Synthesis of S(IV)-Stereogenic Chiral Thio-Oxazolidinones via Palladium-Catalyzed Asymmetric [3+2] Annulations.

Organic molecules bearing chiral sulfur stereocenters exert a great impact on asymmetric catalysis and synthesis, chiral drugs, and chiral materials. Compared with acyclic ones, the catalytic asymmetric synthesis of thio-heterocycles has largely lagged behind due to the lack of efficient synthetic strategies. Here we establish the first modular platform to access chiral thio-oxazolidinones via Pd-catalyzed asymmetric [3+2] annulations of vinylethylene carbonates with sulfinylanilines. This protocol is featured by readily available starting materials, and high enantio- and diastereoselectivity. In particular, an unusual effect of a non-chiral supporting ligand on the diastereoselectivity was observed. Possible reaction mechanisms and stereocontrol models were proposed.

Research Progress on Machine Learning Assisted Non-Targeted Screening Strategy for Identification of Fentanyl Analogs.

In recent years, the types and quantities of fentanyl analogs have increased rapidly. It has become a hotspot in the illicit drug control field of how to quickly identify novel fentanyl analogs and to shorten the blank regulatory period. At present, the identification methods of fentanyl analogs that have been developed mostly rely on reference materials to target fentanyl analogs or their metabolites with known chemical structures, but these methods face challenges when analyzing new compounds with unknown structures. In recent years, emerging machine learning technology can quickly and automatically extract valuable features from massive data, which provides inspiration for the non-targeted screening of fentanyl analogs. For example, the wide application of instruments like Raman spectroscopy, nuclear magnetic resonance spectroscopy, high resolution mass spectrometry, and other instruments can maximize the mining of the characteristic data related to fentanyl analogs in samples. Combining this data with an appropriate machine learning model, researchers may create a variety of high-performance non-targeted fentanyl identification methods. This paper reviews the recent research on the application of machine learning assisted non-targeted screening strategy for the identification of fentanyl analogs, and looks forward to the future development trend in this field.

Structural Analysis and Characterization of 4-F-α-PVP Analog 4-F-3-Methyl-α- PVP Hydrochloride.

OBJECTIVES: To identify 1-(4-fluorophenyl)-2-(1-pyrrolidinyl) pentan-1-one (4-F-α-PVP) analog 1-(4-fluoro-3-methyl phenyl)-2-(1-pyrrolidinyl) pentan-1-one (4-F-3-Methyl-α-PVP) hydrochloride without reference substance. METHODS: The direct-injection electron ionization-mass spectrometry (EI-MS), GC-MS, electrospray ionization-high resolution mass spectrometry (ESI-HRMS), ultra-high performance liquid chromatography-high resolution tandem mass spectrometry (UPLC-HRMS/MS), nuclear magnetic resonance (NMR), ion chromatography and Fourier transform infrared spectroscopy (FTIR) were integrated utilized to achieve the structural analysis and characterization of the unknown compound in the sample, and the cleavage mechanism of the fragment ions was deduced by EI-MS and UPLC-HRMS/MS. RESULTS: By analyzing the direct-injection EI-MS, GC-MS, ESI-HRMS and UPLC-HRMS/MS of the compound in the samples, it was concluded that the unknown compound was a structural analog of 4-F-α-PVP, possibly with one more methyl group in the benzene ring. According to the analysis results of 1H-NMR and 13C-NMR, it was further proved that the methyl group is located at the 3-position of the benzene ring. Since the actual number of hydrogen in 1H-NMR analysis was one more than 4-F-3-Methyl-α-PVP neutral molecule, it was inferred that the compound existed in the form of salt. Ion chromatography analysis results showed that the compound contained chlorine anion (content 11.14%-11.16%), with the structural analysis of main functional group information by FTIR, the unknown compound was finally determined to be 4-F-3-Methyl-α-PVP hydrochloride. CONCLUSIONS: A comprehensive method using EI-MS, GC-MS, ESI-HRMS, UPLC-HRMS/MS, NMR, ion chromatography and FTIR to identify 4-F-3-Methyl-α-PVP hydrochloride in samples is established, which will be helpful for the forensic science laboratory to identify this compound or other analog compounds.

Chloramine-T-Enabled Mass Spectrometric Analysis of C═C Isomers of Unsaturated Fatty Acids and Phosphatidylcholines in Human Thyroids.

Specific locations of carbon-carbon double bonds (C═C) in lipids often play an essential role in biological processes, and there has been a booming development in C═C composition analysis by mass spectrometry. However, a universal derivatization and fragmentation pattern for the annotation of C═C positions in lipids is still challenging and attractive. To expand this field in lipidomics, a flexible and convenient N-tosylaziridination method was developed, with high derivatization efficiency, sensitivity, and specificity. The derivatization was very fast (15 s), and C═C numbers as well as locations could be pinpointed specifically in tandem mass spectra. By qualitative and quantitative studies of paratumor and tumor thyroid tissues of human beings, the total content of unsaturated fatty acids was suggested to be increased in tumor tissues, and good correlations in and between lysophosphatidylcholines and phosphatidylcholines were revealed by Spearman analysis. Further studies of C═C isomers showed that n-6/n-3 ratios were closely associated with human thyroid tumorigenesis, and high ratios of n-6/n-3 isomers seemed to suffer a high risk of carcinogenesis. Other isomers were not very representative; however, C═C in n-9/n-7 could also be significant for oncology research. Generally, it is supposed that both total amounts and C═C isomer ratios were related to cancer, and N-tosylaziridine derivatization could provide an alternative strategy for the C═C isomer study of disease models.

Analysis of the Amine Submetabolome Using Novel Isotope-Coded Pyrylium Salt Derivatization and LC-MS: Herbs and Cancer Tissues as Cases.

The amine submetabolome, including amino acids (AAs) and biogenic amines (BAs), is a class of small molecular compounds exhibiting important physiological activities. Here, a new pyrylium salt named 6,7-dimethoxy-3-methyl isochromenylium tetrafluoroborate ([d0]-DMMIC) with stable isotope-labeled reagents ([d3]-/[d6]-DMMIC) was designed and synthesized for amino compounds. [d0]-/[d3]-/[d6]-DMMIC-derivatized had a charged tag and formed a set of molecular ions with an increase of 3.02 m/z and the characteristic fragment ions of m/z 204.1:207.1:210.1. When DMMIC coupled with liquid chromatography-mass spectrometry (LC-MS), a systematic methodology evaluation for quantitation proved to have good linearity (R2 between 0.9904 and 0.9998), precision (interday: 2.2-21.9%; intraday: 1.0-19.7%), and accuracy (recovery: 71.8-108.8%) through the test AAs. Finally, the methods based on DMMIC and LC-MS demonstrated the advantaged application by the nontargeted screening of BAs in a common medicinal herb Senecio scandens and an analysis of metabolic differences among the amine submetabolomes between the carcinoma and paracarcinoma tissues of esophageal squamous cell carcinoma (ESCC). A total of 20 BA candidates were discovered in S. scandens as well as the finding of 13 amine metabolites might be the highest-potential differential metabolites in ESCC. The results showed the ability of DMMIC coupled with LC-MS to analyze the amine submetabolome in herbs and clinical tissues.

Chiral Analysis of Lactate during Direct Contact Coculture by Single-Cell On-Probe Enzymatic Dehydrogenation Derivatization: Unraveling Metabolic Changes Caused by d-Lactate.

In vitro noncontact cell-based coculture models are frequently employed to study cell-to-cell communication. However, these models cannot accurately represent the complexity of in vivo signaling. d-Lactate is an unusual metabolite produced and released by cancer cells. The characterization of d-lactate is challenging as it shares the same mass but has much lower amounts compared with l-lactate. Herein, d-α-hydroxy acids were specifically recognized and dehydrogenated by d-α-hydroxy acid dehydrogenase. The dehydrogenation products were rapidly quaternized for enhancement of mass signals. An on-probe enzymatic dehydrogenation-derivatization method was proposed for chiral analysis of α-hydroxy acids at the single-cell level. It is a promising amplification methodology and affords over 3 orders of magnitude signal enhancement. Furthermore, direct contact coculture models were used to precisely mimic the tumor microenvironment and explore the communication between cancer and normal cells. Single-cell mass spectrometry (SCMS) was further applied to easily sample cell extracts and study the differences of the aspects of small molecule metabolism in cocultured cells. On the basis of direct contact coculture SCMS, several differential small molecule metabolites and differences of oxidative stress between cocultured and monocultured normal cells were successfully detected. Additionally, d-lactate was discovered as a valuable differential metabolite with application of the two developed methods. It may account for the cancer-associated metabolic behavior of normal cells. These changes could be relieved after d-lactate metabolism-related drug treatment. This discovery may promote the investigation of d-lactate metabolism, which may provide a novel direction for cancer therapy.

Rapid Characterization of Polymer Materials Using Arc Plasma-Based Dissociation-Mass Spectrometry.

Fingerprinting spectra of polymer materials containing information of monomers' molecular weight and detailed structure, constituents, and sequences were obtained by a direct analytical process using arc plasma-based dissociation (APD)-mass spectrometry. The thermal arc plasma generated using a simple arc discharge device induces the dissociation of the polymeric backbone, producing mass spectra with strong regularity within seconds. The molecular weight of the repeating unit was revealed by equal intervals between peak series and protonated monomer ions in the mass spectra. Meanwhile, lots of secondary fragment ions were produced to provide abundant structural information. For polyethers, it is even possible to decipher (read) the "sequence" directly from their spectra. Polymers composed of isomers or only differing in their initiator moieties were easily distinguished with their characteristic APD mass spectra. The spectra were highly reproducible according to the results of similarity calculation. Unlike pyrolysis mass spectrometry, in the APD device, polymers in liquid, solid, powder, and crude samples can be analyzed directly without any pretreatment, and the regular spectra are easier to interpret. Compared with other direct analytical methods, more structural informative spectra can be acquired owing to the high energy, high temperature, and unique chemical reactivity of arc plasma. Thus, this technique is promising to be a valuable tool in rapid elucidation of polymer materials.

Single-Cell On-Probe Derivatization-Noncontact Nanocarbon Fiber Ionization: Unraveling Cellular Heterogeneity of Fatty Alcohol and Sterol Metabolites.

Currently in single-cell mass spectrometry, the analysis of low-abundance cell metabolites such as fatty alcohols and sterols remains a challenge. In most research studies, single-cell samples are analyzed directly after sampling. However, this workflow may exclude many effective sample pretreatment methods such as derivatization for the improvement of detection sensitivity for specific cell metabolites in a single-cell sample. Metabolites in low abundance in a cell may not be detected. Herein on-probe derivatization coupled with noncontact nanocarbon fiber ionization is proposed for sensitive fatty alcohol and sterol metabolite analysis at the single-cell level. Fatty alcohol and sterol metabolites were rapidly quaternized by the single-cell on-probe derivatization method. The reaction products were directly ionized with no postreaction processing. Furthermore, a new ionization source for noncontact nanocarbon fiber ionization was developed to show good compatibility with dichloromethane, a low-polarity solvent used in on-probe derivatization. The quaternized fatty alcohols and sterols exhibited evidently enhanced ionization efficiency in mass spectra. In applications of the developed method, seven kinds of even-numbered-carbon fatty alcohols (C12-C22) and five kinds of sterols were detected in single L-02 and HepG2 cells. Then the L-02 and HepG2 cells were readily discriminated through principal component analysis. Additionally, a rough quantitative analysis of the detected fatty alcohols and sterols in single cells was performed. The mass intensities of fatty alcohols show a significant difference between L-02 and HepG2 cells while those of sterols remain stable.

Arc Plasma-Based Dissociation Device: Fingerprinting Mass Spectrometric Analysis Realized at Atmospheric Condition.

Fingerprinting mass spectrometric analysis at atmospheric conditions has been realized using an arc plasma-based dissociation (APD) device. Because of its high energy, high temperature, and unique chemical reactivity, the thermal plasma can induce dissociation of neutral molecules or ions produced by atmospheric ion sources. Both even/odd electron (fragment) ions would be generated to provide fingerprinting structural information and molecular weight of the compounds simultaneously. Meanwhile, elimination and aromatization were observed as special dissociation patterns in this device, which can be applied in the differentiation of isomers. The good compatibility with atmospheric ion sources is demonstrated by coupling the device with nanoelectrospray ionization (nano-ESI) and zero volt paper spray ionization (PSI), respectively. With erythromycin as the tuning standard, informative dissociation spectra of various compounds can be reproducible, making it possible to establish an arc plasma-based dissociation spectra database. This device allows fingerprinting mass spectrometric analysis, with no need for harsh vacuum conditions and is promising for making a breakthrough in making up the deficiency of atmospheric ionization techniques.

Mass Spectrometry-Based Discovery of New Chemical Scaffold Rearrangement Ions: Aza-biphenylene as a Novel Potent Biradical Agent in Cancer Chemotherapy.

Discovery of a new drug is time-consuming, laborious, and expensive. Herein, a novel integrative strategy for discovering potential new lead compounds has been developed, which was based on the characteristics of mass spectrometry (MS). MS was used to predict the potential forced degradation products (DPs) and metabolites of drugs by electrospray ionization and collision-induced dissociation (CID). Special rearrangement ions representing unique predicted DPs and metabolites were identified. The consistency between the predicted and the measured results was proven by in vitro metabolism and forced degradation of a commercial drug, respectively. From this, new chemical scaffold rearrangement ions named (aza)-biphenylenes, as potent anticancer agents, were discovered. As a representative aza-biphenylene analogue, 2-azabiphenylene was proven in vitro to induce apoptosis and inhibit the growth of various human cancer cells in a dose-dependent manner. Surprisingly, 2-azabiphenylene exhibited the best comparable bioactivity with the positive control sorafenib, but showed significantly lower in vitro cytotoxicity than sorafenib (at least a 5-fold decrease in cytotoxicity) because it could be targeted to the tumor microenvironment at low pH. A biradical mechanism accompanied by a mitochondrion-dependent oxidative stress mechanism was proposed to explore its anticancer mechanism. The highly reactive intermediate aza-biphenylenediyl worked as an active pharmaceutical ingredient and induced apoptosis of cancer cells. This provided the basis for the potential applications of CID-induced special rearrangement ions in developing new lead compounds.

Asymmetric Dearomatization of Indole by Palladium/PC-Phos-Catalyzed Dynamic Kinetic Transformation.

A palladium-catalyzed intermolecular dynamic kinetic asymmetric dearomatization of 3-arylindoles with internal alkynes was developed with the use of achiral Xantphos and chiral sulfinamide phosphine ligand (PC-Phos) as the co-ligands. This method could deliver various spiro[indene-1,3'-indole] compounds in good yields (up to 95 % yield) with up to 98 % ee. The salient features of the transformation include the use of readily available substrates, ease of scale-up and the versatile functionalization of the products. The mechanistic experiments gave some insights on active intermediates.

Quantitative Analysis of Metabolites at the Single-Cell Level by Hydrogen Flame Desorption Ionization Mass Spectrometry.

To date, direct quantitation of cellular metabolites at the picoliter level or in a single cell is still a challenge due to tiny sampling materials, the accuracy of the sampling volume, and the ubiquitous matrix effect. Herein, picoliter magnitude quantitative analysis was performed using a pressure-assisted microsampling probe coupled to the hydrogen flame desorption ionization mass spectrometer (HFDI-MS). The sampling was accurately controlled with a picoliter pump, and the analytes were rapidly vaporized and quantitatively transferred to the gas phase by adequate heat. The vapor-phase analytes reacted with protonated water cluster ions by the proton-transfer reaction (PTR). The accurate sampling, flash thermal desorption, and proton-transfer ionization processes were conducted spatiotemporally, which could greatly reduce matrix effects to facilitate the quantitation of analytes without the internal standard. Furthermore, this workflow enabled the quantitation of cellular metabolites at the picoliter/single-cell level.

Derivatization Strategy for Simultaneous Molecular Imaging of Phospholipids and Low-Abundance Free Fatty Acids in Thyroid Cancer Tissue Sections.

Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) has been applied in many fields for detecting and imaging a variety of metabolites. In cancer research, this fast-growing imaging method also helps to elucidate the connection between the changes of metabolites in the microenvironment and the proliferation and survival of cancer cells. Free fatty acids (FFAs) are a vital building block of phospholipids (PLs) that can serve as a second cellular messenger and provide nutrients in the cancer microenvironment. The metabolism process of FFAs and PLs is highly relevant to the initiation and progression of different cancers. To better understand the metabolism process in cancer tissues, simultaneously detecting and imaging FFAs and PLs is essential. Despite the crucial developments that have been performed in the field of lipids imaging, FFAs and PLs have rarely been detected and imaged simultaneously in positive ion mode with good detection sensitivity. In this work, an on-tissue derivatization method was used to add a permanently quaternary amine onto FFAs; then, the FFAs and PLs were simultaneously imaged in positive ion mode. The derivatized FFAs are suitable for detection in positive ion mode. In comparison with the traditional matrix and the previous derivatization method, our derivatization reagent has a higher sensitivity for imaging FFAs. In addition, for simultaneous imaging analysis of FFAs and PLs, the number of imaged FFAs and PLs is greater than that with the previous on-tissue derivatization method. This high-sensitivity on-tissue derivatization method was applied to detect and image PLs and fatty acids in thyroid cancer tissues. In the MSI experiment, FFA derivatives and PLs were imaged while molecular localization and tissue integrity were maintained. Meanwhile, the correlation between PLs and FFAs was also studied, and the results showed that the correlations between saturated FFAs of C16:0 and C18:0 and PLs are better than the correlations of unsaturated FFAs with PLs.

Validating an ion mobility spectrometry-quadrupole time of flight mass spectrometry method for high-throughput pesticide screening.

The utility of adding ion mobility (IM) to quadrupole time of flight mass spectrometry (IM-QTOF MS) for highly effective analysis of multiple pesticides in complex matrices was evaluated. Based on an in-house IM-MS database, the identification was performed through the match of the protonated ion ([M + H]+) and the CCS value. Moreover, the structural confirmation was achieved by using the accurate masses of [M + H]+ with its fragment ions, and the reference CCS value. The method did not require chromatographic separation and the analysis time of each measurement cycle is 1.6 min. The "cleaned" IM-MS spectra afforded by the drift time filtration improved the reliability of structural confirmation. As a result, the limit of detection (LOD) of 92% of test pesticides under the APCI mode and 58% of test pesticides under the ESI mode spiked in scallion was not more than 20 ng mL-1. In the analysis of practical samples, the identification of pyrimethanil was confirmed in celery, and benalaxyl and tebuconazole were identified as false positives in scallion. The time-saving, extended-scope and high-throughput method described in this work is capable of determining multiple pesticide residues in complex matrices with high sensitivity for monitoring applications.

Stereodivergent Synthesis of Tetrahydrofuroindoles through Pd-Catalyzed Asymmetric Dearomative Formal [3+2] Cycloaddition.

A stereodivergent synthesis of tetrahydrofuroindoles through palladium-catalyzed asymmetric dearomative formal [3+2] cycloaddition of nitroindoles with epoxybutenes was developed. The polarity of the solvent was found to play a key role in the diastereoselectivity. In toluene, good to excellent yields (70-99 %), diastereoselectivity (87/13->95/5 d.r.), and enantioselectivity (85/15-94/6 e.r.) were obtained, regardless of the properties of the substituents on nitroindoles. In acetonitrile, tetrahydrofuroindoles of a different diastereoisomer were produced with good to excellent yields (75-98 %) and stereoselectivity (78/22-93/7 d.r., 93/7-99/1 e.r.). Mechanistic studies were conducted to illustrate the origin of the diastereodivergency. The kinetic experiments indicate that the rate-determining step of this reaction is different in different solvents. ESI-MS experiments also support the existence of key palladium complex intermediates and the catalytic cycle of the reaction.

Phosphine-Catalyzed Difunctionalization of ß-Fluoroalkyl α,ß-Enones: A Direct Approach to ß-Amino α-Diazo Carbonyl Compounds.

An efficient and practical phosphine-catalyzed vicinal difunctionalization of ß-fluoroalkyl α,ß-enones with TMSN3 has been developed. Using dppb as the catalyst, the reaction worked efficiently to yield various ß-amino α-diazocarbonyl compounds in high yields (up to 94 %). This work marks the first efficient construction of α-diazocarbonyl compounds by phosphine catalysis. Meanwhile, the asymmetric variant induced by the nucleophilic bifunctional phosphine P4 led to various chiral fluoroalkylated ß-amino α-diazocarbonyl compounds in high yields and enantioselectivity. NMR and ESI-MS studies support the existence of the key reaction intermediates. In contrast, ß-azide carbonyl compounds would be furnished in good yields from ß-fluoroalkylated ß,ß-disubstituted enones.

Multifunctional Carbon Fiber Ionization Mass Spectrometry.

A carbon fiber ionization (CFI) technique was developed for the mass spectrometric analysis of various organic compounds with different polarities. The design of the CFI technique was based on the good compatibility and dispersion of samples and solutions in different solvents on carbon fiber. As a fast, convenient, and versatile ionization method, CFI-MS is especially efficient for analyzing many low/nonpolar organic compounds, such as polycyclic aromatic hydrocarbons, long-chain aliphatic aldehydes, sensitive steroids, terpenoids, and organometallic compounds. Some of these compounds may not be well-analyzed by electrospray ionization or electron ionization mass spectrometry. On the basis of our experimental results, the major ion formation mechanism of CFI-MS was suggested to involve desorption in a steam-distillation-like process, and then, ionization occurred mainly via corona discharge under high voltage. CFI-MS could not only work alone but also be coupled with separation techniques. It works well when coupled with supercritical fluid chromatography (SFC) as well as in the analysis of exhaled human air. The high flexibility and versatility of CFI-MS has extended its applications in many areas, such as fast chemical screening, clinical testing, and forensic analysis.

Chromatographic peak reconstruction algorithm to improve qualitative and quantitative analysis of trace pesticide residues.

RATIONALE: In order to improve analysis of analytes in trace amounts in a complex matrix, we developed a novel post-processing method, named Chromatographic Peak Reconstruction (CPR), to process the recorded data from gas chromatography/time-of-flight mass spectrometry (GC/TOFMS). METHODS: For a trace ion, the relative deviation (δ) between the adjacent scanned mass-to-charge ratios (m/z) was found to be inversely proportional to its MS peak intensity. Based on this relationship, the thresholds of δ value within the specified intensity segments were estimated by the CPR and used to screen out the suspicious scan-points in the extracted ion chromatographic (EIC) peak. Then, the intensities of these suspicious scan-points were calibrated to reconstruct a new EIC peak. RESULTS: In the qualitative analysis of 118 pesticides, 107 out of the test pesticides can be confirmed. The corrected response ratios of the qualitative ion (q) over the quantitative ion (Q), q/Q, became closer to their references. In the quantitative analysis of 10 test pesticides at 5 ppb, the relative errors of the calculated concentrations after using the CPR were below ±1.55%, down from ±2.29% without using the CPR. CONCLUSIONS: The developed CPR showed great potential in the analysis of trace analytes in complex matrices. It was proved to be a helpful data processing method for the monitoring of trace pesticide residues. Copyright © 2016 John Wiley & Sons, Ltd.

Highly selective Pd-catalyzed intermolecular fluorosulfonylation of styrenes.

A novel Pd-catalyzed intermolecular regio- and diastereoselective fluorosulfonylation of styrenes has been developed under mild conditions. This reaction exhibits a wide range of functional-group tolerance in styrenes and arylsulfinic acids to afford various ß-fluoro sulfones. Preliminary mechanistic study reveals an unusual mechanism, in which a high-valent L2Pd(III)F species side-selectively reacts with a benzylic carbon radical to deliver a C-F bond. This pathway is distinct from a previously reported radical fluorination reaction.

Solvent-assisted electrospray ionization for direct analysis of various compounds (complex) from low/nonpolar solvents and eluents.

Electrospray ionization (ESI) is a powerful ionization technique with a wide range of applications. However, the analytes in low/nonpolar solvents cannot be analyzed directly in electrospray ionization-mass spectrometry (ESI-MS), because low/nonpolar solvents are incompatible with ESI, because of their low conductivity. To circumvent this problem, we introduce an electrospray-based ionization method termed solvent-assisted electrospray ionization (SAESI). With the help of electrospray solvents at the tip of the spray needle, compounds in "non-electrospray ionization-friendly" solvents can be ionized directly using solvent-assisted electrospray ionization-mass spectrometry (SAESI-MS). The key features that the assistant solvent can be chosen flexibly and makes little interference to samples lead to better ionization performance in detection of organic reaction intermediates and real-time analysis of polymers and chiral drugs separated by gel permeation chromatography (GPC) and normal phase liquid chromatography (NPLC). Furthermore, it can achieve online hydrogen/deuterium (H/D) exchange reaction and even mitigate the signal suppression caused by strong acid modifiers in liquid chromatography. In addition, all parts of this device are commercially available and it only requires two parameters to be optimized, which makes SAESI easy to handle.