Haloalkane | EPFL Graph Search

The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely used commercially. They are used as flame retardants, fire extinguishants, refrigerants, propellants, solvents, and pharmaceuticals. Subsequent to the widespread use in commerce, many halocarbons have also been shown to be serious pollutants and toxins. For example, the chlorofluorocarbons have been shown to lead to ozone depletion. Methyl bromide is a controversial fumigant. Only haloalkanes that contain chlorine, bromine, and iodine are a threat to the ozone layer, but fluorinated volatile haloalkanes in theory may have activity as greenhouse gases. Methyl iodide, a naturally occurring substance, however, does not have ozone-depleting properties and the United States Environmental Protection Agency has designated the compound a non-ozone laye

Synthetic methodologies for C-C and C-N bond formation involving alkyl radicals

Guido Barzanò

C-C and C-N bonds are some of the most common structures in molecules ranging from drugs to catalysts and to food additives. Many coupling reactions were developed to form these types of bonds with excellent selectivity and good performance. Still, the synthesis of some of those species either depends on traditional methods or requires expensive and rare reagents and catalysts. The use of precious metals in chemistry, and particularly in the industry, can make molecular synthesis expensive and energy-intensive since the extraction of those materials is costly. Moreover, in homogeneous catalysis, the recovery of metal-based catalysts is almost impossible, making these processes unsustainable for the future. Thus, the discovery of chemical reactions that donât involve precious materials is indispensable. This thesis concentrates on the development of two chemical transformations, one performing an sp2-sp3 radical reductive coupling, one performing a photocatalyzed alkyl amination, involving inexpensive reagents and catalysts. The first chapter reviews the existing methodologies which use alkyl radicals to form carbon-carbon and carbon-nitrogen bonds. Alkyl radicals are formed from alkyl halides and pseudo-halides (Acids, esters, tosylates, etc.) via oxidation or reduction performed by metal or photoredox catalyst. The wide variety of available methodologies was illustrated, highlighting the advantages and weaknesses of each reaction. The second chapter of this dissertation is devoted to the development of a new iron-based catalytic method to form stereoselectively Z-alkene boron species from the corresponding boron-alkyne. This novel stereoselective method opens a new way to obtain these types of molecules with cheap reagents, in high yields, with excellent stereoselectivity (Z:E ratio >10:1), and with good tolerance of functional group. The reaction is radical based, avoiding the problem of beta-hydride elimination, which usually occurs in ionic reactions involving metal centers. In order to prove the versatility of this method, the vinyl boron compound formed from this reaction was used for further functionalizations. The formal total synthesis of a 5-HT2c receptor agonist was successfully performed, improving the overall yield of the process, and avoiding the use of expensive and polluting chemicals. The third chapter of this thesis is concentrated on the development of a tandem photoredox/metal base catalyzed functionalization of anilines and imines with alkyl carboxylic esters. In this reaction, no late transition metal is used, and the traditional metal-based photocatalyst is substituted with an inexpensive and more efficient organic dye. The alkylation of amines is a challenging topic in organic chemistry and classical nucleophilic substitution lacks selectivity and scope. Harvesting visible light with a photoredox catalyst opens the possibility to a radical pathway, making this coupling easy and with high tolerance for functional groups. In order to understand the catalytic cycle of the reaction, additional mechanistic studies were conducted, leading to some insight on how this reaction works.

EPFL2020

Synthesis and structure-activity studies of well-defined nickel complexes as catalysts for cross coupling of alkyl electrophiles

Pablo Marcelo Perez Garcia

This dissertation is devoted to the development of well-defined nickel complexes as catalysts for cross coupling processes of alkyl electrophiles. In chapter one, we summarize recent cross coupling methodologies of alkyl electrophiles using nickel based catalysts. The description of each study includes the coupling conditions, the substrate scope and the mechanistic considerations. In chapter two, we report the development of high diastereoselective alkyl-alkyl Kumada coupling method for 1,3- and 1,4-substituted cyclohexyl halides and tetrahydropyrans using an amido bis(amine) nickel complex "Nickamine" as catalyst. The stereochemical properties of the starting materials and of the coupling products were determined by NMR techniques. The mechanistic investigations of the coupling provided evidence of a reversible activation of the alkyl halide. In chapter three, we present the synthesis of new bidentate amido â amine ligands derived from 2,5-dimethylpyrrolidine or Î±-methylbenzylamine. The ligands were used to synthesize well-defined bidentate nickel complexes by transmetallation from the corresponding lithium complexes. A complex having an Î±-methylbenzylamine derived ligand and 2,4-lutidine as co-ligand was an effective catalyst for the coupling of non-activated secondary iodides with alkyl Grignard reagents. An enantiomerically pure version of this complex was synthesized and no racemization was observed during the synthesis. The chiral complex showed no asymmetric induction capacity as a cross coupling catalyst. In chapter four, the synthesis of new amido bis(amine) pincer ligands derived from Î±-methylbenzylamine or pyrrolidine are described. The metallation of a NNN ligand derived from Î±-methylbenzylamine was not possible by transmetallation from the corresponding lithium complex or by oxidative addition from the corresponding chloroamine. A well-defined pincer nickel complex was synthesized by Li â Ni transmetallation using a NNN ligand having dimethyl amino and pyrolidine donors. Crystal structure analysis shows that the pyrrolidine donor is slightly less hindered. This complex is an effective catalyst for alkyl-alkyl and alkyl-aryl Kumada coupling of non-activated primary and secondary alkyl halides. The coupling process shows good functional group tolerance. This is the first time that a well-defined nickel pincer complex shows high catalytic activity for Kumada coupling reactions of sterically hindered alkyl substrates. In chapter 5, a well-defined nickel pincer complex bearing an alkyl amine donor is synthesized. The complex is able to catalyzed direct coupling of non-activated primary halides with terminal alkynes at room temperature. The catalysis has a good substrate scope and high functional group tolerance. Kinetic data suggest that the new pincer ligand is hemilabile, and the dissociation of the alkyl amine donor is the turnover-determining step of the catalysis. An intermediate Ni-alkynyl species has been isolated and structurally characterized. The reactivity of this species gives insight into the nature of the active species for the activation of alkyl halide.

EPFL2015

Creating Tertiary and Quaternary Carbon Centers by Nickel and Copper-Catalyzed Cross-Coupling Reactions of Alkyl Electrophiles

Peng Ren

Transition-metal-catalyzed C-C coupling reactions have been extensively studied in the past three decades. These reactions have become invaluable to fundamental research and industrial applications, because they can be used construct complicated molecules from simple precursors. Among them, the coupling systems of aryl, alkenyl, and alkynyl halides have been well-optimized, while the coupling of non-activated alkyl halides, especially secondary alkyl halides, is still difficult. In the first chapter, the development of the transition-metal-catalyzed alkyl-alkyl cross-coupling reactions is introduced and summarized, and the difficulties and potential improvements are discussed. In chapter 2, a structure-activity study is described for Ni-catalyzed alkyl-alkyl Kumada- type cross coupling reactions. A series of new nickel(II) complexes bearing bidentate and tridentate amino-amide ligands were synthesized and structurally characterized. The coordination geometries of these complexes include square planar, tetrahedral, and square pyramidal. The complexes had been examined as pre-catalysts for the cross coupling of non- activated alkyl halides, particularly secondary alkyl iodides, with alkyl Grignard reagents. Comparison was made to the results obtained with the previously reported Ni pincer complex [(MeN2N)NiCl] (1). A transmetalation site in the pre-catalysts is necessary for the catalysis. The coordination geometries and spin-states of the pre-catalysts have little or no influence. The work led to the discovery of several well-defined Ni catalysts that are significantly more active and efficient than the pincer complex (1) for the coupling of secondary alkyl halides. The best catalysts are [(HNN)Ni(PPh3)Cl] (24) and [(HNN)Ni(2,4-lutidine)Cl] (27). The improved activity and efficiency were attributed to the fact that the phosphine and lutidine ligands in these complexes could dissociate from the Ni center during catalysis. The activation of alkyl halides was shown to proceed via a radical mechanism. After investigating how secondary alkyl halides could couple with primary Grignard reagents in high yields using nickel catalysts, the complementary methodology, the coupling of non-activated alkyl electrophiles with secondary and tertiary alkyl nucleophiles, is described in chapter 3. It was found that simple copper(I) chloride could catalyze the cross- coupling of non-activated primary alkyl halides and tosylates with secondary and tertiary alkyl Grignard reagents. The method is highly efficient, practical, and general. A wide range of functional groups can be tolerated, such as ester, ketone, amide, nitrile, and heterocylic groups. In chapter 4, a series of new copper complexes bearing hemilabile ligands were synthesized and structurally characterized. Among them, the copper complex [(MeN2N)Cu(PPh3)] (36) was shown to have the highest catalytic activity towards alkylation of benzoxazoles with secondary alkyl halides. The higher efficiency of 36 relative to other copper catalysts might result from a hemilabile property of the pincer ligand. An important additive, bis[2-(N,N-dimethylamino)ethyl] ether (BDMAEE) is also identified. This is the first time that non-activated secondary alkyl halides have been used as electrophiles in the alkylation of benzoxazoles.

EPFL2012