The Analog Revolution and Its On-Going Role in Modern Analytical Measurements.

The electronic revolution in analytical instrumentation began when we first exceeded the two-digit resolution of panel meters and chart recorders and then took the first steps into automated control. It started with the first uses of operational amplifiers (op amps) in the analog domain 20 years before the digital computer entered the analytical lab. Their application greatly increased both accuracy and precision in chemical measurement and they provided an elegant means for the electronic control of experimental quantities. Later, laboratory and personal computers provided an unlimited readout resolution and enabled programmable control of instrument parameters as well as storage and computation of acquired data. However, digital computers did not replace the op amp's critical role of converting the analog sensor's output to a robust and accurate voltage. Rather it added a new role: converting that voltage into a number. These analog operations are generally the limiting portions of our computerized instrumentation systems. Operational amplifier performance in gain, input current and resistance, offset voltage, and rise time have improved by a remarkable 3-4 orders of magnitude since their first implementations. Each 10-fold improvement has opened the doors for the development of new techniques in all areas of chemical analysis. Along with some interesting history, the multiple roles op amps play in modern instrumentation are described along with a number of examples of new areas of analysis that have been enabled by their improvements.

Zoom-TOFMS: addition of a constant-momentum-acceleration "zoom" mode to time-of-flight mass spectrometry.

In this study, we demonstrate the performance of a new mass spectrometry concept called zoom time-of-flight mass spectrometry (zoom-TOFMS). In our zoom-TOFMS instrument, we combine two complementary types of TOFMS: conventional, constant-energy acceleration (CEA) TOFMS and constant-momentum acceleration (CMA) TOFMS to provide complete mass-spectral coverage as well as enhanced resolution and duty factor for a narrow, targeted mass region, respectively. Alternation between CEA- and CMA-TOFMS requires only that electrostatic instrument settings (i.e., reflectron and ion optics) and ion acceleration conditions be changed. The prototype zoom-TOFMS instrument has orthogonal-acceleration geometry, a total field-free distance of 43 cm, and a direct-current glow-discharge ionization source. Experimental results demonstrate that the CMA-TOFMS "zoom" mode offers resolution enhancement of 1.6 times over single-stage acceleration CEA-TOFMS. For the atomic mass range studied here, the maximum resolving power at full-width half-maximum observed for CEA-TOFMS was 1,610 and for CMA-TOFMS the maximum was 2,550. No difference in signal-to-noise (S/N) ratio was observed between the operating modes of zoom-TOFMS when both were operated at equivalent repetition rates. For a 10-kHz repetition rate, S/N values for CEA-TOFMS varied from 45 to 990 and from 67 to 10,000 for CMA-TOFMS. This resolution improvement is the result of a linear TOF-to-mass scale and the energy-focusing capability of CMA-TOFMS. Use of CMA also allows ions outside a given m/z range to be rejected by simple ion-energy barriers to provide a substantial improvement in duty factor.

Extension of the focusable mass range in distance-of-flight mass spectrometry with multiple detectors.

RATIONALE: Distance-of-flight mass spectrometry (DOFMS) is a velocity-based mass separation technique in which ions are spread across a spatially selective detector according to m/z. In this work, we investigate the practical mass range available for DOFMS with a finite-length detector. METHODS: A glow-discharge DOFMS instrument has been constructed for the analysis of atomic ions. This instrument was modified to accommodate two spatially selective ion detectors, arranged co-linearly, along the mass-separation axis of the analyzer. With this geometry, each detector covers a different portion of the distance-of-flight spectrum and ions are detected simultaneously at the two detectors. The total flight distance covered by the two detectors is 106 mm and simulates DOF detection across a broad mass range. RESULTS: DOFMS theory predicts that ions of all m/z values are focused at a single flight time, but at m/z-dependent flight distances. Therefore, ions that are detected across a wide portion of the DOF axis should all yield the same peak widths. With a focal-plane camera detector and a micro-channel plate/phosphor-screen detection assembly, we found simultaneous, uniform focus of (40)Ar(2)(+) and of (65)Cu(+) and (63)Cu(+) with the ions spread 82 mm across the DOF axis. This detection length, combined with the current instrument geometry, allows for a simultaneously detectable m/z value of 4:3 (high mass-to-low mass). CONCLUSIONS: These results are the first experimental verification that constant-momentum acceleration (CMA)-DOFMS provides energy focus across an extended detection length. Evidence presented demonstrates that DOFMS is amenable to detection with (at least) a 100-mm detector surface. These results indicate that DOFMS is well suited for detection of broader mass ranges.

Undetected components in natural mixtures: how many? What concentrations? Do they account for chemical noise? What is needed to detect them?

By definition, information about the set of components in a complex mixture below the detection limit is not directly available. However, if the composition of natural mixtures follows a natural law, the application of this law would enable the prediction of analytically important characteristics of that "hidden" fraction of the mixture. We have found that the analytical responses of compounds in three disparate natural mixtures (extracellular metabolites, light crude oil, and plant extracts) follow a log-normal (LN) distribution to a very high degree of correlation. Through the application of the LN model, the total number of components potentially detectable and the LN parameters of their analytical response distribution have been determined. From this distribution, one can predict the degree of analytical selectivity and dynamic range that would be required to detect any additional fraction of the components present. The data analyses of the studied mixtures reveal that the LN distribution parameters differ from one mixture type to another and that important information regarding the sample and the method employed is obtained. Further, the background level or "chemical noise" in the determinations studied agrees with the predicted cumulative responses of the undetected components. If generally applicable, the LN model will provide characterization parameters for mixture types, a means to assess completeness of analytical methods, and a model for theorists in mixture composition.

Resolution and mass range performance in distance-of-flight mass spectrometry with a multichannel focal-plane camera detector.

Distance-of-flight mass spectrometry (DOFMS) is a velocity-based mass-separation technique in which ions are separated in space along the plane of a spatially selective detector. In the present work, a solid-state charge-detection array, the focal-plane camera (FPC), was incorporated into the DOFMS platform. Use of the FPC with our DOFMS instrument resulted in improvements in analytical performance, usability, and versatility over a previous generation instrument that employed a microchannel-plate/phosphor DOF detector. Notably, FPC detection provided resolution improvements of at least a factor of 2, with typical DOF linewidths of 300 µm (R((fwhm)) = 1000). The merits of solid-state detection for DOFMS are evaluated, and methods to extend the DOFMS mass range are considered.

Inductively Coupled Plasma Zoom-Time-of-Flight Mass Spectrometry.

A zoom-time-of-flight mass spectrometer has been coupled to an inductively coupled plasma (ICP) ionization source. Zoom-time-of-flight mass spectrometry (zoom-TOFMS) combines two complementary types of velocity-based mass separation. Specifically, zoom-TOFMS alternates between conventional, constant-energy acceleration (CEA) TOFMS and energy-focused, constant-momentum acceleration (CMA) (zoom) TOFMS. The CMA mode provides a mass-resolution enhancement of 1.5-1.7× over CEA-TOFMS in the current, 35-cm ICP-zoom-TOFMS instrument geometry. The maximum resolving power (full-width at half-maximum) for the ICP-zoom-TOFMS instrument is 1200 for CEA-TOFMS and 1900 for CMA-TOFMS. The CMA mode yields detection limits of between 0.02 and 0.8 ppt, depending upon the repetition rate and integration time-compared with single ppt detection limits for CEA-TOFMS. Isotope-ratio precision is shot-noise limited at approximately 0.2% relative-standard deviation (RSD) for both CEA- and CMA-TOFMS at a 10 kHz repetition rate and an integration time of 3-5 min. When the repetition rate is increased to 43.5 kHz for CMA, the shot-noise limited, zoom-mode isotope-ratio precision is improved to 0.09% RSD for the same integration time.

Distance-of-Flight Mass Spectrometry: What, Why, and How?

Distance-of-flight mass spectrometry (DOFMS) separates ions of different mass-to-charge (m/z) by the distance they travel in a given time after acceleration. Like time-of-flight mass spectrometry (TOFMS), separation and mass assignment are based on ion velocity. However, DOFMS is not a variant of TOFMS; different methods of ion focusing and detection are used. In DOFMS, ions are driven orthogonally, at the detection time, onto an array of detectors parallel to the flight path. Through the independent detection of each m/z, DOFMS can provide both wider dynamic range and increased throughput for m/z of interest compared with conventional TOFMS. The iso-mass focusing and detection of ions is achieved by constant-momentum acceleration (CMA) and a linear-field ion mirror. Improved energy focus (including turn-around) is achieved in DOFMS, but the initial spatial dispersion of ions remains unchanged upon detection. Therefore, the point-source nature of surface ionization techniques could put them at an advantage for DOFMS. To date, three types of position-sensitive detectors have been used for DOFMS: a microchannel plate with a phosphorescent screen, a focal plane camera, and an IonCCD array; advances in detector technology will likely improve DOFMS figures-of-merit. In addition, the combination of CMA with TOF detection has provided improved resolution and duty factor over a narrow m/z range (compared with conventional, single-pass TOFMS). The unique characteristics of DOFMS can enable the intact collection of large biomolecules, clusters, and organisms. DOFMS might also play a key role in achieving the long-sought goal of simultaneous MS/MS. Graphical Abstract ᅟ.

Distance-of-Flight Mass Spectrometry with IonCCD Detection and an Inductively Coupled Plasma Source.

Distance-of-flight mass spectrometry (DOFMS) is demonstrated for the first time with a commercially available ion detector-the IonCCD camera. Because DOFMS is a velocity-based MS technique that provides spatially dispersive, simultaneous mass spectrometry, a position-sensitive ion detector is needed for mass-spectral collection. The IonCCD camera is a 5.1-cm long, 1-D array that is capable of simultaneous, multichannel ion detection along a focal plane, which makes it an attractive option for DOFMS. In the current study, the IonCCD camera is evaluated for DOFMS with an inductively coupled plasma (ICP) ionization source over a relatively short field-free mass-separation distance of 25.3-30.4 cm. The combination of ICP-DOFMS and the IonCCD detector results in a mass-spectral resolving power (FWHM) of approximately 900 and isotope-ratio precision equivalent to or slightly better than current ICP-TOFMS systems. The measured isotope-ratio precision in % relative standard deviation (%RSD) was ≥0.008%RSD for nonconsecutive isotopes at 10-ppm concentration (near the ion-signal saturation point) and ≥0.02%RSD for all isotopes at 1-ppm. Results of DOFMS with the IonCCD camera are also compared with those of two previously characterized detection setups.

Jim Morrison, Friend and Colleague.

Our long-time association with Jim Morrison and the work that came from it is the result of a series of fortunate coincidences. We are pleased to be able to share recollections here of our interactions with Jim and how his life and work have influenced us and the field of mass spectrometry.

Interleaved Distance-of-Flight Mass Spectrometry: A Simple Method to Improve the Instrument Duty Factor.

Distance-of-flight mass spectrometry (DOFMS) is a velocity-based, spatially dispersive MS technique in which ions are detected simultaneously along the plane of a spatially selective detector. In DOFMS, ions fly though the instrument and mass separate over a set period of time. The single flight time at which all ions are measured defines the specific m/z values that are detectable; the range of m/z values is dictated by the length of the spatially selective detector. However, because each packet of ions is detected at a single flight time, multiple groups of ions can fly through the instrument concurrently and be detected at a single detector. In this way, DOFMS experiments can be interleaved to perform several mass separation experiments within a single DOF repetition period. Interleaved operation allows the orthogonal acceleration region to be operated at a repetition rate higher than the reciprocal of the flight time, which improves the duty factor of the technique. In this paper, we consider the fundamental parameters of interleaved DOFMS and report first results.

Constant-momentum acceleration time-of-flight mass spectrometry with energy focusing.

Fundamental aspects of constant-momentum acceleration time-of-flight mass spectrometry (CMA-TOFMS) are explored as a means to improve mass resolution. By accelerating all ions to the same momentum rather than to the same energy, the effects of the initial ion spatial and energy distributions upon the total ion flight time are decoupled. This decoupling permits the initial spatial distribution of ions in the acceleration region to be optimized independently, and energy focus, including ion turn-around-time error, to be accomplished with a linear-field reflectron. Constant-momentum acceleration also linearly disperses ions across time according to mass-to-charge (m/z) ratio, instead of the quadratic relationship between flight time and m/z found in conventional TOFMS. Here, CMA-TOFMS is shown to achieve simultaneous spatial and energy focusing over a selected portion of the mass spectrum. An orthogonal-acceleration time-of-flight system outfitted with a reduced-pressure DC glow discharge (GD) ionization source is used to demonstrate CMA-TOFMS with atomic ions. The influence of experimental parameters such as the amplitude and width of the time-dependent CMA pulse on mass resolution is investigated, and a useful CMA-TOFMS focusing window of 2 to 18 Da is found for GD-CMA-TOFMS.

How constant momentum acceleration decouples energy and space focusing in distance-of-flight and time-of-flight mass spectrometries.

Resolution in time-of-flight mass spectrometry (TOFMS) is ordinarily limited by the initial energy and space distributions within an instrument's acceleration region and by the length of the field-free flight zone. With gaseous ion sources, these distributions lead to systematic flight-time errors that cannot be simultaneously corrected with conventional static-field ion-focusing devices (i.e., an ion mirror). It is known that initial energy and space distributions produce non-linearly correlated errors in both ion velocity and exit time from the acceleration region. Here we reinvestigate an old acceleration technique, constant-momentum acceleration (CMA), to decouple the effects of initial energy and space distributions. In CMA, only initial ion energies (and not their positions) affect the velocity ions gain. Therefore, with CMA, the spatial distribution within the acceleration region can be manipulated without creating ion-velocity error. The velocity differences caused by a spread in initial ion energy can be corrected with an ion mirror. We discuss here the use of CMA and independent focusing of energy and space distributions for both distance-of-flight mass spectrometry (DOFMS) and TOFMS. Performance characteristics of our CMA-DOFMS and CMA-TOFMS instrument, fitted with a glow-discharge ionization source, are described. In CMA-DOFMS, resolving powers (FWHM) of greater than 1000 are achieved for atomic ions with a flight length of 285 mm. In CMA-TOFMS, only ions over a narrow range of m/z values can be energy-focused; however, the technique offers improved resolution for these focused ions, with resolving powers of greater than 2000 for a separation distance of 350 mm.

Distance-of-flight mass spectrometry: a new paradigm for mass separation and detection.

Distance-of-flight mass spectrometry (DOFMS) offers the advantages of physical separation of ions, array detection of ions, focusing of initial ion energy, great simplicity, and a truly unlimited mass range. DOFMS instrumentation is similar to that of time-of-flight mass spectrometry (TOFMS) and shares its ion-source versatility, batch analysis, and rapid spectral-generation rate. With constant-momentum ion acceleration and an ion mirror, there is a time at which ions of all mass-to-charge values are energy focused at their particular distances along the flight path. A pulsed field orthogonal to the flight path drives the ions to reach the detector array at this specific time. Results from a 0.29-m proof-of-principle instrument verify the theoretically predicted energy focus and demonstrate how the range of mass-to-charge values that impinge on the detector array can be readily changed. DOFMS could be combined sequentially with TOFMS to enable simultaneous scanless tandem mass spectrometry.

First distance-of-flight instrument: opening a new paradigm in mass spectrometry.

A new instrumental concept, distance-of-flight mass spectrometry (DOFMS), is demonstrated experimentally. In DOFMS the mass-to-charge ratio of ions is determined by the distance each ion travels during a fixed time period; the mass spectrum is then recorded with a position-sensitive detector. The DOF approach provides a new way to separate and quantify components of complex samples. Initial results are demonstrated with a glow discharge ion source and a microchannel plate-phosphor screen detector assembly for atomic ion determination. This detection system demonstrated mass spectral peak widths of approximately 0.65 mm, corresponding to resolving powers of approximately 400-600 for a number of elemental samples.

Axial focusing following low kinetic energy pulsed extraction from a miniature linear ion trap.

Using an axial focusing miniature linear ion trap with tubular end cap lenses (MLIT) we have investigated spatial focusing on ion ejection using low kinetic energy pulsed extraction methods. Ion packet widths focused to ca. 1 mm (in both the radial and axial planes) are produced following collisional cooling with helium buffer gas in an MLIT. Small axial and radial packet widths as well as application of DC extraction voltages allow different ion focusing techniques to be used on batch ion extraction. In particular, controlling the position of the space focus plane (commonly used in time-of-flight mass spectrometry) following low kinetic energy ( approximately 10 eV) ion ejection from an MLIT through the application of DC extraction voltages is illustrated. Prior to simultaneous ion ejection, induced axial ion oscillation through a change in the DC potential well shape is also shown to be useful for separating and controlling different mass/charge ion packet spatial distributions in the region of an orthogonal time-of-flight (o-TOF) push pulse.

Achievement of energy focus for distance-of-flight mass spectrometry with constant momentum acceleration and an ion mirror.

Distance-of-flight mass spectrometry (DOF-MS) has not yet been implemented, though it has many potential advantages in a variety of applications. Impeding the implementation of DOF-MS is the development of the required array detectors and working out the equivalents to the focusing methods now used in time-of-flight (TOF) mass analyzers. Ideally, a batch of ions composed of a variety of m/z values, despite initial distributions of space and energy, would be spatially focused at their respective flight distances at the same time. First-order energy focusing, including ion turnaround, is shown to be accomplished by the use of an ion mirror in conjunction with constant momentum acceleration of the initial ion packet. The initial spatial dispersion is maintained throughout the flight path. With zero initial spatial ion spread, energy focusing to achieve resolutions in the tens of thousands is shown to be feasible with ions from the elemental and isotope ratio mass regions through the extremely high m/z range. With moderate spatial spread taken into account, the DOF-MS approach is shown to achieve resolutions competitive with quadrupole and ion trap mass analyzers. Advantages of DOF-MS include all the advantages of TOF-MS plus simpler detector electronics and the improved signal-to-noise ratio and dynamic range afforded by array detection.

Axial ion focusing in a miniature linear ion trap.

A novel miniature linear ion trap with a total length of 19 mm and a quadrupole rod length of 15 mm has been fabricated to enable ion focusing in the axial plane (between the end caps). Each end cap includes an inwardly projecting tubular section, which prevents dc fringe fields from penetrating to the center of the miniature linear ion trap and aids in ion extraction. Axial focusing of ion packets to dimensions of less than 1 mm through collisional cooling is predicted and demonstrated in the miniature linear ion trap. Due to this demonstrated collisional cooling, narrow kinetic energy distributions are also illustrated on batch ion extraction as might be useful for ion transfer to enable subsequent mass analysis.