Reaction progress kinetic analysis

The experimental method used for this kinetie study is reaetion ealorimetry. In the ealorimeter, the energy enthalpy balance is continuously monitored the heat signal can then be easily converted in the reaction rate (in the case of an isothermal batch reactor, the rate is proportional to the heat generated or consnmed by the reaction). The reaction orders and catalyst stabihty were determined with the methodology of reaction progress kinetic analysis (see refs. (8,9) for reviews). 

The investigation of the driving forces and robnstness of proline-catalyzed aldol reaction is performed by ntilizing the methodology of reaction progress kinetic analysis. 

We first consider the simple example of an uncatalyzed Diels-Alder reaction shown in Scheme 50.2 in order to demonstrate the use of different excess experiments. The Diels-Alder reaction is known to exhibit second overall order kinetics, as shown in eq. (4). We demonstrate with this known case how reaction progress kinetic analysis may be used to extract the reaction orders in both substrate concentrations, [5] and [6]. ... 

We now describe a second set of experiments that are critical to reaction progress kinetic analysis when it is carried out on catalytic systems. Determining... 

Reaction progress kinetic analysis offers a reliable alternative method to assess the stability of the active catalyst concentration, again based on our concept of excess [e]. In contrast to our different excess experiments described above, now we carry out a set of experiments at the same value of excess [ej. We consider again the proline-mediated aldol reaction shown in Scheme 50.1. Under reaction conditions, the proline catalyst can undergo side reactions with aldehydes to form inactive cyclic species called oxazolidinones, effectively decreasing the active catalyst concentration. It has recently been shown that addition of small amounts of water to the reaction mixture can eliminate this catalyst deactivation. Reaction progress kinetic analysis of experiments carried out at the same excess [e] can be used to confirm the deactivation of proline in the absence of added water as well to demonstrate that the proline concentration remains constant when water is present. 

Herein we provide insight into their extremely high substrate selectivity and explore in detail aspects like regioselectivity, diasteroselectivity, and enantioselectivity in the oxidation of a wide range of substrates. Further details into the selectivity of this catalyst are provided by a mechanistic investigation performed employing the so-called "reaction progress kinetic analysis" approach recently developed by Blackmond [33]. 

FIGURE 2.6 Mechanistic hypothesis for terminal alkene epoxidation with hydrogen peroxide mediated by lb on the basis of the results of reaction-progress kinetic analysis and P and F NMR studies. 

D. G. Blackmond, Reaction progress kinetic analysis A powerful methodology for mechanistic studies of complex catalytic reactions, Angew. Chem. Int. Ed. 44 (2005) 4302. 

S. P. Mathew, S. Gunathilagan, S. M. Roberts, D. G. Blackmond, Mechanistic insights from reaction progress kinetic analysis of the polypeptide-catalyzed epoxidation of chalcone, Org. Lett. 7 (2005) 4847. 

In our illustration of the graphical manipulations of data using reaction progress kinetic analysis, we will make use of the example of a model reaction, the intermolecnlar aldol reaction between acetone 1 and aldehyde 2 to form the aldol addition product 3, mediated by proline 4, as shown in Scheme 27.1. The demonstration by List, Lemer, and Barbas in 2000 that proline mediates intermolecular aldol reactions with a high degree of asymmetric induction heralded a revolution in the field of organocatalysis, encompassing the discovery of new catalysts and new catalytic transformations." ... 

Our task is to find values for x, y, and z that hold over the range of concentrations under which the reaction will be carried out. An important further consideration for catalytic reactions is the question of whether the catalyst concentration remains constant over the course of the reaction. The methodology of reaction progress kinetic analysis offers experimental protocols as described below that allow us to probe catalyst robusmess as well as substrate dependences. 

The key to reaction progress kinetic analysis lies in making use of the reaction stoichiometry. For the aldol reaction of Scheme 27.1, a mass balance tells us that for each molecule of ketone 1 consumed, one molecule of aldehyde 2 is also consumed. The parameter of interest for our analysis is the difference between the initial concentrations of the two substrates. This parameter is a constant in any given experiment, and we call it the excess, or [e], with units of molarity (Equation 27.5). 

The excess [e] can be large, small, positive, or negative. When pseudo-zero-order conditions in [2] are employed, [e] is [1]. Under conditions of practical synthetic experiments, [e] is usually small, and [1] and [2] are only slightly different from each other. These synthetically relevant conditions are employed in reaction progress kinetic analysis. 

Now we are prepared to illustrate these experimental protocols of reaction progress kinetic analysis using data from reaction calorimetric monitoring of the aldol reaction shown in Scheme 27.1. We turn hrst to the issue of catalyst stability using our same excess protocol. In these aldol reactions, it was noted that the active catalyst concentration can be effectively decreased by the formation of oxazolidinones between proline and aldehydes or ketones, and that addition of water can suppress this catalyst deactivation. Same excess reactions carried out in the absence of water and in the presence of water are shown in Figure 27.3a and Figure 27.3b, respectively. The plots do not overlay in the absence of water, but they do when water is present. The overlay in these same [e] experiments in Figure 27.3b means that the total concentration of active catalyst within the cycle is constant and is the same in the two experiments where water is present. 

We show in this work that by applying the methodology of reaction progress kinetic analysis to data acquired by accurate and continuous monitoring of a complex multistep reaction with an in situ probe, we are able both to provide a quantitative assessment of the reaction orders for two separate substrate concentrations as well as to delineate conditions under which the stability of the catalyst and the robustness of the process is insured. Even without knowledge of the reaction mechanism or of the nature of the catalytic intermediate species, this information is sufficient to allow safe and efficient scale-up of the reaction as well as to provide a basis for further optimization aimed both at efficient production and detailed mechanistic nnderstanding. 

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