between N-boc cysteine methyl ester and allyl alcohol was conducted in non-deuterated solvents while its time-resolved behaviour was characterised with step tracer experiments.
Through the application of spectral modeling the signal area for each reactant can be deconvoluted in the online spectra and thus converted to the respective concentrations or molar ratios. The signals which were suitable for direct integration were used herein for comparison purposes of both methods.