The molecules to be examined are transferred into the gas phase (desorption) and ionized . The ions are then accelerated by an electric field and fed to the analyzer, which "sorts" them according to their mass-to-charge ratio m / z (also m / q ), for example separating them spatially into partial beams like in a sector field mass spectrometer. The molecules can be fragmented in the process. The fragmentation is often desired, especially with the comparatively complex biopolymers , since the fragments are more easily transferred into the gas phase, for example when examining proteins . The high vacuum required for desorption into the gas phase is now usually generated by the combined use of a rotary vane pump and a turbo-molecular pump .
Mass spectrometry is used in many areas. It is used, among other things, in the characterization of chemical compounds , in biochemistry for the investigation of biomolecules , in medicinal chemistry for the identification of substances in body fluids or organs , in forensic investigations, in doping controls , in environmental analysis , in the analysis of chemical warfare agents and explosives . There are very different techniques that differ depending on the effort, application and accuracy. It is advantageous in many areas that the amount of data is quite small and thus a coupling with databases of mass spectra is easily possible, e.g. B. Mascot for proteins. It is also relatively easy to couple a mass spectrometer with an HPLC system (mostly ESI -MS) or a gas chromatograph (often EI -MS) and thus obtain the various mass spectra of the individual fractions one after the other .
Mass spectrometry is based on a hypothesis put forward by British chemist William Prout in the early 19th century that every type of atom has a defined mass - then known as the atomic weight . He had established that the mass of the atoms of some chemical elements was an integral multiple of the mass of the hydrogen atom . Later and more precise measurements by Jöns Jakob Berzelius (1828) and Edward Turner (1832) seemed to refute this hypothesis. B. determined a mass for the chlorine atom that is 35.45 times the hydrogen mass. In the middle of the 19th century, Julius Plücker observed the influence of magnetic fields on the glow of gas discharge tubes .
Eugen Goldstein and Wilhelm Wien published the so-called canal rays and their deflection by fields in 1886 and 1898 . However, they had not yet recognized the far-reaching consequences of their discoveries in 1886.
Later, starting in 1897, Joseph J. Thomson published various experiments in which he deflected cathode rays from various cathode metals with electromagnetic fields in vacuum tubes , and established correct equations for the relationship between mass, speed and orbital radius. In 1913 he published a method to expose photo plates with the help of a mass spectroscope and thus to carry out qualitative and quantitative investigations on the gases contained in a tube.
In 1918 Arthur Jeffrey Dempster designed and built the first modern mass spectrometer, which was 100 times more accurate than all previous developments, and laid the foundation for the design of today's mass spectrometers. It had a magnetic sector analyzer. Because of this development, he was able to identify the uranium isotope with mass 235 in 1935.
A student of Thomson, the British chemist and physicist Francis William Aston , built his first mass spectrometer around the same time, which he reported on in 1919. With his new technique he was able to observe the isotopes of chlorine ( 35 Cl and 37 Cl), of bromine ( 79 Br and 81 Br) and of krypton ( 78 Kr, 80 Kr, 82 Kr, 83 Kr, 84 Kr and 86 Kr) . Aston was finally awarded the Nobel Prize in Chemistry in 1922 for his studies of isotopes. By using the technique of electrofocusing, he was able to observe no fewer than 212 of the 287 isotopes known at the time. In 1932, Kenneth Bainbridge developed a mass spectrometer with a resolution of 600 and an accuracy of 1: 10,000. He used it to confirm the energy-mass equivalence of Albert Einstein , E = mc 2 .
In 1934 Josef Mattauch and Richard Herzog described a double-focusing mass spectrometer (Mattauch-Herzog geometry, built by Mattauch and Herzog in 1936), which Mattauch used for the most precise atomic mass determinations of the time.
In 1939, Alfred Nier and Earl A. Gulbransen (1909-1992) described the isotope ratio of carbon . In 1946 William E. Stephens developed pulsed ionization, which increased the measurable mass range and created the basis for the first time-of-flight mass spectrometer . The first time-of-flight mass spectrometer was built in 1948 by AE Cameron and DF Eggers. A significant improvement in resolution was achieved in 1955 by William C. Wiley and his colleague Ian H. McLaren .
During the Manhattan project , large isotope enrichment systems ( calutrons ) based on the principle of mass spectrometers were built to build atomic bombs . In the 1950s, Roland Gohlke and Fred McLafferty used a mass spectrometer as a detector for a chromatography method for the first time. Both coupled a gas chromatograph with a mass spectrometer. This method made it possible for the first time to separate and identify substance mixtures in a plant. For use in a gas chromatographic method, however, the corresponding compounds must be volatile in a vacuum and, at the same time, evaporable without decomposition. In 1953 Wolfgang Paul developed the quadrupole , which made it possible to select the mass-to-charge ratio of flying ions.
Wolfgang Paul also developed the ion trap , with which ions could be held in a defined small space. In 1989, Wolfgang Paul received the Nobel Prize in Physics for his discoveries . From 1959, mass spectrometry was used by Klaus Biemann and colleagues for protein identification .
The previous methods for generating the required ions were very aggressive and led to many fragments when measuring organic compounds. Therefore, from the 1960s, the development of ever gentler ionization methods began. Chemical ionization (CI) was published by Burnaby Munson and Frank H. Field in the mid-1960s . The connection of two mass spectrometers via a collision chamber by Jean Futrell and Dean Miller led to the development of the first tandem mass spectrometer in 1966 . In 1969 HD Beckey published field desorption (FD).
In 1974, developed Alan G. Marshall and Melvin B. Comisarow from the University of British Columbia inspired by the Fourier transform - nuclear magnetic resonance spectroscopy - (FT-NMR) and ion cyclotron resonance methods (ICR) is a Fourier transform mass spectrometer (FT-ICR -Mass Spectrometry). The differentiation of radioisotopes and other isotopes with the same mass-to-charge ratio using a cyclotron was first described by Richard A. Muller . In 1977 Boris A. Mamyrin and colleagues solved the problem of broad initial energy distributions with the reflectron . In the late 1970s, Jim Morrison used three quadrupoles in series, the first quadrupole serving as a mass filter, the second to fragment molecules, and the third to detect the molecular ions. By increasing the pressure by adding an inert gas , Christie Enke , Richard Yost and Jim Morrison were able to achieve a collision-induced fragmentation of molecules to be examined without the use of lasers in 1979 . This enabled macromolecules to be examined more closely. In 1978 Calvin Blakly , Mary McAdams and Marvin Vestal developed thermospray ionization with a heated nozzle through which a liquid sample containing ammonium acetate was evaporated into a vacuum. From 1981 Michael Barber and colleagues developed the ionization method of almost atom bombardment , in which the ionization was achieved by accelerated atoms. Tandem mass spectrometry was used from 1981 by Donald F. Hunt and colleagues for protein sequencing from protein mixtures. For elemental analysis , from 1980 Robert S. Houk and Alan L. Gray developed ICP-MS , with a sensitivity in the range of ppb or ppt.
Later, a variety of ionization methods for a wide variety of purposes were further developed, such as electrospray (ESI, from 1968), chemical ionization at atmospheric pressure (APCI, from 1974), and matrix-assisted laser desorption / ionization (MALDI, from 1985 ).
From 1982 John Bennett Fenn developed electrospray ionization for biomolecules. In 1987 Koichi Tanaka published a liquid matrix with metal colloids for biomolecules. Fenn and Tanaka received the Nobel Prize in Chemistry for this in 2002. In 1999, Alexander Makarov developed the Orbitrap mass spectrometer .
Parameters of a mass spectrometer
A mass spectrometer is characterized by various parameters: the mass resolution, the mass accuracy, the mass range, the linear dynamic range and the measuring rate.
The mass resolution means the minimum mass difference Dm, the need to have two ions, so that they can be resolved. The resolution of a mass spectrometer is given in the Thomson (Th) unit , although often only the resolving power R is given. This is defined as the ratio of a mass to the mass difference of the next mass that appears separate (R = m / Δm) . For example, with a resolving power of 4000 the peaks at 4000 Th and 4001 Th would still be seen separately, but also the peaks at 2000 Th and 2000.5 Th since 2000 / (2000.5 - 2000) = 4000 the two terms resolution and resolving power are often not kept separate.
There are several definitions of resolution:
- With the 10% intensity method, Δm is defined as the mass deviation at which the intensity of a peak drops to 10% of the maximum.
- With the 10% valley method, Δm is defined as the mass deviation at which the valley between two peaks of equal size falls to 10% of the maximum.
- In the 50% intensity method, Δm is defined as the mass deviation at which the intensity of a peak drops to 50% of the maximum.
- With the half- width method (FWHM, full width at half maximum height ), dm is defined as the full peak width at half the peak height.
The mass accuracy indicates how precisely the mass of the particle can be determined. This information is often given in parts per million (ppm), i.e. H. a molecule having the nominal mass 500 may 0.0005 ppm at an accuracy of 1 u exactly be determined.
The mass span is the analyzable mass range of a mass spectrometer. The linear dynamic range is the area where the signal intensity is proportional to the concentration. The measuring rate is the number of measurements per unit of time.
Structure of a mass spectrometer
A mass spectrometer (MS) consists of an ion source, an analyzer and a detector. Each of these components exists in different designs and functional principles, which in principle can be freely combined, although preferred combinations exist. These are described below.
The analyte is ionized in the ion source . This can be done with the help of various methods. The choice of method depends mainly on the type of substance to be analyzed and how gently ionization is to be carried out. The ions are usually extracted from the ion source using an electric field and transferred to the analyzer. The ions can be generated in various ways. Often come impact ionization , in particular electron impact (EI) or chemical ionization (CI), photoionization (PI), field ionization (FI), fast atom bombardment (FAB), inductively coupled plasma (ICP), matrix-assisted laser desorption / ionization (MALDI ) and electrospray ionization (ESI).
In the analyzer or mass selector, the ions are separated according to their mass-to-charge ratio (if the charge is known, you can use it to infer the mass of the ion directly). There are several very different ways in which this mass separation occurs. Depending on the method, the separating power is also quite different. The individual separation methods are discussed in the section Types of Analyzers .
The detector is used to detect the previously separated ions. Photomultipliers , secondary electron multipliers (SEV), Faraday receivers , Daly detectors , microchannel plates (MCP) or channeltrons can be used as detectors . The SEV is sometimes used in combination with a conversion dynode, in which the ions collide with a metal surface due to an applied high acceleration voltage (up to 25 kV) and the SEV then detects the released electrons. In the early days of mass spectrometry, photographic disks were also used.
FT-ICR and Orbitrap mass spectrometers measure currents ( image currents ) which are generated by the moving ion packets in the detector plates. In this case, the ions are not absorbed by the detector and can therefore be measured several times. This makes a decisive contribution to the high measurement accuracy of these instruments.
Types of analyzers
Mass spectrometers are typed by the analyzer used.
Single particle mass spectrometer
Particles can be analyzed in real time using a single particle mass spectrometer . The result is information about the chemical composition and information about the size. The instrument consists of four components:
|1||Intake system||Absorption of particles in a vacuum chamber|
|2||Detection unit||Determination of the airspeed to determine the particle size and the time of ablation|
|3||Laser pulse||Evaporation and ionization of particles|
|4th||mass spectrometry||Analysis of the mass-to-charge ratio of ions|
The associated working method is single particle mass spectrometry . The particles are examined directly from the ambient air, which enables rapid analysis with high sensitivity. Further advantages are a high time resolution and a low risk of contamination of the samples, since they do not have to be stored first. In this way, accurate statistics can be generated from large amounts of data. The analysis is carried out with algorithms based on C ++ and Matlab .
Sector field mass spectrometer
The radius of the circular paths that they traverse in the fields depends on the energy (in the electric field) and the momentum (in the magnetic field) of the ions. Knowing the charge, the energy and the momentum, the mass can then be determined. Sector field mass spectrometers can be built in such a way that ions with slightly different speeds are imaged on a point in the detector (speed focusing). Ions whose trajectory is slightly inclined can also be mapped onto a point (directional focusing). Mass spectrometers that can do both at the same time are called double focusing. The focusing is necessary in order to still obtain an acceptable intensity of the measurement signal with a high resolution. Sector field mass spectrometers achieve resolutions of up to 100,000 and were the mass spectrometers with the highest resolution before the development of FT ion traps. Today, they are rarely used, for example, the stable isotope mass spectrometry and in the ultra trace analysis .
Quadrupole mass spectrometer
In the quadrupole mass spectrometer, the generated ions are accelerated by a static, electric field and fly through four central parallel rod electrodes, the intersection points of which form a square with a plane perpendicular to the cylinder axis ( quadrupole ). In the alternating field between the quadrupole rods, m / q selection takes place, so that only particles with a defined mass can pass through the field.
Time-of-flight mass spectrometer (TOFMS)
The time-of-flight mass spectrometer (TOFMS) makes use of the fact that the ions all have the same energy when they enter the analyzer and therefore light ions are faster than heavy ions. Therefore, when flying through a field-free space, light ions reach the detector sooner than heavy ions. The time-of-flight analyzer thus only consists of a tube under vacuum with a very fast detector at the end. The resolution is up to R = 15,000 (10% method). In practice, devices with ion mirrors or reflectrons have proven to be effective, in which the flight distance is doubled by an additional electric field at the end of the original flight direction. In addition, this technology achieves a further focus.
Ion trap mass spectrometer
In ion trap mass spectrometers, the ions are kept in a defined area by electromagnetic fields and can thus be analyzed and manipulated. In the quadrupole ion trap, the ions are collected and stabilized by a cooling gas, often helium. This absorbs the thermal energy of the ions and ensures that the ions collect in the center of the quadrupole and are in a calm and orderly state. When a certain voltage is applied, a certain type of ion, which is characterized by a certain mass, is made unstable, leaves the quadrupole and can be detected by means of an electron multiplier. In ion trap mass spectrometers, multiple repetition of excitation and mass selection is possible without the need for an additional component. The following types of ion trap mass spectrometers exist:
- Quadrupole ion trap
- Linear trap
- Fourier transform ion cyclotron resonance (FT-ICR)
MS / MS (also tandem mass spectrometry)
To study fragmentation or to decisively improve the selectivity and sensitivity (detection limit) of a quantification method, one either couples several analyzers one after the other (sequentially) or works in ion traps . If the devices work sequentially, so-called collision cells are installed between two analyzers in order to supply the ions with energy through collisions with an inert gas (usually nitrogen or argon ). The ions then disintegrate very specifically to form other (lighter) ions.
Many combinations of the analyzers are possible. The most common are triple quadrupole (QqQ), Q- TOF , tandem-TOF (TOF-TOF) and meanwhile also as high-resolution mass spectrometry as TRAP- FTICR and TRAP- Orbitrap .
The most widespread are so-called triple quadrupole MS (QqQ, also known as triple quads ), usually coupled with HPLC . A quasi-molecular ion is usually produced by electrospray ionization (ESI), which is isolated in the first analyzer quadrupole and then excited in the second quadrupole - the so-called collision cell or shock chamber.
A collision gas (usually argon, helium or nitrogen) can be fed into the collision chamber. The pressure is selected in such a way that, on average, a generated ion collides with a gas molecule at most once. This method enables generated ions to be further fragmented.
The third quadrupole offers the possibility of "scanning", ie to determine all productions of the ion isolated in the first quadrupole (English parent ion ), or to selectively observe only one known fragment ion . By recording all fragment ions, conclusions can be drawn about the structure. By observing only one or two fragment ions, quantification can be performed very sensitively and selectively. This technique is also known as Multiple Reaction Monitoring (MRM).
There are also other techniques for MS / MS and also so-called MS n , i.e. multiple mass spectrometry . In ion traps you can isolate an ion and then supply it with energy either by collision (usually with helium) or by radiation and then fragment it in the trap ( in-trap fragmentation ). This can be carried out several times in a row (i.e. MS n ). In addition to collision, infrared lasers , electron capture dissociation or electron transfer dissociation (ETD) can also be used as fragmentation methods.
Triple quads are the most widely used mass spectrometers for quantitative analyzes in the field of HPLC-MS . The tandem mass spectrometry is u. a. also used in the field of protein characterization , e.g. B. in de novo peptide sequencing .
In the Isobarenmarkierung ( English isobaric labeling ) the provided to the assayed molecules with different labels which, although isobaric (same starting material own), but in the tandem mass spectrometer of different weights and therefore distinguishable fragments (specifically reporter ions ) resulting. There are two commercially available isobaric tags , Tandem Mass Tags (TMT) and iTRAQ . TMT exists as a duplex or 6-plex, while iTRAQ is available as a 4-plex or 8-plex.
Coupling with chromatography processes
In the case of very complex samples (e.g. in food analysis) it is useful to separate them using a separation process provided before they are fed to the mass spectrometer. In this sense, mass spectrometry is often operated together with gas chromatography ( GC-MS ) or liquid chromatography ( LC-MS ). Coupling with capillary electrophoresis ( CE-MS ) and ion mobility spectrometry ( IMS-MS ) are less common . In some cases, multi-dimensional separation techniques are also used. B. GCxGC-MS . Time-of-flight mass spectrometers are particularly suitable in combination with multi-dimensional gas chromatography, because mass spectra can be recorded very quickly over a large m / q range with them. The GCxGC process allows precise separation and detection of different classes of compounds from complex matrices (e.g. petroleum samples). To do this, two GC columns with different polarity are connected in series.
Evaluation of the mass spectra
The prerequisite for determining the mass m is the knowledge of the charge q of the ion, because the analyzers can only separate the ions according to the ratio m / q . However, q is always an integral multiple of the elementary charge e: q = z · e , and mostly z = +1 (simply positively charged). As a unit of m / q which was Thomson Th proposed: [ m / q ] = Th.
The data supplied by the detector are discrete values which normally have an equidistant distance , which is predetermined by the scanning of the detector. This data can be displayed directly. This form of representation is called “profile data” in English, which is of particular interest if the peak width is important. Alternatively, the data can be further processed into a histogram, this form of representation is called “centroid data”: the individual peaks are assigned an intensity based on their area, which is located at the location of the greatest value. First, the mass of the analyte must be determined. Usually this is the mass of the heaviest ion detected ( molecular peak or molecular ion peak ). The molecular ion peak belongs to the heaviest ion that is displayed in the mass spectrum of a substance, i.e. the simply ionized molecule. However, a large part of the ions are often split during electron ionization. As a test, the electron energy can be reduced so that fewer ions are split and the molecular peak is more clearly visible.
The further evaluation is based on the fact that the atoms of the various chemical elements have different mass defects. Therefore, a list of possible sum formulas can be given from a very precisely determined mass. With light molecules there is only one or a few suitable elementary compositions. As the mass or number of heteroatoms increases, so does the number of possible combinations.
For heavier molecules, there are therefore many possible empirical formulas to choose from. The isotopic compositions of the various elements provide further information. For example, the carbon consists of 98.9% of 12 C and 1.1% of 13 C. Depending on how many C atoms there are in the molecule, in addition to the main signal, there are secondary signals in the spectrum, those from the main peak are removed by 1 Th , 2 Th etc. and have a characteristic intensity ratio to the main signal. The halogens chlorine and bromine , sulfur and silicon also have characteristic isotope ratios, which are used for identification.
The methods mentioned are also applicable to the fragments. Molecules often break at characteristic points. The structural formula can finally be determined from the mass of the fragments and possibly further information.
Primarily in positive EI ionization mass spectra generated help mass spectral libraries . The best known are the Wiley and NIST mass spectrum libraries under the abbreviations of their distributors . Identification can be made using the Peak Counting Score .
The quantification of compounds is made easier in mass spectrometry by the fact that isotope-labeled ( 13 C-labeled or deuterated ) internal standards can be used for the analysis . ( Isotope dilution analysis )
The proprietary data formats of the individual device manufacturers represent a problem with the data evaluation. The data are stored in their own binary data formats. In most cases, the respective manufacturer supplies evaluation programs integrated into their own control and management software. In order to use programs from third parties, data conversion for data export is often required, for which there are freely available solutions in the field of research.
Mass spectra consist of several different groups of peaks :
- the molecular ion
- Isotope peaks
- Fragment peaks
- metastable peaks
Mass Spectrometry shows first of all a peak for the molecular ion , which acts as radical - cation M + . occurs as a result of the removal of an electron from the molecule. However, the molecular peak cannot always be detected or can be very weak. In a homologous series, the molecular peak decreases with increasing number of branches and with increasing mass. Identifying the molecular ion can be difficult. The nitrogen rule is a useful aid : if the molecular mass is an even number, the compound contains no nitrogen or an even number of nitrogen atoms. Molecular ion peaks are often accompanied by an M-1 peak resulting from the loss of a hydrogen radical.
Further peaks, with an m / z ratio greater than that of the molecular ion, arise from isotope distribution . The so-called M + 1 peak is caused by a built-in isotope of higher mass, either 2 H or 13 C; the M + 2 peak has two isotopes of higher mass etc. The natural abundance of higher isotopes is low for frequently occurring elements such as hydrogen , carbon and nitrogen and thus also the height of the resulting isotope peaks, the frequency decreases rapidly with increasing mass. With the halogens chlorine and bromine, however, higher isotopes are quite common, which is expressed in a characteristic signal.
Peaks with a lower mass than the molecular ion are the result of fragmentation . The peak with the highest intensity is called the base peak; it does not necessarily have to correspond to the molecular ion. There are numerous reaction pathways for fragmentation, but only newly formed cations appear in the mass spectrum, while radical fragments or neutral fragments do not.
Metastable peaks are broad peaks at non-integer mass values. These peaks result from fragments with lower kinetic energy if fragmentation takes place in front of the ionization chamber. With their help, the relationship between two peaks can be proven, which are linked via a single-stage decay process.
In analytics or analytical chemistry, mass spectrometry is used as an analytical method for determining chemical elements or compounds . In this form, mass spectrometers are used in many areas of natural science and technology for the analysis of materials, including chemistry, biology, archeology and climatology.
Mass spectrometers are also used in particle physics . In this area, however, the goal is not so much the analysis of chemical elements, but rather the determination of the masses of elementary particles or atomic nuclei as well as the detection of as yet unknown particles.
For an analyte (the substance to be tested), the frequency with which charged molecules ( ions ) and their mass fragments occur is determined. Mass spectrometry is an important method in analytical chemistry for elucidating the structure and composition of compounds and mixtures. The qualitative (detection of unknown substances) and quantitative (how much substance of a compound is present) detection of very small amounts of substance (approx.> 10 −15 g = 1 fg (femtogram)) is possible.
Isotope ratios of different elements are used in geology to date the age of rock bodies as well as for thermochronology and can provide information about whether and when a rock was subsequently heated again after its formation. The ratio of 39 Ar to 40 Ar is very suitable for this .
Isotope ratios of some elements allow conclusions to be drawn about the nutrition of the people whose bones are examined. See also isotope investigation . The isotope ratio of carbon 14 C to 12 C in the organic material of archaeological finds makes it possible to determine the time since the plant formation of the measured substance. Accelerator mass spectrometry is used to measure 14 C.
Mass spectrometry is used in proteomics and metabolomics , where the use largely corresponds to that in chemistry. Biological samples, especially proteins , however, require special sample preparation and measurement methodology due to the molecular size and the special issue (identity, sequence , post-translational modification ) in order to clarify systemic relationships . Mass spectrometric methods are e.g. B. ITRAQ , ICAT , SILAC , Tandem Mass Tag or label- free mass spectrometric quantification . Amino acid sequences can be determined by de novo peptide sequencing . The mass spectrometry of proteins was named method of the year 2012 by the journal Nature Methods .
A MassTag-PCR can be used to identify and quantify nucleic acids labeled as UV-labile.
The ratio of the frequency of certain isotopes in samples of sediments , tree rings and ice cores allows conclusions to be drawn about the climate of the past. For example, water containing isotope 16 O evaporates more easily than water containing isotope 18 O. Ice ages, during which large amounts of water are withdrawn from the water cycle as an ice sheet, shift the frequency of these isotopes in the sea and thus also in newly falling snow. The amount of inland ice at the time the sample was formed can be inferred from the oxygen isotope level .
Mass spectrometry is also used in many technical areas. It can be used, for example, to identify the end point of etching processes. Another area of application is the setting and optimization of the gas supply in coating processes (more precisely chemical vapor deposition ). After the reaction, the exhaust gas is examined for unused reaction gases and the gas supply is adjusted accordingly. However, mass spectrometry can also be used to analyze the deposited materials. With the help of SIMS , depth profiles can also be created, which is used, among other things, for the analysis of thin layers .
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