Introduction

Even though mass spectrometry has evolved rapidly into many fields since the beginning of its widespread use in the 1950s, its true evolution began on, or in close contact with, the synthetic lab bench. Klaus Biemann, who passed away in 2016, was one of the first and foremost proponents of introducing the world of organic chemistry to mass spectrometry, and perhaps described the marriage of both disciplines best within his book from 1962, Mass Spectrometry: Organic Chemical Applications: “…the most useful data are obtained if the originator of the problem and the person determining the spectrum are in close contact. The most ideal situation results if both the chemistry and the mass spectrometry required for the solution of a given problem are carried out by the same individual…” Biemann, along with a veritable pantheon of chemists and physicists, sought to nurture and expand the burgeoning field of mass spectrometry. Thanks in large part to their efforts, mass spectrometry has grown into one of the most crucial analytical techniques ever developed with significant impacts into every corner of science. Some of those who had been vital to the development of improvements for these instruments began early on to explore their applications to improving synthetic experimental procedures. This long history of using mass spectrometers to solve problems at the laboratory bench has brought forth improvements to instrumentation, as well. The need to ionize and introduce a multitude of sample types, including those taken directly from “wet” organic chemistry or biological samples, has fueled many of the advances that have been embraced by the mass spectrometry community. With the vastly improved instrumentation that is so commonly available today, new areas of research in organic chemistry are just now opening that combine the collective knowledge gained by both the organic chemist and the mass spectrometrist. This widespread adoption would appear to be the fruitful result of decades of hard work to ensure a mass spectrometer in every lab, indeed “in every fume hood.” However, with the rapid expansion of mass spectrometry into new fields of research, there comes the inevitable danger of a lack of understanding of fundamental mass spectrometric principles and mechanisms by researchers in those fields. Left unchecked, this has the potential to lead to widespread misunderstanding and in turn disillusion.

Innovations in Organic Chemistry Fueled by Mass Spectrometry

From its inception, mass spectrometry has been used to solve some of the most difficult analytical challenges. In the first half of the 20th century, physicists embraced the ability of mass spectrometers to give them very precise isotopic ratios [1, 2], a technique that would later help synthetic chemists to identify molecular formulas for compounds of interest. It was becoming readily apparent to a select few organic chemists in the 1950s to 1960s that mass spectrometry, when combined with infrared, ultraviolet, and nuclear magnetic resonance spectra, could provide a far more complete set of data that easily complemented these other methods[3]. Initial databases [4] of mass spectra compiled by the petroleum industry in the USA during the Second World War had proven that a wealth of information, such as isotopic ratios and partial pressures, could already be obtained or calculated mathematically from petroleum distillate and byproducts producing spectra as simple as that seen in the mass spectrum of methane in Figure 1 [5]. Ideally, these compounds were fairly volatile and consisted of simple, easy to interpret structures. Gas chromatography coupled to mass spectrometry (GC/MS) [6,7,8] became the standard for volatile analysis, due to the relative ease with which samples could be introduced into the vacuum environment of the mass spectrometer. In other cases, the need to derivatize compounds to improve their volatility was justified by the improved data that could be obtained on previously unidentified molecules by mass spectrometry. Throughout the 1950s, chemists began to realize that the mass spectra produced from these instruments were accurate enough to distinguish between isomers and functional groups based on fragments and isotopic ratios, and a flurry of papers [9,10,11,12] ensued. One excellent example of the utility of mass spectrometry was in the early analysis of “human hair fat” by both typical spectroscopic means [13], as well as by mass spectrometry [14]. The use of mass spectrometry for detecting free fatty acids prevented the need for extracting 45 kg worth of human hair, while still providing an analysis of the long-chain alcohols present. Unfortunately, many of these early findings were very difficult to share with colleagues, as they were not able to be computerized, and searching through spectra often meant doing so one at a time at the site of the instrument. Nonetheless, soon other fields began to see the advantages of such a rapid and quantitative, albeit more expensive, technique. Food chemists and natural product chemists began utilizing mass spectrometers for unknown compound identification, wherein a single mass spectrum could give both structural and conformational data. Great progress was made in analyzing alkaloids isolated from natural sources [15,16,17] by mass spectrometry, rather than relying on just spectroscopic, combustion, or melting point data. Indeed, in some instances, mass spectrometry provided information that could not have been attained otherwise. A prime example of this is the detection of two different isoquinoline alkaloid isomers within cactus plant samples [18]; while both could be detected by mass spectrometry, typical workup procedures converted the N-methyl isoquinoline structure into the C-methyl structure, rendering their isolated detection impossible. In another instance [19], R.G. Cooks et al. confirmed the structure by mass spectrometry of cassipourine, which was not confirmed by total synthesis until over a decade later [20]. This and previous work led to a lengthy review article on the uses of mass spectrometry [21]. Based on these advances in the knowledge and understanding of fragmentation patterns of molecules, mass spectra could now be interpreted with much greater precision and speed; this was vital for chemists who quite often had to deal with alkaloids and other complex, naturally-occuring compounds that were present in mixtures or plant material. Because of this, the search for techniques that could handle more complex mixtures was paramount. Beginning in the 1960s with techniques like mass-analyzed kinetic energy spectrometry (MIKES) [22,23,24], the search for ionization mechanisms that could give more structural information without the need for derivatization or extensive sample pretreatment began. However, this new area of research was used only sparingly [25] to analyze mixtures from bulk-phase solution reactions.

Figure 1
figure 1

As early as the 1940s, spectra of petroleum distillates provided a wealth of information, such as the isotopic ratios shown here in a methane spectrum. Reprinted (adapted) with permission from [5]. Copyright 1957, American Chemical Society

One of the driving forces behind developing sample introduction techniques for larger or less stable compounds came about not from pure organic chemists, but from biochemists. GCMS initially helped solved many of the problems associated with Edman degradation seen throughout the 1960s, and many advances were made in unlocking the amino acid sequences of proteins where Edman degradation alone was not sufficient for identification [26,27,28,29]. After the successes of coupling gas chromatography to mass spectrometry, the ability to analyze samples from liquid phase, rather than gas-phase, seemed to be the key to unlocking the potential of analyzing even more difficult biomolecules. However, it was not without its own hurdles to overcome. While GC-MS is capable of introducing a relatively small amount of gaseous sample into the “leak” in the front of a mass spectrometer and saw many advancements early on, a liquid interface introduces orders of magnitude more matrix and is not compatible with vacuum. Because of this, development of LC interfaces to mass spectrometers proceeded much slower. Through the 1970s–1990s, techniques were developed to help combat this problem of sample introduction, including moving-belt interface (MBI) [30,31,32], direct liquid introduction (DLI) [33,34,35], thermospray [36,37,38], fast-atom bombardment [39,40,41], capillary electrophoresis [42,43,44,45], and eventually electrospray ionization (ESI) [46,47,48,49,50] and matrix-assisted laser-desorption ionization (MALDI) [51,52,53,54,55]. It would appear that with the explosion of these softer ionization techniques, the ability to analyze complex synthetic reactions would be better than ever before. It is wise, however, not to underestimate the challenges presented whenever developing and introducing new techniques to the scientific world at large.

Case Study I—Identification of Alkaloids

The initial surge of developments in mass spectrometry spurred on by World War II coincided with tremendous development in the realm of natural product chemistry. Both areas benefited from the desire to find new resources in areas such as medicine and fuels and utilize them. Natural product chemistry became a booming field, with hundreds upon hundreds of new compounds being isolated from plant sources around the globe. Unfortunately, identifying the structures of these compounds often required synthetically derivatizing them and comparing their combustion and mixed melting point data to known standards; this was a labor intensive process, and required relatively large amounts of sample. It was at this time that Klaus Biemann, newly minted to a faculty position in 1957 at MIT, realized the potential of the mass spectrometer as the newest analytical tool that could succeed where previous methods had failed. One such example was determining the structure of sarpagine, isolated from Rauwolfia serpentina root (Figure 2). The proposed structure was to be confirmed by derivative synthesis, but the synthetic route to this derivative proved difficult and had not found its way into the literature even years later. Biemann recognized that by making small, synthetically simple changes to the structure, the relative isotopic ratios of the two molecules would essentially remain the same; the only change would come from the shifted masses due to the derivatization. This technique, which would later come to be known as the “mass spectrometric shift technique,” had a major impact on the study of natural products in conjunction with isotopic labeling. Structures that had previously been difficult or impossible to determine by conventional means could be elucidated within a relatively short amount of time with high accuracy utilizing less than a milligram of precious unknown. This was especially important for Biemann’s following work on quebrachamine isolated from Aspidosperma quebracho blanco, which had no derivatizable groups present and was also found in only very small quantities. By using the recently developed technique of gas-liquid chromatography and fraction collection, minute portions of this extract were able to be compared to analogs via the shift technique and the final structure was finally deduced. Regrettably, the novelty of these techniques, as impressive as they were, made publishing the data on the quebrachamine extracts difficult, as one assistant editor responded, “It is quite possible that in the future natural products chemists will take the turn your work has indicated…However, until this is more common, a clear indication of the extent of your departure from past methods is necessary.” At least a small portion of this concern was also shared by Biemann, who remarked somewhat portentiously that he feared “other workers in the field of alkaloid chemistry may use these mass spectrometric techniques too freely or may draw unjustified conclusions.” Indeed, many of the pioneers in organic mass spectrometry, such as Fred McLafferty [56] and John Beynon [57], shared in his optimism and trepidation and had published volumes of their own on the capabilities (and shortcomings) of mass spectrometry as an analytical technique. In the modern era, applications derived from these pioneers show great promise, but not without their own set of challenges and setbacks.

Figure 2
figure 2

Chemical structures of (a) sarpagine, (b) the originally proposed synthetic derivative, and (c) the compound synthesized by Biemann et al to demonstrate the mass shift technique along with (b)

Case Study II—Illicit Drugs

Within the realm of illicit drug manufacture, the ability to track impurities arising from organic synthesis is a powerful tool that can elucidate not only the drug being produced, but also the route being used and even the progress to the final product itself. Route-specific impurities are an excellent fingerprinting tool for forensic chemists and have been the target of many different mass spectrometric applications [58,59,60,61,62,63,64,65]. However, despite progress towards the on-line monitoring of the production of some pharmaceuticals [66] or monitoring of illicit chemicals within the atmosphere [67], the direct analysis of an ongoing illicit reaction is still in its infancy. Direct analysis in real-time-mass spectrometry (DART-MS) has become a popular sample introduction technique, but has mainly been used as a tool for seized solid or liquid samples [68, 69]. Ambient techniques could be applied readily to an ongoing illicit synthesis when a mass spectrometer is incorporated into the fume hood. In order to produce fentanyl via the Valdez method [70], N-phenethylpiperidone, or NPP, can be produced from 2-bromoethylbenzene and piperidone. This reaction can be achieved using a variety of reagents [71], but the Valdez route is one of the fastest and simplest procedures within the literature. Within this reaction pathway, there are many byproducts that are capable of being formed. Knowing that precursors and impurities could possess a volatility and membrane permeability that would allow their access via membrane-inlet mass spectrometry (MIMS), a “cook”, or simulated clandestine synthesis, was performed (Figure 3) within the fume hood and the effluent from aliquots of these reactions were analyzed. After analyzing the data, it was apparent that diisopropylethylamine (DIPEA) was a major impurity within the effluent of the reaction and highly membrane permeable. This reagent is used only in the final step of the Valdez method, and therefore could be considered a good candidate for MIMS detection of illicit samples. Considering the very large and varied group of compounds typically found as impurities within fentanyl reactions [59, 60], this could prove an invaluable technique for sampling illicit exhibits while not exposing the operator to a highly potent opioid. Additionally, this MIMS technique could prove to be more well suited for fentanyl and its analogs, as these compounds are typically not volatile enough for GC-MS detection without high temperatures, which can cause excessive column bleed and shorten the life of an instrument. As the synthesis was carried out, each aliquot showed successively higher mass peaks and are indicative of what step has been reached within the synthesis of fentanyl. Subsequent research could show that this stepwise analysis of each synthetic route performed within the fume hood could indicate volatile route-specific markers. The ability to quantitatively monitor an illicit reaction can provide a wealth of data for forensic practitioners. Understanding the underlying organic chemistry and how these complex mixtures can be produced can give forensic chemists an excellent fingerprint of both methods and products of illicit synthesis and can guide the benchtop organic chemist. This is, lamentably, not the current state of forensic science. In many cases bogged down by shrinking budgets and a lack of research community [72], instrumentation small and rugged enough to foster new innovations and be found “in every fume hood” are passed over in favor of those that are firmly established within the status quo.

Figure 3
figure 3

MIMS detection of effluent from synthetic products of fentanyl via the Valdez method, including (a) the intermediate N-phenethylpiperidone (NPP), (b) the reaction to produce the final product from 4-anilino-N-phenethylpiperidine (4-ANPP), and (c) the effluent from the final product fentanyl. Fragment spectra are consistent with EI fragmentation of fentanyl and its precursors, and the m/z 72 peak found in the final step comes from the membrane-permeable reagent diisopropylethylamine (DIPEA)

However, this is not always the case. The information gained from these fentanyl analyses (along with others) done directly within the fume hood has allowed for portable mass spectrometry solutions to be developed for fieldable applications. By developing a fieldable mass spectrometer that utilizes a membrane inlet and single quadrupole mass analyzer, selected membrane-permeable compounds, such as small aromatics common within clandestine synthesis, can be quantitatively detected with very low limits of detection within ambient air. This technology has been implemented into a mobile system and deployed in several scenarios [73, 74], the most notable of which is the detection of effluent from a mock clandestine synthesis of methamphetamine precursor material [75]. This and other technologies, sometimes referred to as “chemical sniffing,” have also been reviewed [76] as novel instrumentation seeks to gain a foothold within the forensic science community.

Current Avenues of Research

Despite the recent history of mass spectrometry being used by biochemists for the elucidation and structural confirmation of many proteins and peptides, the very heart of mass spectrometry is still at the organic benchtop. Sadly, only within the last few years have new developments in mass spectrometry been explored within the context of modifying, improving, or exploring reaction pathways. ESI-MS has been used to probe many reactions typically carried out at the bench and has shown great promise for elucidating intermediates within solution phase, probing mechanisms and reaction rates, and investigating the behavior of ionic species within the gas phase (Figure 4) [77]. Research has proceeded roughly divided between using the electrospray source as a probe of bulk solution-phase phenomena, or using it as an on-line approach to reaction monitoring. The Morita-Baylis-Hillman reaction is used to create new carbon-carbon sigma bonds within molecules typically from an imine or aldehyde and an alkene with an electron-withdrawing group attached. This reaction is fairly straightforward and has been applied to the synthesis of many difficult molecules, including some natural products. However, the exact mechanism of the reaction is still under debate; experimental and theoretical data has been evolving ever since the reaction was first discovered. To that end, ESI-MS was used [78] to probe the reaction during its course, with intermediates being removed from the reaction as aliquots and analyzed. Due to the power of MS/MS and the gentle ionization from solution to gas-phase, important intermediates to this reaction were identified for the first time. This experimental data helped to empirically prove what many other groups had surmised from only kinetic and theoretical experiments. In addition to the Morita-Baylis-Hillman reaction, other reactions have been studied as well, including the Biginelli reaction [79], Pauson-Khand reaction [80], tandem Heck-lactonization reaction [81], and Sandmeyer’s reaction [82].

Figure 4
figure 4

(a) Diagram depicting the flow of intermediates within the Stille reaction. (b) ESI(+)-MS spectrum depicting precatalyst palladium ion at m/z 630. (c) ESI(+)-MS spectra after addition of 3,4-dichloroiodobenzene (d) ESI(+)-MS spectrum after addition of vinyltributyltin depicting intermediates at m/z 569, 657, and 958 (5b, 7b, and 5a, respectively). Reprinted (adapted) with permission from [77]. Copyright 2007, American Chemical Society

Alternatively, other experiments have been carried out to analyze the progress of reactions, including the use of electrospray-assisted laser desorption ionization (ELDI). By including a certain concentration of carbon powder within the reaction medium, a laser can be applied to the surface of the surface. As the carbon absorbs most of the ionizing energy from the pulsed laser, analytes of interest absorb this energy and are desorbed from solution into the ESI stream. As the reagents are mixed, ions of interest were monitored [83] and the epoxidation product of chalcone can be clearly seen growing in as chalcone is seen to disappear from the ESI spray. Improving of yield has also been shown with ESI-MS, and the exact mechanism of the process has been investigated. Utilizing the Fischer indole synthesis, it has been shown [84] that rather than depending on just solution or gas-phase parameters, the greatly enhanced efficiency of ESI towards reactions involves interfacial effects and occurs within the microdroplets of the spray [85]. Simplistic methods of improving reaction yields by altering the bulk-phase environment, such as using sonication [86,87,88] or microwave-irradiation [89, 90], have shown great promise in the past. It is not so dissimilar to imagine the ability of mass spectrometers to perform a similar alteration. These ESI-MS experiments are helping shed light on previously unknown or contested mechanisms within complex organic reactions [91, 92].

Reactions carried out within the electrospray mechanism have shown increased reaction rates, and research in the past decades into coupling ESI-MS to on-line synthesis platforms provides the backdrop for small, on-line organic syntheses carried out within ESI-MS (Figure 5) [93]. The continuous-flow production of diphenhydramine has been shown with such a microfluidic device [94], and modifications for waste, product collection, and the exploration of experimental conditions to improve yield are all being considered. Perhaps one of the most simple and powerful techniques discovered recently in this area is extractive electrospray ionization-mass spectrometry (EESI) [95,96,97,98]. This technique uses two different nebulizers positioned at an angle to the inlet cone of the mass spectrometer. One of these nebulizers contains the electrospray solvent and charge carrier, while the other nebulizer contains the sample solution. This technique has also been used with a nitrogen flow over a reaction flowing through directly into the stream of charged microdroplets without the need for liquid flow from the reaction chamber. By utilizing this technique, samples have been taken from relatively undiluted, complex biological matrices [99] (urine, milk, etc) (Figure 6) [100], as well as directly from ongoing chemical syntheses [101]. In the case of sampling from a nitrogen flow over the synthesis, reactants, products, and intermediates were all able to be detected, and the analysis of the effluent from the reaction matched previous data taken from the solution phase to determine when the reaction endpoint had been reached. This tehnique has already fostered review articles [102,103,104] centered around its future, especially for the analysis of complex biological samples and in vivo studies where matrix effects and speed of analysis play a significant role.

Figure 5
figure 5

Diagram depicting the use of a transfer tube for improving upon the Hantzsch synthesis of 1,4-dihydropyridines at a distance of (a) 20 cm, (b) 55 cm, (c) 70 cm, and (d) 90 cm. The product, (9), can be seen to increase substantially as the distance from the spray source to the ion capillary increases, with a relative decrease in starting material (2) and intermediates (3–6). Reprinted (adapted) with permission from [93]—Published by the Royal Society of Chemistry

Figure 6
figure 6

(a) Intensity plots for each of four compounds detected in rat urine samples from different diets and (b) collisionally-induced dissociation (CID) spectra for each of the four compounds [a-d] (alloxan, 3-hydroxykynerenine, gluconic acid, and glucose, respectively). Reprinted (adapted) with permission from [100]. Copyright 2007, American Chemical Society

Challenges

It is an incredible thing to imagine a mass spectrometer in every fume hood in every lab, but the stark reality of mass spectrometry is that even over half a century after their implementation, these instruments are still considered by many organic chemists as ‘black boxes’. When it comes to benchtop organic chemistry, there is a modern disconnect. The past decade has seen a myriad of papers published in inorganic, organic, and surface chemistry journals involving the use of mass spectrometry to probe reaction mechanisms, and yet, there is often little discussion or experimental procedure designed with the shortcomings of ambient ionization in mind. As these fields expand rapidly based upon these findings, the potentiality for erroneous or poorly investigated results increases dramatically. By properly addressing these issues in experiments and utilizing the portability and ruggedness of modern mass spectrometers coupled to ambient ionization, organic chemists will be able to explore new areas of research directly from the fume hood.

Progess in the area of portable mass spectrometers has seen a rapid expansion within the past 15 years. Specifically, significant progress has been made in mass spectrometer portability within that time. Although some of the earliest attempts at creating portable mass spectrometers began decades earlier [105], these were highly specialized instruments built specifically for only one experiment. It is worth noting the difference between “portable” mass spectrometers, which are composed of the entire analytical instrument and typically are able to be carried by one person, and “miniaturized” mass analyzers, which have been reviewed previously [106] but are beyond the scope of this article. Research into fieldable instruments spans many different mass analyzers, including rectilinear ion traps [107], quadrupoles [74], time-of-flight (TOF) [108], toroidal ion traps [109], cylindrical ion traps [110], three-dimensional (3D) ion traps [111], linear ion traps [112], and planar linear ion traps [113], in addition to others [76]. In general, these instruments are designed to be portable, have low power requirements, and require less training than conventional benchtop mass spectrometers (Figure 7). Because of this, they are uniquely suited to overcome some of the problems associated with implementing a mass spectrometer in the fume hood. However, many of these technologies have yet to be commercialized and are not yet optimized or widely available.

Figure 7
figure 7

A simplified approach to fieldable analysis is shown here incorporating ambient ionization via low temperature plasma (LTP) ionization with a portable mass spectrometer. This technique utilizes a lightweight, handheld probe for the sample introduction, along with intuitive software for processing data. These end-user considerations further improve ease of use and throughput. Reprinted (adapted) with permission from [115]. Copyright 2014, American Chemical Society

Beginning with the advent of desorption electrospray ionization (DESI) in 2004 [114], the combination of ambient ionization with these portable MS appeared as a viable way to introduce a sample into the mass spectrometer with little or no sample preparation and offered rapid (~ 5 s) total ionization and analysis times. Ambient ionization techniques have expanded dramatically and a wide variety of acronyms have been used to describe them, including low-temperature plasma (LTP) [115], direct analysis in real time (DART) [116], extractive electrospray ionization (EESI) [117], laser ablation electrospray ionization (LAESI) [118], electrospray-assisted laser desorption/ionization (ELDI) [119], and paperspray ionization (PS-MS) [120], among others. In order to bring clarity to how these techniques ionize a sample, more mechanistic approaches have identified a few distinct ionization mechanisms [121] within this diverse group of acronyms. For the implementation of mass spectrometers into synthetic benchtop applications, these techniques must be understood by this mechanistic approach. By providing this framework, the numerous applications of these techniques can be used to bridge the gap between both analytical and synthetic perspectives.

Although the variety of techniques available to be introduced directly into fume hoods is daunting, this variety does provide synthetic chemists with customized, in situ solutions. Ambient ionization with corona discharge can allow for rapid analysis directly from glass capillaries of both solids and liquids [122]. Using DESI as the ionization technique directly from TLC plates [123] combines the ease of use of both techniques to separate and analyze with no sample preparation and very little training. Reactions requiring precise quantitation, such as reaction progress monitoring, could be used with a portable linear quadrupole mass analyzer. Alternatively, a reaction requiring the rapid identification of multiple byproducts or impurities could utilize the power of MSn and ion trap mass analyzers. Ambient techniques can even be paired with precise motorized controls to allow for MS imaging across surfaces, such as tissue sections [124]. By tailoring the analysis to the experiment and performing the analysis directly from the hood, these ambient, fieldable techniques can empower the synthetic chemist with real-time data.

It has already been shown that mass spectrometers can speed up reaction times, improve yields, unlock new fragile intermediates for study, and provide for continuous-flow chemistry that is inherently scalable to production level. In addition, mass spectrometers could potentially offer many other improvements within the fume hood such as fast and reliable reaction parameter changes. The ability to eliminate multiple batch processes needed to determine what experimental conditions provide the best results could all be combined into one, automated system. There are a number of hurdles to overcome before then, however. There are currently only a very few number of reactions that have been probed by techniques such as ESI and ELDI, and the applicability of these techniques to different reaction conditions is limited by the abilities of the instrumentation. Additionally, fouling of microreactors with reagents or reaction conditions unsuitable for current microfluidics reactors will have to be overcome. Apart from being able to identify ions within the solution phase of reactions, there is also the need to isolate the product(s).

The problems faced today with trying to employ a mass spectrometer in every fume hood are indeed the same problems foreseen by many of the early pioneers of this field. Even as ambient ionization techniques [125] seek to probe reaction mechanisms and identify transient intermediates that have never been isolated in bulk solution phase experiments, there are still many unanswered questions. Conditions within the electrospray ionization mechanism are decidedly different from those in bulk solution, made evident in some cases by reaction rates that are orders of magnitude greater [93, 126] or molecules that ionize differently within both mediums [127]. While this can be advantageous when performing experiments on trying to improve reaction yields at the bench, it can prove difficult to those attempting to investigate reaction mechanisms within bulk solution. Low concentration of reactive intermediates, solvent effects on intermediate stability, the transient nature of some organometallic intermediates, and the detection of intermediates within complex matrices like blood are just a few of the hurdles that are yet to be overcome. Additionally, modern organic chemists seeking to employ mass spectrometry to monitor and improve their reactions directly at the bench are presented with a dizzying array of ambient ionization possibilities [128]. It is paramount that organic chemists, who have far more modern tools available to them than in decades past, seek to explore reactions and their mechanisms using ambient ionization techniques in combination with other techniques, such as condensed phase [129] or computational studies. Being able to corroborate mechanistic data taken from ambient ionization techniques in the gas-phase with bulk-phase studies would help provide a clearer picture of similarities or differences between the two, and several reviews have already addressed some of these issues [127, 130, 131].

Conclusion

Many new areas of research into utilizing mass spectrometry for improving organic reactions are being explored by the works of Cooks and others, but there is still room for improvement before we have reached the point to have a “mass spectrometer in every hood.” Beyond novel ionization mechanisms and reaction phenomena within the front end of the mass spectrometer, the idea of using portable mass spectrometers along every step of a synthesis is an idea that has never quite caught on, despite the tools and talent being available. Hopefully, the future will continue to produce novel work wherein synthetic organic chemists begin to utilize mass spectrometers along every step of their work.