Horbaczewskyj, Christopher Stefan (2019) Monitoring, Modelling and Optimisation of Continuous Flow Reactions Using On-line Mass Spectrometry. PhD thesis, University of Leeds.
Abstract
An on-line mass spectrometry method has been developed to monitor, model and optimise continuous flow reactions. This method makes use of dual-piston pumps, tubular reactor block, Vici sample actuator, an Advion expression Compact Mass Spectrometer (CMS) and other analytical systems to investigate a variety of chemical systems based on their need for process improvement. Full reaction automation employed MATLAB, the Snobfit algorithm, along with Modde DoE software. On-line mass spectrometry has advantages over other analytical techniques as it has shorter acquisition times (2-60 s), low chemical sensitivity (~108 mol%) and chemical identity as well as the potential to provide quantitative information. In this work, reaction quantitation has been explored using four chemical systems, where each of them was monitored by a variety of analytical techniques, with the overall aim being to examine if on-line mass spectrometry can be used for quantitative analysis. For all cases investigated, process improvements were made whilst also determining optimal operating conditions to improve conversions, yields or selectivities as well as looking at reaction waste reduction. Flow chemistry and the work conducted has shown how waste can be reduced for certain reactions when compared to more traditional approaches. This method relies on machine learning, full process automation and quick process analytical technology to determine optimum conditions as well as build large reaction data sets. Large data sets were created using a hybrid DoE-kinetic composite circumscribed orthogonal design. Mass spectrometry provided valuable reaction information and has the potential for reaction quantitation depending on the required application, reaction system and ionisation settings. Compound thermal stability can be problematic in APCI+ mode whilst ion suppression is problematic in ESI+ mode. Still a versatile analytical tool, on-line mass spectrometry was found to be inherently quantitative. The continuous-flow-on-line-MS-self-optimisation platform was used to investigate a variety of different reactions to show versatility of the MS system. These reactions are summarized below. 1) An N-Boc deprotection of AZD5634 for optimisation and process scale-up, with achieved conversions >95% and scale-up to pilot and commercial scale using on-line mass spectrometry). 2) An N-Boc deprotection reaction using a hybrid DoE-kinetic model for optimisation and large data set generation, with achieved conversion >90%. 3) An SNAr reaction of AZD4547 for product selectivity and yield improvement, with achieved conversion of ~38% and DP yield of ~30%. 4) The synthesis and optimisation of Fe-N-heterocyclic carbene complexes using an electrochemical method for use in a C-H hydroxylation reaction. Optimum electrochemical conditions of either 7 V and 4 minutes residence time, or 2.5 V and 15 minutes residence were achieved.
Introducing a new way to analyze and present mass spectral data, the Advion Interchim Scientific® Peak Express® patented software uses the delta spectrum (ΔS) to quickly and automatically detect significant peaks within mass spectra based on their relative change in intensity over time instead of their absolute intensity.
Find impurities and minor components that would otherwise be missed
Find unknowns in complex samples such as natural products
Automatically find adducts, dimers, fragments, side reactions, and other unexpected compounds in real time and post processing
Control mass-directed purification without providing an exact mass
Get extracted ion chromatogram (XIC) quality data while scanning the entire mass range
USDA-ARS, Cornell University, Michigan State University
Abstract
The common dry bean (Phaseolus vulgaris L.) is a globally produced pulse crop and an important source of micronutrients for millions of people across Latin America and Africa. Many of the preferred black and red seed types in these regions have seed coat polyphenols that inhibit the absorption of iron. Yellow beans are distinct from other market classes because they accumulate the antioxidant kaempferol 3-glucoside in their seed coats. Due to their fast cooking tendencies, yellow beans are often marketed at premium prices in the same geographical regions where dietary iron deficiency is a major health concern. Hence, this study compared the iron bioavailability of three faster cooking yellow beans with contrasting seed coat colors from Africa (Manteca, Amarillo, and Njano) to slower cooking white and red kidney commercial varieties. Iron status and iron bioavailability was assessed by the capacity of a bean based diet to generate and maintain total body hemoglobin iron (Hb-Fe) during a 6 week in vivo (Gallus gallus) feeding trial. Over the course of the experiment, animals fed yellow bean diets had significantly (p ≤ 0.05) higher Hb-Fe than animals fed the white or red kidney bean diet. This study shows that the Manteca yellow bean possess a rare combination of biochemical traits that result in faster cooking times and improved iron bioavailability. The Manteca yellow bean is worthy of germplasm enhancement to address iron deficiency in regions where beans are consumed as a dietary staple.
Analysis was performed by LC/MS using the Advion expression Compact Mass Spectrometer (CMS).
The cannabinoid makeup of cannabis has significantly changed over the past few decades. Efforts to increase the psychotropic effects of cannabis have resulted in a THC content for current strains of the crop of 30 to 40 percent compared with only 5 percent 30 years ago. Up-regulating the THC content of the plant causes a loss of other cannabinoids the plant is producing. Some of these other cannabinoids, such as CBD, are believed to be responsible for its medical benefits.
Furthermore, no pesticides can currently legally be used during the production process. However, a recent test showed that two out of three samples of legal cannabis samples had pesticide residues above the legal limit for an edible. Once sample exceeded the limit by a factor of 1,600. Such a sample poses a consumer health risk and clearly shows the potential for illegal growing procedures or unclear product streams in the marketplace.
Additionally, cannabis contains more than 400 chemical compounds, 80 of which are unique to cannabis. This fact, plus the finding of cannabinoid receptors in human nerve, immune and brain cells explains why this product is such an interesting target for medicinal use.
This webinar examines three different workflows surrounding compact mass spectrometry as they apply to cannabis law enforcement, it’s natural product research, and product control.
In this webinar, Advion’s Scientific Founder, Jack Henion, Ph.D., will discuss his research using a direct analysis probe coupled with the expression CMS to analyze chemical compounds in Cannabis.
During this webinar you will learn more about:
A simple, sensitive and selective ASAP sample introduction approach to measure the presence and relative quantitative composition of two isobaric compounds, CBDA and THCA, contained in a complex sample such as hemp or cannabis plants or their corresponding extraction products.
Measurement of differences in the relative composition of CBDA and THCA fragment ions originating from the same precursor ion.
Applicability to screening plant and plant product materials such as hemp or marijuana to monitor out-of-specification composition.This webinar was featured by Lab Manager’s Tech Trends webinar series, “Tools for the Cannabis Testing Lab.”
This webinar was hosted by Lab Manager and recorded 4/11/19.
Thanks to the diminishing size and cost of mass spectrometers, coupled with their increasing robustness and ease of use, universities are now starting to furnish their undergraduate chemistry laboratories with this advanced analytic tool.
“My favorite learning environment is the laboratory,” explains Paul A. Flowers, professor of analytical chemistry at University of North Carolina at Pembroke. “I like teaching students fundamentals through bona fide research experiences.” Flowers began using mass spectrometry in the teaching laboratory about six years ago and hasn’t looked back.
Learn more about the integration of mass spectrometry for teaching with this free whitepaper.
The expression® CMS provides essential information quickly and improves the chemist’s workflow by using a direct analysis probe, otherwise known as ASAP® (Atmospheric Solids Analysis Probe) permits chemists affordable and reliable sample analysis of solid and liquid samples such as reaction mixtures, food samples, natural products and tablets.
Chemists simply dip the closed end of a glass capillary into the sample of interest (even complex mixtures) or scrape the surface of a solid, and then place the capillary into the CMS for analysis. Clean-up and analysis is a single step. Involatile buffers and salts remain on the capillary ensuring they do not suppress ionization or interfere with the measurement, while the compounds of interest are identified by the CMS.
The Atmospheric Solids Analysis Probe (ASAP™) allows chemists to directly analyze liquid and solid samples by mass spectrometer without the need for sample preparation. The inert ASAP (iASAP) is a modification of this technique, allowing easy sampling of air-sensitive compounds, such as metal catalysts and organometallics, from reactions that are carried out in a glove box or Schlenk line to prevent oxidation.
The technique allows a synthetic chemist to perform real-time reaction monitoring by sampling the compound with the special iASAP probe, which is designed to provide access to the sample without disturbing the inert environment, then transferring the sample to the CMS, while continuing to protect it in an inert environment where it is ionized by atmospheric pressure chemical ionization (APCI). Mass Spectra are acquired in seconds.
Volatile Atmospheric Pressure Chemical Ionization (vAPCI) combined with Advion Interchim Scientific’s expression® compact mass spectrometer (CMS) is a fast and easy method to analyze the headspace of a sample with no additional sample prep.
The vAPCI ion source is a simple, powerful tool for gas phase sample analysis. The technique can quickly and confidently identify compounds in air, breath, headspace and other gas samples.
Direct sample analysis of liquids, solids and powders without chromatography is as easy as it sounds, and provides mass spectral information within seconds. The video demonstrates analysis of a reaction mixture.
