Investigation and application of liquid chromatography mass spectrometry in the analysis of polar, less volatile and thermal unstable organic pollutants in environmental and biological samples 1

1 Chapter One Introduction & Literature Review 1.1 GENERAL INTRODUCTION TO LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY (LC-MS) In recent decades, LC-MS has experienced impressive progress, both in terms of technological development and application The combination of chromatography (for separation) and mass spectrometry (as a sensitive detector that provides structural information) has proved to be a primary technology for the detection and characterization of various molecules, providing the analytical chemist with one of the most powerful analytical tools of modern times The key advantages of LC-MS are [1]: Selectivity: LC-MS is not constrained by chromatographic resolution coeluting peaks can be isolated by “mass selectivity.” Peak assignment: LC-MS creates a unique “chemical fingerprint” for the compound of interest, ensuring correct peak assignment even in the presence of interfering compounds Molecular weight information: confirmation for known compounds, identification for unknowns Structural information: controlled fragmentation in LC-MS allows for structural elucidation Rapid method development: LC-MS can be used for the identification of eluted analytes without retention time validation Quantitation: quantitative and qualitative data can be obtained easily with limited instrument optimization More importantly, with the development of atmospheric pressure ionization (API) interface techniques, LC-API-MS has assumed great importance in the analysis of polar, low volatile, and thermally instable organic compounds, for which direct analysis by GCMS is not possible [2] 1.2 INTRODUCTION AND BASIC PRINCIPLES 1.2.1 LC and MS Liquid chromatography (LC) is a physical separation method by which the components to be separated are selectively distributed between two immiscible phases: a liquid mobile phase and a stationary phase bed through which the liquid mobile phase passes The chromatographic process occurs as a result of repeated sorption/desorption steps during the movement of the analytes along the stationary phase The separation is due to differences in distribution coefficients of the individual analytes within the sample [3-6] Because a high-pressure pump is required to move the mobile phase and analytes through the column, LC is also known as high performance liquid chromatography (HPLC) Mass spectrometry (MS), as one of LC detection techniques, has attracted growing interest because of the potential to yield information on the relative molecular mass (Mr) and the structure of the analyte, which cannot be found using other detection systems, such as ultraviolet (UV), refractive index (RI) and fluorescence At present, MS is the most sensitive method of molecular analysis MS is based on the detection of emitted ions that have been separated or filtered according to their mass-to-charge (m/z) ratio The resulting mass spectrum is a plot of the relative abundance of the generated ions as a function of the m/z ratio Because extreme selectivity can be obtained, mass detection combined with chromatographic separation is invaluable in quantitative trace analyses [79] 1.2.2 LC-MS Coupling 1.2.2.1 General problems When searching for a suitable technique for the analysis of mixtures that, often contain unknowns and/or analytes in low concentration, the combination of chromatography (for separation) with mass spectrometry (as detector that provides sensitive and structural information) appears to be an obvious choice However, liquid chromatography coupled to mass spectrometry is an odd combination In HPLC, the sample is in solution and at atmospheric pressure, while the mass analysis of ions takes place within a vacuum [10] In developing on-line LC-MS, three fundamental compatibility problems had to be solved Firstly, LC is preferred over gas chromatography (GC) in analysis of samples with high polarity and low volatility In contrast, one of the prerequisites for mass spectrometric analysis is the formation of volatilized ions Second difficult problem to be solved was the necessity to eliminate the mobile phase Water flowing at a rate of ml/min from a conventional 4.6-mm-ID LC column is converted into vapor (at atmospheric pressure) at 1244 ml/min, which is far too much for standard MS vacuum systems to handle Third, salts and other additives within the mobile phase are often involatile (e.g., phosphates, NaCl, etc.) [10] 1.2.2.2 General introduction of interface techniques The aforementioned problems have been solved by the development of interface techniques that: 1) transfer the analyte from the LC column to the MS ion source and prepare the analyte for ionization, 2) cope with the solvent from the LC, 3) bridge the pressure difference between column outlet and mass analyzer [11-16] The first experiments that couple LC with MS date back to the late 1960s The actual breakthrough in the development of coupling techniques was the introduction of the moving-belt interface (MB) in 1974 that, became the first commercial LC-MS interface [11] Subsequently, many interface techniques have been rapidly developed, such as particle beam (PB) [12], continuous flow fast atom bombardment (cf-FAB) [13,14], direct liquid introduction (DLI) [15], thermospray (TSP) [16], and more recently, the API technique (APCI and ESI) [16] Both MB and PB interfaces rely on the removal of solvent prior to entering the MS [17] MB separates the condensed liquid-phase side of the LC from the high vacuum of the MS and uses a belt to transport the analytes from one to the other The mobile phase of the LC is deposited on a band and evaporated [18, 19] Most moving-belt analyses deal with volatile analytes, that consequently limit the application of MB LC-MS The PB interface provides the opportunity to use EI/CI without the mechanical transportation portion used in MB [20] The LC elutent is forced through a small nebulizer with the aid of following He gas to form a stream of uniform droplets These droplets move through a desolvation chamber and evaporate, leaving a solid particle These particles are separated from the gas and transported into the MS source using a differentially pumped momentum separator The PB interface can be considered as the successor of the MB, giving better stability and more robustness Furthermore, this is of growing importance in LC-MS interfacing because relatively volatile analytes can be examined Many pesticides are not sufficiently volatile to be amenable to GC/MS, but can be analyzed by PB LC-MS DLI or cf-FAB interfaces reduce the flow entering the MS using a splitting device A serious drawback of this approach is the reduction in sensitivity caused by the split factor The flow rate magnitude, used with a classic 4.6 mm i.d column (1 ml/min) is only tolerated by techniques such as TSP and API [21] The TSP interface was developed by Vestal et al [22-24] As the name thermospray implies, heating of liquid flow leaving an LC system creates a spray of superheated mist containing small liquid droplets A major advantage of TSP over other LC-MS interfaces is its ability to handle the high flow-rates delivered by LC (up to mL/min) The TSP interface was developed to solve two problems: 1) to reduce the pressure of the solvents, and 2) generate ions of the analyte, that are frequently nonvolatile This particular interface was developed for a system that, for a number of years, was considered to be the easiest, most versatile, and powerful LC-MS interface technique [23, 24] However, with the advent of new, more adaptable and robust LC-MS interfaces based on atmosphericpressure ionization (e.g., APCI and ESI), the use of TSP diminished rapidly [25] 1.2.2.3 API technique in LC-MS The earliest LC-MS techniques (DLI, TSP, MB, and PB), though commercialized, were often difficult to use, had limited sensitivity, and were not robust However, they were very useful for specific applications The overwhelming increase in LC-MS applications is primarily the result of the sensitivity and ruggedness of ESI and APCI, which are both API techniques The advantages of API techniques were summarized by Voyksner with four key points [26]: API approaches can handle volumes of liquid typically used in LC, API is suitable for the analysis of non-volatile, polar, and thermally unstable compounds typically analyzed by LC, API-MS systems are sensitive, offering comparable or better detection limits than achieved by GC-MS, API systems are very rugged and relatively easy to use 1.2.2.3.1 ESI The first attempts to use electrospray (ES) as an MS interface date back to the late 1960s and early 1970s At that time, Dole et al investigated the possibility of producing gas- phase ions from macromolecules in solution, utilizing an atmospheric pressure electrostatic sprayer for analysis via ion mobility measurements [27-29] The actual origins of the LC–ES-MS coupling were reported in 1984, almost simultaneously by Yamashita and Fenn and Aleksandrov et al [30-32] Yet, the real breakthrough of ESI in the early 1990’s relied on extremely low flow-rates that, introduced protein solutions at the concentration of pmol/µl into the mass spectrometer [33, 34] This breakthrough has revolutionized the applications of MS, especially in biological and environmental analyses [35, 36] The ES process can be divided into three stages: droplet formation, droplet shrinkage and gaseous ion formation [37] The ES process is shown in Fig 1-1 [38], here the liquid flows from the HPLC column, enters a small caliber stainless steel capillary (maintained at a voltage of 3000±4000 V), and are then dispersed into a very fine spray of charged droplets with the same polarity The solvent then evaporates, shrinking the droplet size and increasing the charge concentration at the droplet's surface Eventually, at the Rayleigh limit, Coulombic repulsion overcomes the droplet's surface tension and the droplet explodes This “Coulombic explosion” forms a series of smaller, less charged droplets The process of shrinking immediately followed by explosion is repeated, leading to very small (3–10 nm) charged droplets that are capable of producing gas-phase ions, which gives a very soft ionization technique The ions are sampled through a set of skimmer electrodes and finally analyzed in the MS analyzer Fig 1-1 Droplets and ion production under ES conditions [39] In contrast with all other LC-MS combinations, ESI appears to be a concentrationsensitive device; that is, the response is directly proportional to the concentration of the analyte entering the source, irrespective of the flow-rate at which it is delivered This allows miniaturization of the technique without a loss in sensitivity Another interesting characteristic of ESI is its “softness.” Specifically, very labile structures can be carried as ions into the gas phase without disrupting their structures For the same reason, ESI spectra contain little to no structural information because of the absence of fragmentation Molecular weight information is obtained in the first instance If more structural information is needed (e.g., sequence information of peptides), fragmentation must be induced This is most conveniently done by applying tandem MS There are many reasons for the predominant use of ESI: ease of operation, sensitivity, reliability, robustness, and expanded areas of application ESI is a highly efficient ionization technique that has greatly extended the analytical potential of MS [35], and its interface is currently the most widely applied method for liquid introduction into an MS Additionally, ESI is especially suited for the analysis of compounds ionized in the liquid phase, due to the fact that, the observed ions, generally formed by protonation or deprotonation of the molecule or by adduct formation with solvent ions, directly reflect acid-base equilibrium in solution ESI is a mild ionization technique that efficiently produce protonated (or deprotonated) molecular ions of polar, non-volatile, high molecular mass, and themolabile compounds Therefore, LC-ESI-MS is now widely used for the analysis of polar and small ionic molecules, high molecular-weight proteins, and other biomacromolecules [38] 1.2.2.3.2 APCI The exploration of APCI for LC-MS started in the early 1970s with the research work of Hornning et al on the use of a modified plasma chromatograph-MS combination [40] Further research by the same group led to an APCI source, equipped with either a 63 Ni foil or corona discharge needle as the primary source of electrons used to generate reactant ions [41] The vaporizer for sample and solvent was a heated glass tube filled with a plug of glass wool, directly attached to a small APCI source APCI interface techniques were proven to be fully developed only after Fenn et al [42], demonstrated rapid and accurate molecular-mass determination for large proteins by means of ESI At present, APCI is commercially available and a growing interest in applications involving biological and environmental analysis In an APCI source, the column effluent is nebulized in a heated vaporizer tube (350-500 °C), where solvent evaporation is nearly complete The gas-vapor mixture enters an atmospheric-pressure ion source, wherein analyte ionization is initiated within a corona discharge needle The solvent vapor acts as reagent gas At atmospheric pressure, the ions are extracted and moved into the mass spectrometer by the exactly same set of skimmers used for electrospray (Fig 1-2) [43,44] Fig 1-2 Schematic diagram of the typical layout of an APCI source [45] Ionization occurs through a corona discharge (Fig 1-3), creating reagent ions from the solvent vapor Chemical ionization of the sample molecules is very efficient when at atmospheric pressure, due to the high collision frequency The moderate influences of 10 Table 1-6 LC-MS methods for pesticide residue analysis in solid matrices Pesticides Matrix Sample pretreatment MS-mode Ref APCI–PI–MS LODs (µg/ kg) 10–20 Fenbutatin oxide Fruits Ethyl acetate extraction, concentration Chlormequat Pear Methanol extraction ESI–PI–MS–MS 40 134 Imazethapyr Soil MAE with buffer (pH 10) as solvent; cleanup on C18 SPE cartridge ESI–PI–MS–MS 136 Arylozyphenoxypropionic acids Soil SCEa with methanolbuffer, pH 10; cleanup on Carbograph-1 SPE cartridge ESI–NI–MS 137 Triazines, Phenylureas, Phenoxy acids, Benzonitriles Soil Heated water extraction including trap on SPE carbograph ESI–NI–MS or ESI–PI–MS 2–10 138 Carbamates, Difluben- zuron, Clofetezine, Carbendazim, Thiabendazole Fruits Ethyl acetate extraction, concentration, solvent switch to acetonitrile APCI–NI–MS or APCI–PI–MS 2–35 139 Atrazine, Simazine, Terbutylazine, Prometryn, Linuron, Promecarb, Propoxur Lettuce blueberry Extraction with acetone– water and partition with CH2Cl2 ESI-PI-MS - 124 Aldicarb sulfoxide, Aldicarb sulfone, Methomy, 13Hydroxycarbofuran Green pepper Homogenization with acetone partition with CH2Cl2 APCI-MS 100 140 Aldicarb sulfoxide Adicarb sulfone Carbofuran Methiocarb Sulfoxide Apple, cauliflower, potato, lettuce celery Extraction with methanol, partitioning acetonitrile–CH2Cl2 APCI-PI-MS 10-100 141 Pirimicarb 3Hydroxycarbofurant Hiabendazole Strawberry plum Homogenization with EtOAc and anhydrous Na2SO4 APCI-PI-MS APCI-NI-MS 0.0020.025 142 Carbaryl Banana, carrot, green bean Homogenization with methanol–acetonitrile; partitioning and clean-up celite charcoal; APCI-PI-MS - 143 133 29 Carbaryl, carbofuran Orange Ethiofencarb grape onion Isoprocarb tomatoes Metholcarb oxamyl Propoxur Thiobencarb a SCE, solid column extraction MSPD with 0.5 g C8 clean-up with silica elution with 10 ml of CH2Cl2–acetonitrile; APCI-PI-MS APCI-NI-MS 10-50 144 Barnes et al developed a LC–APCI–MS multi-residue method for the determination of ten pesticides in different types of fruit After extraction with ethyl acetate, solvent evaporation, and a solvent switch to acetonitrile, part of the diluted extract was directly processed with LC-APCI-MS using a switching NI/PI mode during each acquisition The obtained LODs clearly met the required Maximum Residue Level (MRL) for these compounds in foodstuffs [139] Pleasance et al carried out APCI and EIS analyses of N-methylcarbamate pesticides and compared these techniques with TSP- and PB-based interfaces They concluded that an APCI source provides a clear advantage in terms of sensitivity, linearity, and range of compounds to which it is applicable The suitability of LC–APCI-MS for pesticide residue analysis in fruits and vegetables was demonstrated by analysis of green pepper extract spiked at the 0.1 ppm level with Methomyl, Aldicarb and Carbaryl [145] A method involving LC-APCI-MS was first reported for the determination of diflubenzuron in mushrooms, and was subsequently applied to detect diflubenzuron and clofentezine in plums, strawberries, and blackcurrant-based fruit drinks Both positive and negative ionization modes were evaluated No ions attributable to diflubenzuron were observed in the positive mode while in the negative mode, an intense [M-H]- ion was 30 detected Under positive-ion conditions, clofentezine gave a weak spectrum containing [M+H]+ and some higher mass adducts [146-147] 1.5 AIMS OF THE PROJECT So-called “modern pesticides” such as carbamates, as alternatives to organochlorine insecticides, have become increasingly popular in recent years due to their high efficiency as insecticides and their short-term environmental persistence Unfortunately, their acute toxicity represents risks to the environment, with respect to human health and animal life Carbamates and their transformation products (TPs), formed by hydrolytic, photolytic or microbial degradation, are potential contaminants of aquatic environments and food resources because they are highly soluble in water Hence, evaluation and monitoring of trace levels of carbamates and their transformation products from environmental waters is imperative In addition, contaminated water induces carbamate accumulation in aquatic plants and animals, such as algae, fish and shellfish, some of which are included in the common diet and therefore, considered hazardous to human health Thus, it is necessary to study the degradation of carbamate pesticides in plants and organisms LC-MS has become one of most powerful techniques for the analysis of carbamates and their TPs because of their relatively high polarity, low volatility, and thermal instability that prevent direct analysis by GC-MS The separation by time provided by an HPLC system, combined with the separation by mass achieved by an MS often enables a 31 chemist to acquire structural information of specific impurities or degradation products without need of a time-consuming isolation process Furthermore, the detection sensitivity and selectivity make the determination of analytes, at trace levels, in complex matrices possible Hitherto, limited research has been reported on the analysis of carbamates and their TPs, although some of the latter are generally more toxic than the parent compounds Our research interests are focused on the investigation and application of LC-MS (with APCI and ESI) for the analysis of trace amounts of carbamate pesticides in environmental and biological samples To study the factors that influence the degradation behavior of carbamates in various aqueous matrices, the effects of various pHs, matrix types (ultrapure water, drinking water, rain water, seawater and river water), and irradiation sources (sunlight, darkness, indoor lighting and artificial UV lighting) on chemical degradation are investigated The performance of two MS ionization techniques (ESI and APCI) for the identification of major TPs are compared as well To investigate carbamates and their TPs at trace levels in soils, pre-concentration treatments are crucial for increasing analytical sensitivity and accuracy Although microwave-assisted extraction (MAE) has been successfully applied to the simultaneous extraction of toxic organic contaminants from different solid matrices, due to its high extraction efficiency and low solvent consumption, little work has been reported on the MAE of carbamates In this project, MAE is applied for the first time to study the extraction of carbamates in soils The degradation behavior of carbamates under MAE, 32 and the optimization of MAE conditions (extraction solvents, temperature, pressure and heating duration), are investigated systematically To illustrate the advantage of the MAE technique, a comparison between the optimized MAE and SFE techniques for the extraction of carbamate pesticides in soil samples is made as well To evaluate and estimate the potential risk of carbamates and their TPs for aquatic plants and animals, propoxur (one of the carbamate pesticides) and its TP residues are investigated in detail In this research, MAE is applied as a sample pre-concentration technique prior to LC-MS analysis Firstly, our 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From Table 1- 5, it can be seen that various classes of pesticides have been determined by employing either LC-ESI-MS [11 1 -11 7, 12 1, 12 3] or LC-APCI-MS [11 8, 11 9, 12 2] The combination of SPE with... ESI–PI–MS 5? ?10 11 6 GW off-line, 1L, SPE, ESI–NI–MS 5? ?10 11 5 SW off-line, 0.2L, SPE, ESI–PI–MS 20–30 11 7 Imidazolinone DW off-line, 2L, SPE, ESI–PI–MS about 11 3 Phenoxy acid GW off-line, 1L, SPE,... 1L, SPE, ESI–NI–MS 10 –20 11 6 SW off-line, 1L, SPE, ESI–PI–MS 1? ??20 11 1 SW off-line, 0.2L, SPE, ESI–PI–MS 13 –40 11 2 Sulfonylurea GW off-line, 2L, SPE, ESI–NI–MS 5? ?10 11 4 Triazine, Phenylurea GW