In chemistry, reaction progress kinetic analysis (RPKA) is a subset of a broad range of kinetic techniques utilized to determine the rate laws of chemical reactions and to aid in elucidation of reaction mechanisms. While the concepts guiding reaction progress kinetic analysis are not new, the process was formalized by Professor Donna Blackmond (currently at Scripps Research Institute) in the late 1990s and has since seen increasingly widespread use. Unlike more common pseudo-first-order analysis, in which an overwhelming excess of one or more reagents is used relative to a species of interest, RPKA probes reactions at synthetically relevant conditions (i.e. with concentrations and reagent ratios resembling those used in the reaction when not exploring the rate law.) Generally, this analysis involves a system in which the concentrations of multiple reactants are changing measurably over the course of the reaction. As the mechanism can vary depending on the relative and absolute concentrations of the species involved, this approach obtains results that are much more representative of reaction behavior under commonly utilized conditions than do traditional tactics. Furthermore, information obtained by observation of the reaction over time may provide insight regarding unexpected behavior such as induction periods, catalyst deactivation, or changes in mechanism.
Monitoring reaction progress Reaction progress kinetic analysis relies on the ability to accurately monitor the reaction conversion over time. This goal may be accomplished by a range of techniques, the most common of which are described below. While these techniques are sometimes categorized as differential (monitoring reaction rate over time) or integral (monitoring the amount of substrate and/or product over time), simple mathematical manipulation (differentiation or integration) allows interconversion of the data obtained by either of the two. Regardless of the technique implemented, it is generally advantageous to confirm the validity in the system of interest by monitoring with an additional independent method.
Reaction progress NMR NMR spectroscopy is often the method of choice for monitoring reaction progress, where substrate consumption and/or product formation may be observed over time from the change of peak integration relative to a non-reactive standard. From the concentration data, the rate of reaction over time may be obtained by taking the derivative of a polynomial fit to the experimental curve. Reaction progress NMR may be classified as an integral technique as the primary data collected are proportional to concentration vs. time. While this technique is extremely convenient for clearly defined systems with distinctive, isolated product and/or reactant peaks, it has the drawback of requiring a homogeneous system amenable to reaction in an NMR tube. While NMR observation may allow for the identification of a reaction intermediates, the presence of any given species over the course of the reaction does not necessarily implicate it in a productive process. Reaction progress NMR may, however, often be run at variable temperature, allowing the rate of reaction to be adjusted to a level convenient for observation. Examples of utilization of reaction progress NMR abound, with notable examples including investigation of Buchwald–Hartwig amination (One might note that considerable debate surrounded the best approach to mechanistic development of the Buchwald-Hartwig amination as indicated by a number of contradictory and competing reports published over a short period of time. See the designated article and references therein.)
In situ FT-IR In situ infrared spectroscopy may be used to monitor the course of a reaction, provided a reagent or product shows distinctive absorbance in the IR spectral region. The rate of reactant consumption and/or product formation may be abstracted from the change of absorbance over time (by application of Beers' Law). Even when reactant and product spectra display some degree of overlap, modern instrumentation software is generally able to accurately deconvolute the relative contributions provided there is a dramatic change in the absolute absorbance of the peak of interest over time. In situ IR may be classified as an integral technique as the primary data collected are proportional to concentration vs. time. From these data, the starting material or product concentration over time may be obtained by simply taking the integral of a polynomial fit to the experimental curve. With increases in the availability of spectrometers with in situ monitoring capabilities, FT-IR has seen increasing use in recent years. Examples of note include mechanistic analysis of the amido-thiourea catalyzed asymmetric Strecker synthesis of unnatural amino acids and of the Lewis base catalyzed halolactonization and cycloetherification.
In situ UV-vis Analogously to the in situ IR experiments described above, in situ UV-visible absorbance spectroscopy may be used to monitor the course of a reaction, provided a reagent or product shows distinctive absorbance in the UV spectral region. The rate of reactant consumption and/or product formation may be abstracted from the change of absorbance over time (by application of Beer's Law), again leading to classification as an integral technique. Due to the spectral region utilized, UV-vis techniques are more commonly utilized on inorganic or organometallic systems than on purely organic reactions, and examples include exploration of the samarium Barbier reaction.
Reaction calorimetry Calorimetry may be used to monitor the course of a reaction, since the instantaneous heat flux of the reaction, which is directly related to the enthalpy change for the reaction, is monitored. Reaction calorimetry may be classified as a differential technique since the primary data collected are proportional to rate vs. time. From these data, the starting material or product concentration over time may be obtained by simply taking the integral of a polynomial fit to the experimental curve. While reaction calorimetry is less frequently employed than a number of other techniques, it has found use as an effective tool for catalyst screening. Reaction calorimetry has also been applied as an efficient method for mechanistic study of individual reactions including the prolinate-catalyzed α-amination of aldehydes and the palladium catalyzed Buchwald-Hartwig amination reaction.
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![Reaction progress kinetic analysis: a) The simplest case of saturation kinetics extends from the pre-equilibrium situation in which rapid substrate complexation with a catalyst is followed by slow formation of the product. b) The straight portion of the graph for substrate concentration over time is indicative of a zero-order dependence on substrate for most of the reaction, but the curve at low [A] is indicative of a change to (in this case) a first-order dependence on [A]. c) Saturation of the catalyst is apparent at high concentrations of substrate (where the rate has no dependence on [A], but as substrate is consumed, the reaction rate drops with a first-order dependence on [A] to pass through the origin. d) The catalyst resting state also changes, where it exists almost entirely as the substrate-bound complex, Cat–A, at high [A] but increasingly as the free catalyst, Cat, as [A] decreases over the course of the reaction.](https://upload.wikimedia.org/wikipedia/commons/thumb/5/57/Saturation_Kinetics-2.png/1280px-Saturation_Kinetics-2.png?utm_source=en.wikipedia.org&utm_campaign=parser&utm_content=thumbnail)
![Reaction progress kinetic analysis: The rate of product formation in the cyanosilylation of ketone, A, shows a slight non-linear dependence on catalyst loading at high catalyst concentrations. a) This observation, among others, is accounted for by the reversible formation of inactive catalyst complexes. b) Similar behavior at multiple conversion points is consistent with one dominant mechanism operating over the entire course of the reaction.[18]](https://upload.wikimedia.org/wikipedia/commons/thumb/2/27/Rate_vs_Catalyst_Loading_at_Multiple_Conversion_Points.png/1280px-Rate_vs_Catalyst_Loading_at_Multiple_Conversion_Points.png?utm_source=en.wikipedia.org&utm_campaign=parser&utm_content=thumbnail)
![Reaction progress kinetic analysis: a) According to the proposed mechanism for the palladium-catalyzed amination of aryl halides, an induction period will be present as the active catalyst is generated from an inactive pre-catalyst (where L = BINAP). b) This induction period may be observed at early conversion points, before the catalyzed reaction reaches its maximum rate. In same-excess experiments, this will manifest itself in the non-overlying portions of curves designed to intercept the original reaction at intermediate conversion points. Here, a same-excess (e = 0.60 M) of [ArX] relative to [HNR2] and [MOR] is utilized for each of the curves.](https://upload.wikimedia.org/wikipedia/commons/thumb/f/fb/Amination_Kinetics.png/1280px-Amination_Kinetics.png?utm_source=en.wikipedia.org&utm_campaign=parser&utm_content=thumbnail)
