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Ind. Eng. Chem. Res. 2007, 46, 8584-8589
Reaction Calorimetry as a Tool for Understanding Reaction Mechanisms: Application to Pd-Catalyzed Reactions Antonio C. Ferretti,† Jinu S. Mathew,‡,§ and Donna G. Blackmond*,†,‡ Department of Chemical Engineering and Chemical Technology and Department of Chemistry, Imperial College, London SW7 2AZ, United Kingdom
Reaction calorimetry can be employed for kinetic studies of complex catalytic reactions. In the calorimeter, the enthalpy balance around the reactor is continuously monitored and gives a profile of reaction heat vs time, which can be easily expressed in terms of reaction rate, conversion, and concentration of reactants/ products. The data can be further analyzed using a methodology called reaction progress kinetic analysis, where the rate is expressed in terms of the concentration of substrates and a graphical expression is used to analyze the order in each substrate and in the catalyst. When studying a catalytic cycle, we can obtain useful information on catalyst activation/deactivation, substrate or product activation/deactivation, and the ratelimiting step. Thus, a detailed mechanistic picture can be obtained. In the present work we show an example of the role of reaction calorimetry in both fingerprinting and detailed study of some Pd-catalyzed aminations of aryl halides. These reactions are considered to be a very important route in making substituted aromatic amines. We observe how the overall kinetics of the reaction changes when changing the amine; the explanation takes into account the mechanism and proposes a change in the rate-limiting step. Introduction Reaction calorimetry has been used in very different fields. In the last decades it has mainly found application in the areas of process optimization safety and reaction hazard screening. Study of the heat flow from a reaction under “synthetically relefvant” conditions (the concentrations are close to the ones used in operating conditions, rather than the distorted concentration conditions typically employed in kinetic studies) can be used to simulate both process and plant conditions in a very short time. In recent years scientists noticed how the heat profile measured during safety standard procedures could give very useful indications regarding the kinetics of the reaction. Kinetics is an area of expansion in future research. Boudart1 predicted that the 21st century will belong to the rate constant, as the 20th belonged to the rate equation; this can be true in areas involving petrochemical applications, where reactions are usually carried out at high temperatures and pressures and involve several parallel and consecutive elementary steps. On the contrary, in areas such as the pharmaceutical field, the role of the rate equation is in ascendance, as the determination of the rate constants through the rate equation may prove very important in understanding reaction mechanisms, in helping for future catalyst design, and in the research and development of industrial processes.2 The rate equation can also be very useful to researchers who need a rapid way to assess catalyst performance under the same conditions used during the commercial process. The determination of the rate equation is possible in this field, given the common features of the pharmaceutical reactions, which are usually carried out at mild conditions, in batch stirred reactors, often with homogeneous catalysts; side reactions are usually minimized by the choice of an appropriate catalyst and ligand. * To whom correspondence should be addressed. Tel.: +44 (0)20 75941193. Fax: +44 (0)20 75945804. E-mail: d.blackmond@ imperial.ac.uk. † Department of Chemical Engineering and Chemical Technology. ‡ Department of Chemistry. § Current address: Pfizer Global R&D, Sandwich CT13 9NJ, U.K.
In our group we believe that, whenever the objective is to derive a mechanistic picture of a reaction, kinetic measurements should be made at the outset of the investigation. This is in contrast with what is generally assumed, where kinetic experiments are performed when a fairly precise mechanism has already been determined by other techniques. Reaction progress kinetic analysis, which we will present in the following sections, provides a straightforward tool that streamlines kinetic studies. Reaction progress kinetic analysis can provide a wealth of information, which can help in the formulation of a mechanistic proposal and, on the other hand, can quickly discard incorrect mechanisms. This methodology can also be effective in investigating catalyst deactivation. Also, once a rough mechanism is sketched, it can point out right away information about the rate-limiting step. It is possible to postulate the intermediates’ relative populations even before knowing their structure, and to distinguish between two mechanistic proposals. Most important, kinetics can streamline the planning of successive experiments, such as the stoichiometric study of individual steps, or spectroscopic studies. Mechanistic-based rate equations can be extracted from in situ techniques with relatively few experiments. Reaction progress kinetic analysis relies on in situ techniques that allow following the reaction during its course. Reaction calorimetry has proven to be an easy to use and powerful tool. Reaction Calorimetry Let us examine how reaction calorimeters can be used for the study of kinetics. Today, very sophisticated calorimeters are available on the market that can monitor reactions involving very small quantities of solvent (for example,
