Chemical Reaction Kinetics

In today's fast-paced pharmaceutical, agrichemical and fine chemical sectors, the mounting pressure to shorten development cycles requires a shift toward more efficient research methodologies. This white paper examines how the integration of data-rich experimentation (DRE) and kinetic modeling provides the deep process understanding necessary to meet these timelines. By leveraging high-density data, researchers can streamline workflows, enhance process safety, and ensure sustainability throughout the scale-up process.

Reaction kinetics provide a measurement of reaction rates, factors that affect the speed of a chemical reaction and insight into reaction mechanisms. Understanding the kinetics of a reaction is critical for being able to control a reaction and direct the desired outcome of the reaction. By testing and identifying how variables affect the rate of a reaction, products are optimized and by-products are reduced.

From investigation of reaction kinetics, both the individual orders of elementary steps in a reaction and the overall order of the reaction are determined. The order of a reaction is important to know because it defines the relationship between the concentration of reactants and the rate of reaction. For example, if a reaction is second order overall, it means that the reaction rate increases by the square of the concentration of the reactants. The order of the individual reactants is determined and reflects how much the concentration of an individual reactant either accelerates or slows down a reaction. 

In-situ Molecular Spectroscopy Yields Kinetic Rate Information

By measuring changes in concentration of reaction species as a function of time under actual reaction conditions, in-situ spectroscopy like ReactIR and ReactRaman provide critical information for chemical kinetic studies. Typically, chemical reaction kinetics are calculated from initial rate studies. One reagent is held at an artificially high concentration so that the concentration is effectively constant, and the kinetic rates are calculated from the change in concentration of another reagent. Because of the impediments associated with offline analysis, most of the concentration changes are never captured beyond the first few minutes, so the experiment must be repeated multiple times under varying concentrations.

In contrast, ReactIR and ReactRaman provide continuous data over the course of a reaction, allowing the calculation of rate laws with fewer experiments, as a result of the comprehensive nature of the data.

In-situ Reaction Sampling to Support Analysis by Offline Analytical Methods

When syntheses require offline analysis by HPLC or NMR or MS, EasySampler provides reaction samples without disturbing the reaction mixture. The system extracts a reaction sample automatically at pre-set time intervals, quenches and dilutes them to prepare for analysis. In addition to providing necessary kinetic information, EasySampler provides samples for offline quantitative analysis by chromatography that can be used to calibrate the spectroscopic measurements via univariate or multivariate methods. These calibration sets allow ReactIR and ReactRaman to provide direct quantitative measurement in real-time on reaction mixtures.

The value of in-situ measurements for obtaining kinetic information:

• Measure concentration vs time data for reactants and products throughout the entire course of the reaction so that no information is missed
• Enable data-rich experiments for advanced kinetic techniques such as RPKA
• Reduce the number of experiments needed to determine rate constants, rate laws and other important kinetic information
• Rapidly test the effects of reaction variables on reaction outcome
• Obtain complete information for corroborating postulated reaction mechanisms 

Foth, P. J., Malig, T. C., Yu, H., Bolduc, T. G., Hein, J. E., & Sammis, G. M. (2020). Halide-Accelerated Acyl Fluoride Formation Using Sulfuryl Fluoride. Organic Letters, 22(16), 6682–6686. 

The authors report a novel method for SO₂F₂-mediated substitution reactions starting from carboxylic acids. They determined that the SO₂F₂- mediated acid activation forms a transient anhydride intermediate that transforms into the analogous acyl fluoride. They also report that tetrabutylammonium chloride or bromide accelerate the formation of acyl fluoride.

ReactIR measurements provided insight into the mechanism of the sulfuryl fluoride-mediated reaction of 3-phenylpropionic acid to the corresponding acyl fluoride by detecting the transient anhydride intermediate and by tracking a band at 1846 cm^-1 associated with the formation of the acyl fluoride product. Also, ReactIR measurements showed that the rate of conversion to the acyl fluoride was enhanced with the presence of the tetrabutylammonium halides. By tracking the formation and conversion of the anhydride intermediate via the 1820 cm^-1 C=O peak, the authors showed that the tetrabutylammonium halides accelerate the conversion of the anhydride to the acyl fluoride. Furthermore, using the IR data with kinetic modeling via COPASI (Complex Pathway Simulator), they found strong support for their proposed mechanism for the halide acceleration process.

Malig, T. C., Yunker, L. P. E., Steiner, S., & Hein, J. E. (2020). Online HPLC Analysis of Buchwald-Hartwig Aminations from within an Inert Environment. Chemrxiv.org. 

The capability of online HPLC analysis of reaction mixtures is very useful in situations where in-situ spectroscopic measurements are less feasible due to overlapping spectral peaks or low concentration of key species. The authors report the development of a reaction monitoring system that draws a timed sample from a reaction mixture contained in a glove box, dilutes the sample, passes it on to a HPLC residing outside the glove box for analysis and then prepares the entire system for the next reaction sample. A microprocessor handles and automates the steps of this system. They employed this new system to track reaction kinetics for a series of Buchwald-Hartwig aminations. The various amination reactions exhibited interesting and somewhat unexpected profiles. For example, syntheses using aryl halides iodobenzene and bromobenzene exhibited distinct profiles that did not demonstrate classical kinetics.

A key component in this automated system is the EasySampler probe used to withdraw a diluted reaction sample and deliver it to a syringe pump, which in turn sends the sample to an injection loop on a nanovalve. Under computer control, the injection loop is aligned between the HPLC pump and the column for sample injection and analysis. The system automatically flushes the lines and fills the EasySampler probe with diluent in preparation for withdrawing the next sample. 

Wei, B., Sharland, J. C., Lin, P., Wilkerson-Hill, S. M., Fullilove, F. A., McKinnon, S., Blackmond, D. G., & Davies, H. M. L. (2019). In Situ Kinetic Studies of Rh(II)-Catalyzed Asymmetric Cyclopropanation with Low Catalyst Loadings. ACS Catalysis, 10(2), 1161–1170. 

The authors point out the importance of dirhodium tetracarboxylates as catalysts for reactions with diazo compounds, in which the nitrogen is eliminated and transient metal carbene intermediates are formed. These catalysts have proven to be useful for a number of syntheses including enantioselective cyclopropanations. Due to the cost of rhodium and other factors, they were interested in investigating cyclopropanations using these rhodium catalysts at very low loadings. Specifically, they investigated cyclopropanation kinetics using a series of newly available chiral dirhodium catalysts in order to determine their relative performance at low catalyst loadings.

In-situ FTIR measurements using ReactIR technology proved to be an ideal means for investigating these reactions by tracking the rate of disappearance of the azide IR peak at 2103 cm-1. The kinetics of the cyclopropanations for a number of different catalysts were measured, but the researchers decided to further explore one of the catalysts with slower rates since it demonstrated the highest level of enantioselectivity. They found that reducing the catalyst loading from 0.0025 mol% to 0.001 mol% caused the enantioselectivity to decrease. In order to achieve high enantioselectivity at the lower catalyst loadings, a series of experiments was carried out with a variety of solvents and reaction conditions. They found that dimethyl carbonate proved to be a superior solvent for achieving both lower loadings and high enantioselectivity. The researchers applied this new information to the synthesis of an important intermediate in the synthesis of a hepatitis C drug, resulting in a 200-fold decrease in catalyst loading with even higher enantioselectivity.

Gain in-depth information about reaction kinetics, mechanisms and pathways. Support safe and optimized scale-up of chemistry. ReactIR and ReactRaman in-situ spectroscopy provide real-time monitoring of chemical reactions for batch and continuous flow syntheses. 

• Develop real-time trending profiles for key reaction species: reactants, intermediates, products and byproducts
• Obtain data-rich information for traditional kinetic analysis or Reaction Progress Kinetics Analysis (RPKA) methods
• Monitor reactions where removing a sample for offline analysis is difficult, impossible or undesirable (low temperature, elevated temperature/pressure, viscous, toxic reagents, highly energetic reactions, air/moisture sensitive, transient intermediates)
• Investigate key stages of a reaction or process, such as reaction start, induction period, accumulation, conversion and endpoint. Detect reaction stalling or upsets. Rapidly determine the effect of variables on reactions.
• Enhance understanding of solution crystallization processes with ReactRaman for monitoring crystallographic form and polymorphism, and ReactIR for investigating solvent effects and supersaturation. 

EasySampler is an automated, unattended technology delivering representative and reproducible samples. The probe-based technology has a micro-pocket, which takes samples at any given time, quenches in-situ and dilutes for ready to analyze offline samples. 

EasySampler supports reaction understanding by providing samples on demand. Sampling is performed under reaction conditions, making it truly representative. The samples, once collected and time stamped, can be analyzed via offline analytical methods and the result integrated back into the data stream. An additional value lies in the increased data quality through automatic and seamless data collection. The increased accuracy and precision of automated sampling provides higher quality versus manual sampling. 

In-depth knowledge of chemical reaction kinetics and mechanisms of reaction steps  accelerate the development and optimization of processes. Reaction Lab is a modeling tool that provides in-depth knowledge about the kinetics of reaction steps in a process. It aids in the optimization of these reactions by modeling the effects of a range of variables simultaneously, thereby revealing the best set of operating conditions for the reaction. Reaction Lab facilitates understanding of reaction mechanisms and permits processes to be more effectively designed based on this insight. Kinetics modeling also enables a greater understanding of the potential robustness of a reaction. The response of the reaction to the effect of varying specific parameters and conditions can be observed, and response surfaces generated that give insight into yield/impurity tradeoffs.

To get the maximum value from kinetic modeling, it is important to use experimental data from analytical methods. Reaction Lab accommodates data from offline and online methods. Experimental data enables the calculation of accurate rate constants and activation energies for use in models. For very fast reactions, or for reactions that at times exhibit periods of rapid change in composition, more data points are required than offline methods can provide. Real-time, in-situ spectroscopic analysis by ReactIR or ReactRaman is ideal for these situations as well as for reactions that have unstable analytes or where accessing a sample is difficult or dangerous. In all cases, accurate experimental data for kinetics requires excellent temperature control of reactions as provided by automated chemical reactors. 

The combination of in-situ PAT and Reaction Lab kinetic modeling supports the development of robust, scalable processes by ensuring that individual reaction steps are well understood and thoroughly optimized.