Microwave-assisted flow processing in heterogeneously copper nano-catalyzed reactions

In the last decades, micro-processing and microwave technology have been established as mature technologies, however, mainly instigated by academia. Many advances in micro-process technology have led to novel routes and/or process windows to replace batch operations by more efficient continuous processes, both at lab and at industrial scales. Especially, the fine-chemicals industry has been recognized for realistic implementation of these technologies with respect to both scale as well as cost. In this thesis, the major hurdles to combine microwave and micro-processing technology for organic syntheses have been addressed. In comparison to gas-phase reactions, metal-catalyzed liquid-phase organic synthesis requires different operational process windows to realize successful implementation of micro-processing. Major issue here is to avoid solid bases and slurry catalysts by including pre-treatment steps and depositing catalysts onto structured supports. In addition, the use of metals as catalysts under microwave irradiation is known for rapid energy absorption and, therefore, requires special attention regarding temperature control. The Ullmann-type coupling reaction and the Simmons-Smith type cyclopropanation are both intensively employed in the fine-chemicals industry and were, therefore, investigated over various novel heterogeneous Cu catalysts in this project. The Cu-catalyzed coupling of aromatic compounds is not only an excellent example to investigate the benefits of integrated microwave and micro/milli-reactor technologies, but also for its potential applications in the production of pharmaceutically active molecules, such as antivirals and antibiotics (e.g. Vancomycin). This type of organic reactions provides considerable challenges to overcome, both with respect to the severe reaction conditions and, undoubtedly, the sustainability of heterogeneous catalysis which substantially contributes to the cost in flow processing. More importantly, however, was the use of heterogeneous CuZn nano-colloids which, as oxidative stable "metallic microwave-absorber", provide an additional benefit (but also point of attention) regarding the higher temperatures at the locus of the reaction. Therefore, monometallic and bimetallic Cu-based nanoparticles with a narrow size-distribution and a high resistance against oxidation and agglomeration were developed. The chemical and colloidal stability of these Cu-based nanoparticles, including their purity and morphology, could be significantly improved by coating the copper nanoparticles with poly(N-vinylpyrrolidone). These nano-catalysts were then tested for their performance in the Ullmann-type coupling reaction and the Simmons-Smith cyclopropanation. Subsequently, these novel nano-catalysts were immobilized onto a microwave-transparent TiO2 support and used in a fixed-bed reactor. Novel routes for the preparation of highly active TiO2-supported Cu and CuZn catalysts were proposed and applied in Cu-catalyzed organic reactions. The copper oxidation was significantly suppressed by using CuZn/TiO2 catalytic films and a strong relation between the catalyst composition and activity was found for the Ullmann C O coupling reaction. This novel preparation method was based on titania dip-coating onto glass beads, obtaining either structured mesoporous or non-porous titania thin films, which could be loaded with the catalyst nanoparticles by deposition onto the calcined films. These catalysts were analyzed using various characterization techniques and in operando synchrotron X-ray absorption spectroscopy, giving a better understanding of their catalytic behavior. Besides catalyzing a reaction, the energy supply towards the catalyst surface is obviously as important and has been also investigated in this project. This issue has been addressed separately, because in traditional reactors the energy supply is particularly governed by classical heat transfer limitations. Furthermore, the troubleshooting of the major obstacles for continuous operations to synergize the benefits of microwave systems and micro/milli-processing in flow synthesis has been targeted. A micro fixed-bed reactor was designed, using packed spherical glass beads coated with the catalyst and support, for kg-scale flow operations in the Ullmann C-O coupling. In addition, the influence of reactor shape and dimensions for effective microwave irradiation was studied. Experimental evidence of complete microwave penetration in the radial direction was found, allowing rapid and controlled heating without significant radial temperature gradients in the flow-through reactors. The above mentioned developments in chemistry, nano-catalysis and reactor engineering were the basis for an extended cost study, consisting of 14 process scenarios. In this way, the cost-impact of micro-processing and microwave heating for liquid-phase reactions in fine-chemicals synthesis could be envisaged. Two examples were studied, i.e. the Ullmann-type coupling reactions and the Aspirin synthesis. It could be concluded that the operating costs in the Ullmann-type processes compared to those of the Aspirin synthesis can be defined as either material based (e.g. reactant excess, pretreatment and catalyst synthesis) or downstream processing based (e.g. work-up, waste treatment) processes. The impact of integrating microwave heating and micro-processing systems on profitability was evaluated with respect to operational costs and chemical productivity. This techno-economic evaluation provided a route map, highlighting feasible routes to combine different technologies, chemical processes and catalyst systems

Synthesis, Characterization, and Oxygenation Studies of Carboxylate-Bridged Diiron(II) Complexes with Aromatic Substrates Tethered to Pyridine Ligands and the Formation of a Unique Trinuclear Complex

In this study, diiron(II) complexes were synthesized as small molecule mimics of the reduced active sites in the hydroxylase components of bacterial multicomponent monooxygenases (BMMs). Tethered aromatic substrates were introduced in the form of 2-phenoxypyridines, incorporating hydroxy and methoxy functionalities into windmill-type diiron(II) compounds [Fe[subscript 2](μ-O[subscript 2]CAr[superscript R])[subscript 2](O[subscript 2]CAr[superscript R])[subscript 2](L)[subscript 2]] (1–4), where[superscript –]O[subscript 2]CAr[superscript R] is a sterically encumbering carboxylate, 2,6-bis(4-fluorophenyl)-, or 2,6-bis(p-tolyl)benzoate (R = 4-FPh or Tol, respectively). The inability of 1–4 to hydroxylate the aromatic substrates was ascertained. Upon reaction with dioxygen, compounds 2 and 3 (L = 2-(m-MeOPhO)Py, 2-(p-MeOPhO)Py, respectively) decompose by a known bimolecular pathway to form mixed-valent diiron(II,III) species at low temperature. Use of 2-(pyridin-2-yloxy)phenol as the ligand L resulted in a doubly bridged diiron complex 4 and an unprecedented phenoxide-bridged triiron(II) complex 5 under slightly modified reaction conditions.National Institute of General Medical Sciences (U.S.) (Grant GM032134

EXPLORATION INTO THE SCOPE AND MECHANISM OF THE PLATINUM-CATALYZED ACYLATION OF 2-(ARYLOXY)PYRIDINES

Transition metal catalysts have played a key role in direct C-H bond functionalization. However, one main drawback of these reactions is that oxidants and additives are often required to regenerate the active catalyst, oxidize the substrates, or promote the reaction. These needed reagents can often add significant cost and safety concerns to the synthesis. Recently the Huo group has discovered a unique platinum catalyzed acylation reaction to produce alpha-keto esters via C-H functionalization using ethyl chorooxoacetate, a cheap and readily accessible reagent. This reaction eliminated the need for any oxidants or additives and, more importantly, was free of any decarbonylation side reactions (see below). Further reaction optimization was performed to lower the catalyst loading. It was found that with the addition of potassium carbonate, strong acids that were produced during the C-H activation step (B) were neutralized thus allowing the catalyst to coordinate to the 1a more readily. The range of the overall synthesis was explored using different acylating agents. Finally, Hammett analysis was used to study the substituent effects of this reaction. Experimental results will be reported, and the significance of these findings will be discussed

Platinum Catalyzed Synthesis of Alpha-Ketoester via C-H Functionalization

Alpha-ketoesters have proven to be useful in a variety of fields. They have found wide spread applications in pharmaceuticals, photochemistry, and biology. Additionally, they are of great interest in synthetic chemistry and are frequently used as a precursor to many useful organic compounds including alpha-keto acids, alpha-hydroxy acids, and alpha-amino acids. Numerous methods have been reported for synthesizing alpha-ketoesters but they all amount to a few notable drawbacks. Herein reported is a potentially more effective transition metal catalyzed reaction to synthesize alpha-ketoester via C-H functionalization. A series of ligands with structural modifications have been designed, synthesized and acylated to shed light on the scope and limitations of the reaction. An inexpensive and readily accessible reagent namely ethyl chlorooxoacetate was employed as the acylating reagent. Reaction conditions were optimized by screening various solvents and catalysts. A variety of solvents were found useful in this reaction, including chlorobenzene, benzonitrile, toluene, and m-xylene although the best results were obtained when chlorobenzene was used. The reaction showed great tolerance to both electron withdrawing and donating groups on the phenyl ring however some electronic effects were observed and it was found that the presence of electron withdrawing group on the phenyl ring decelerated the acylation reaction. Experimental results of the acylation reaction will be reported and the mechanistic implications of these results will be discussed

Structure-Activity Studies Of 7-Heteroaryl-3-Azabicyclo[3.3.1]Non-6-Enes: A Novel Class Of Highly Potent Nicotinic Receptor Ligands

The potential for nicotinic ligands with affinity for the α4β2 or α7 subtypes to treat such diverse diseases as nicotine addiction, neuropathic pain, and neurodegenerative and cognitive disorders has been exhibited clinically for several compounds while preclinical activity in relevant in vivo models has been demonstrated for many more. For several therapeutic programs, we sought nicotinic ligands with various combinations of affinity and function across both subtypes, with an emphasis on dual α4β2-α7 ligands, to explore the possibility of synergistic effects. We report here the structure-activity relationships (SAR) for a novel series of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes and characterize many of the analogues for activity at multiple nicotinic subtypes. © 2012 American Chemical Society

RAPID AMINATION OF METHOXY PYRIDINE WITH ALIPHATIC AMINES

A n-BuLi triggered practical amination protocol of methoxy pyridine derivatives with aliphatic amines was developed. The reaction could finish in 30 min for primary amines and 10 min for secondary amines. The amination is further highlighted by its excellent reactivity and substrate scope.KEYWORDS: amination, methoxy pyridines, n-BuLi, transition-metal-fre

Copper-Mediated Decarboxylative C–H Arylation of Phenol Derivatives with ortho-Nitrobenzoic Acids Using Phenanthroline-Based Bidentate Auxiliary

A copper-mediated decarboxylative C–H arylation of phenol derivatives with ortho-nitrobenzoic acid salts via phenanthroline-directed C–H cleavage has been developed. The N,N-bidentate phenanthroline auxiliary uniquely promotes the reaction only in the presence of a copper salt to produce the corresponding biaryls in acceptable yields. Moreover, the directing group can be easily introduced and removed. Additionally, preliminary computational mechanistic studies with DFT have also been performed.Takamatsu K., Hayashi Y., Kawauchi S., et al. Copper-Mediated Decarboxylative C–H Arylation of Phenol Derivatives with ortho-Nitrobenzoic Acids Using Phenanthroline-Based Bidentate Auxiliary. ChemistrySelect 4, 11833 (2019); https://doi.org/10.1002/slct.201902860