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The Buchwald-Hartwig amination reaction is widely used in the production of N-arylated amines in the pharmaceutical industry. The reaction is betweenan aryl halogen and a primary or secondary amine in the presence of a base and a homogeneous catalyst giving the desired N-arylated amine. Due to mild reaction conditions and a high selectivity with respect to the N-arylated amine compared to more traditional methods of production ( e.g. reductive nitration, Ullmann-type reactions, benzyne pathway), it has proved to be a convenient method to produce N-arylated amines. The intention of this thesis is to increase the understanding of the chemical reaction mechanisms and kinetics for the Buchwald-Hartwig amination reaction. Also, to develop methods for application of these mechanisms and kinetics to optimize and scale up an organic synthesis to an industrial pharmaceutical production. The Buchwald-Hartwig amination reaction between p-bromotoluene and piperazine in the presence of the homogeneous catalytic system Pd(dba)2/(±)BINAP and the base NaO-t-Bu was investigated in two different classes of solvents: Aprotic, non-polar and aprotic, polar. The reaction was carried out using microwaves as heating source and it was found that the product distribution was strongly dependent on the class of the solvent. Based on the experimental results the selectivity towards the desired mono-substituted. aryl piperazine was calculated, and it was found that the most appropriate solvent for the Buchwald-Hartwig amination reaction under the conditions applied was m-xylene. Furthermore, the applicability of four different heterogeneous palladium catalysts have been evaluated on the Buchwald-Hartwig amination reaction. The catalyst, which provided the highest selectivity toward the desired amination reaction was found to be a polymer supported palladium dichloride/triphenylphosphine catalyst. Experimental investigations of the catalyst in a reactor setup showed that the undesired reduction reaction of the aryl halide was dominating when the catalyst was reused, washed in solvent prior to reaction, and when additional reactants were added to an already reacted reaction mixture. A significant wash out of triphenylphosphine and palladium from the catalyst was also identified during the course of reaction and separation. Finally, the influence on the reaction rate and product distribution of the reaction between has been investigated. The following parameters were considered: concentration of the homogeneous Pd-catalyst, ratio between the palladium source and the active ligands, and the presence of water and ambient air. It was found that an increased concentration of the catalyst gave an increased rate of consumption of p-bromotoluene, but also an increased production of undesired side products. Variation in the molar ratio between the palladium source and the active ligands revealed that the rate of consumption of p-bromotoluene increased until the ratio reached 1:1.5 where the rate of consumption of p-bromotoluene began to decrease. Water (molar ratios of p-bromotoluene to water of 1:1 to 1:4) was found to lower the rate of reaction significantly. Conducting the reaction in an atmosphere of ambient air, as opposed to inert N2, may lead to an increased formation of a homo-coupling product of p-bromotoluene. A kinetic model for the reaction was also presented. A sensitivity analysis of the model suggested that the rate constants which have the most significant impact on the course of reaction are the ones connected to the oxidative addition of aryl halide, amine coordination, and deprotonisation of the amido complex. With a fixed set of rate constants it was possible to predict the course of reaction for different concentrations of the catalyst, though some deviation was seen at low concentration.
|Place of Publication||Kgs. Lyngby|
|Publisher||Department of Chemical and Biochemical Engineering|
|Number of pages||130|
|Publication status||Published - 2007|