Mechanistic investigations of metal-catalyzed (poly)esterification reactions

The ester bond is an important structural motif in organic molecules, that among others find application as pharmaceuticals, fragrances or coatings. Although the direct coupling of carboxylic acids and alcohols is known for more than a century, it is still the most prominent route to synthesize the ester moiety. This chemical transformation affords the desired ester bond and water as the only by-product, but high reaction temperatures are required. Therefore, the use of a catalyst that can lower the reaction temperature and enable mild reaction conditions is highly desirable. Lewis acidic metals exclusively catalyze the desired esterification reaction and are therefore intensively explored as catalysts. Although a wide variety of different metal salts were found to be effective catalysts, understanding the origin of their catalytic activity is still limited. Mechanistic studies are severely complicated due to in situ transformation of the catalyst, since all reaction components (carboxylic acid, alcohol, ester and water) have the ability to coordinate to the Lewis acidic metal center. In this thesis, we have shed light on the structure of various in situ formed Lewis acidic metal catalysts, potential intermediates and have provided deeper mechanistic understanding of the catalytic cycle. Besides the direct (poly)esterification reaction also the nickel-catalyzed carbon-oxygen bond forming reaction between an organic halide and a carboxylic acid is investigated. Also here, mechanistic understanding of the catalytic cycle is hindered by many side reactions, either by reaction with one of the reaction components, or by other (deactivation) reactions

Spectroscopic Investigation of the Activation of a Chromium-Pyrrolyl Ethene Trimerization Catalyst

1-Hexene is an important α-olefin for polyethylene production and is produced from ethene. Recent developments in the α-olefin industry have led to the successful commercialization of ethene trimerization catalysts. An important industrially applied ethene trimerization system uses a mixture of chromium 2-ethylhexanoate, AlEt3, AlEt2Cl, and 2,5-dimethylpyrrole (DMP). Here, we have studied the activation of this system using catalytic and spectroscopic experiments (XAS, EPR, and UV–vis) under conditions employed in industry. First, chromium 2-ethylhexanoate was prepared and characterized to be [Cr3O­(RCO2)6(H2O)3]­Cl. Next, the activation of chromium 2-ethylhexanoate with AlEt3, AlEt2Cl, and DMP was studied, showing immediate reduction (<5 ms) of the trinuclear Cr­(III) carboxylate and formation of a neutral polynuclear Cr­(II) carboxylate complex. Over time, this Cr­(II) carboxylate complex is partially converted into a chloro-bridged dinuclear Cr­(II) pyrrolyl complex. In cyclohexane, small quantities of an unknown Cr­(I) complex (∼1% after 1 h) are observed, while in toluene, the quantity of Cr­(I) is much higher (∼23% after 1 h). This is due to the formation of cationic bis­(tolyl)­Cr­(I) complexes, which likely leads to the observed inferior performance using toluene as the reaction solvent. Catalytic studies allow us to exclude some of the observed Cr­(I) and Cr­(II) complexes as the active species in this catalytic system. Using this combination of techniques, we have been able to structurally characterize complexes of this selective Cr-catalyzed trimerization system under conditions which are employed in industry

Titanium-catalyzed esterification reactions: beyond Lewis acidity

Esterification is a key reaction and is used in many synthetic and industrial processes, yet the detailed mechanism of operation of often-used (Lewis acid) catalysts is unknown and subject of little research. Here, we report on mechanistic studies of a titanium aminotriphenolate catalyst, using stoichiometric and catalytic reactions combined with kinetic data and density functional theory (DFT) calculations. While often only the Lewis acidity of the Ti-center is taken into account, we found that the amphoteric nature of this catalyst, combining this Lewis acidity with Brønsted basicity of a Ti-bound and in situ formed carboxylate group, is crucial for catalytic activity. Furthermore, hydrogen bonding interactions are essential to pre-organize substrates and to stabilize various intermediates and transition states and thus enhancing the overall catalytic reaction. These findings are not only applicable to this class of catalysts, but could be important for many other esterification catalysts

The predictive value of the 'VMS frail older patients' for adverse outcomes in geriatric inpatients

Background/Objective: The Dutch Safety Management system (VMS) screening for frail older patients is used as a predictor for adverse outcomes. We aimed to determine the predictive value of the VMS for adverse outcomes in geriatric inpatients. Design: Retrospective cohort study in geriatric inpatients. Outcomes were institutionalization, readmission and mortality (3- and 12-months). Logistic regression analysis was performed to assess the predictive value of the number of positive VMS domains, a VMS score >= 1, and individual domains for adverse outcomes. Results: We included 477 patients. Median age was 85 years (54-99) and 37% were male. Eighty-seven % scored positive on delirium risk, 57% on fall risk, 39% on malnutrition and 64% on physical impairment. One-hundredthirty-five patients (28%) were institutionalized, 78 patients (16%) were readmitted and mortality rate was 127 (27%) at 3 months and 184 (39%) at one year. The VMS was not predictive for readmission (OR 1.6; 95%-CI 0.213.7) and mortality, (OR 0.6 95%-CI 0.2-2.0 and OR 1.1; 95%-CI 0.3-3.7). For institutionalization, delirium risk (OR 2.2; 95%-CI 1.1-4.4), physical impairment (OR 1.8; 95%-CI 1.1-2.9) and a positive score on all four domains were predictive (OR 12.1 95%-CI-1.4-101.7). Malnutrition was predictive for readmission (OR 1.74; 95%-CI 1.05-2.91) and three-month mortality (OR 1.69; 95%-CI 1.11-2.57), delirium risk for one -year mortality (OR 2.0; 95%-CI 1.0-4.0) . Conclusions: Almost all geriatric inpatients scored positive on at least one domain of the VMS. The number of positive VMS domains had some predictive value for institutionalization. Individual domains were able to predict adverse outcomes

Mechanistic elucidation of monoalkyltin(iv)-catalyzed esterification

Monoalkyltin(iv) complexes are well-known catalysts for esterification reactions and polyester formation, yet the mode of operation of these Lewis acidic complexes is still unknown. Here, we report on mechanistic studies of n-butylstannoic acid in stoichiometric and catalytic reactions, analyzed by NMR, IR and MS techniques. While the chemistry of n-butyltin(iv) carboxylates is dominated by formation of multinuclear tin assemblies, we found that under catalytically relevant conditions only monomeric n-BuSn(OAc)(3) and dimeric (n-BuSnOAc(2)OEt)(2) are present. Density functional theory (DFT) calculations provide support for a mononuclear mechanism, where n-BuSn(OAc)(3) and dimeric (n-BuSnOAc(2)OEt)(2) are regarded as off-cycle species, and suggest that carbon–oxygen bond breaking is the rate-determining step

Exogenous Ligand-Free Nickel-Catalyzed Carboxylate O-Arylation:Insight into Ni^I/Ni^III Cycles**

Nickel-catalyzed cross-coupling reactions have become a powerful methodology to construct C-heteroatom bonds. However, many protocols suffer from competitive off-cycle reaction pathways and require non-equimolar amounts of coupling partners to suppress them. Here, we report on mechanistic examination of carboxylate O-arylation under thermal conditions, in both the presence and absence of an exogeneous bipyridine-ligand. Furthermore, spectroscopic studies of the novel ligand-free carboxylate O-arylation reaction unveiled the resting state of the nickel catalyst, the crucial role of the alkylamine base and the formation of an off-cycle NiI−NiII dimer upon reduction. This study provides insights into the competition between productive catalysis and deleterious pathways (comproportionation and protodehalogenation) in the commonly proposed self-sustained NiI/NiIII catalytic cycle. Thereby we show that for productive nickel-catalyzed carboxylate O-arylation a choice must be made between either mild conditions or equimolar ratios of substrates