Alkaline Salts of Sodium and Potassium: from C–X Reduction to C–H Functionalization and Beyond

The discovery and contemplations of Gilbert N. Lewis (1875–1946) regarding the concept of electron pair acceptors has led to an improved fundamental understanding of molecular interactions. Lewis’s recognition that acidic character can exist in substances not containing hydrogen (i.e., Brønsted acids) led to the classification of a new group of reagents and catalysts for organic synthesis: Lewis acids. Over the last half-century, the application of these reagents and catalysts has in turn led to the discovery of a plethora of new chemical reactions, enabling previously unknown transformations. It has also been appreciated that electron pair donors (i.e., Lewis bases) are characterized by analogous and opposite behavior. Perhaps most intriguing is that in certain cases Lewis bases are capable of modifying simultaneously the electrophilic and nucleophilic character of the substance to which they are coordinated. It is also known that neutral tetravalent silicon can act as a Lewis acid for a variety of nucleophiles (i.e., Lewis bases) generating pentavalent Si species; these adducts are observed to have enhanced electrophilicity at Si and enhanced electron density at the ligands bound to silicon. In the case of organosilanes wherein at least one of the groups on silicon is a hydrogen (i.e., a hydrosilane), the reaction with Lewis bases can lead to pentavalent adducts with weakened Si–H bonds wherein the H has enhanced hydridic character. This property has been exploited by researchers in a number of ways, perhaps most prevalently in the development of hydrosilanes as mild reducing agents for the reduction of carbonyl compounds or for the mechanistically-related carbonyl hydrosilylation reaction. This thesis details the discovery and development of fundamentally new chemical reactivity of silanes enabled by their interaction with basic salts of certain alkali metals (and includes some, but certainly not all of the work that I have performed in this area). First, it was found that specific combinations of hydrosilanes with basic alkali metal salts – in particular KOt-Bu – under certain conditions form exceptionally powerful reductive couples capable of selectively cleaving strong aromatic C–O and C–S bonds with exceptional effectiveness and novel selectivity. Second, I found that certain modifications and elaborations of this chemical system lead to dramatic changes in the operative reaction manifold: from C–X bond cleavage to E–Si bond formation. I determined that this concept of activating hydrosilanes with alkaline salts of the alkali metals can be harnessed for the mild and efficient construction of a wide array of E–Si bond classes by catalytic crossdehydrogenative coupling. Surprisingly, these challenging chemistries all occur in the absence of transition metal species, providing new horizons and opportunities for investigating Earth-abundant elements as catalysts and reagents for a host of applications.</p

Lewis-base silane activation: from reductive cleavage of aryl ethers to selective ortho-silylation

We report a transition-metal-free protocol for the efficient reductive cleavage of diaryl and aryl alkyl ethers. The combination of triethylsilane with common bases forms an unusually powerful reductive couple that regioselectively ruptures lignin- and coal-related C–O bonds in aromatic ethers. Interestingly, with certain bases and temperature regimes ortho-directed C–H silylation efficiently competes with the latter process. However, careful tuning of the reactions conditions allows for the selective reductive cleavage of lignin model compounds to their corresponding phenolic and aromatic constituents

Electron transfer and hydride transfer pathways in the Stoltz-Grubbs reducing system (KOtBu-Et3SiH)

Recent studies by Stoltz, Grubbs et al. have shown that triethylsilane and potassium tert-butoxide react to form a highly attractive and versatile system that shows (reversible) silylation of arenes and heteroarenes as well as reductive cleavage of C-O bonds in aryl ethers and C-S bonds in aryl thioethers. Their extensive mechanistic studies indicate a complex network of reactions with a number of possible intermediates and mechanisms, but their reactions likely feature silyl radicals undergoing addition reactions and SH2 reactions. This paper focuses on the same system, but through computational and experimental studies, reports complementary facets of its chemistry based on (a) single electron transfer (SET), and (b) hydride delivery reactions to arenes

Silylation of C–H bonds in aromatic heterocycles by an Earth-abundant metal catalyst

Heteroaromatic compounds containing carbon–silicon (C–Si) bonds are of great interest in the fields of organic electronics and photonics1, drug discovery, nuclear medicine and complex molecule synthesis, because these compounds have very useful physicochemical properties. Many of the methods now used to construct heteroaromatic C–Si bonds involve stoichiometric reactions between heteroaryl organometallic species and silicon electrophiles or direct, transition-metal-catalysed intermolecular carbon–hydrogen (C–H) silylation using rhodium or iridium complexes in the presence of excess hydrogen acceptors. Both approaches are useful, but their limitations include functional group incompatibility, narrow scope of application, high cost and low availability of the catalysts, and unproven scalability. For this reason, a new and general catalytic approach to heteroaromatic C–Si bond construction that avoids such limitations is highly desirable. Here we report an example of cross-dehydrogenative heteroaromatic C–H functionalization catalysed by an Earth-abundant alkali metal species. We found that readily available and inexpensive potassium tert-butoxide catalyses the direct silylation of aromatic heterocycles with hydrosilanes, furnishing heteroarylsilanes in a single step. The silylation proceeds under mild conditions, in the absence of hydrogen acceptors, ligands or additives, and is scalable to greater than 100 grams under optionally solvent-free conditions. Substrate classes that are difficult to activate with precious metal catalysts are silylated in good yield and with excellent regioselectivity. The derived heteroarylsilane products readily engage in versatile transformations enabling new synthetic strategies for heteroaromatic elaboration, and are useful in their own right in pharmaceutical and materials science applications

Sodium Hydroxide Catalyzed Dehydrocoupling of Alcohols with Hydrosilanes

An O–Si bond construction protocol employing abundantly available and inexpensive NaOH as the catalyst is described. The method enables the cross-dehydrogenative coupling of an alcohol and hydrosilane to directly generate the corresponding silyl ether under mild conditions and without the production of stoichiometric salt byproducts. The scope of both coupling partners is excellent, positioning the method for use in complex molecule and materials science applications. A novel Si-based cross-coupling reagent is also reported

A potassium tert-butoxide and hydrosilane system for ultra-deep desulfurization of fuels

Hydrodesulfurization (HDS) is the process by which sulfur-containing impurities are removed from petroleum streams, typically using a heterogeneous, sulfided transition metal catalyst under high H_2 pressures and temperatures. Although generally effective, a major obstacle that remains is the desulfurization of highly refractory sulfur-containing heterocycles, such as 4,6-dimethyldibenzothiophene (4,6-Me_2DBT), which are naturally occurring in fossil fuels. Homogeneous HDS strategies using well-defined molecular catalysts have been designed to target these recalcitrant S-heterocycles; however, the formation of stable transition metal sulfide complexes following C–S bond activation has largely prevented catalytic turnover. Here we show that a robust potassium (K) alkoxide (O)/hydrosilane (Si)-based (‘KOSi’) system efficiently desulfurizes refractory sulfur heterocycles. Subjecting sulfur-rich diesel (that is, [S] ∼ 10,000 ppm) to KOSi conditions results in a fuel with [S] ∼ 2 ppm, surpassing ambitious future governmental regulatory goals set for fuel sulfur content in all countries. Fossil fuels contain naturally occurring organosulfur impurities, with quantities varying depending on the type of feedstock. These sulfur-containing organic small molecules poison catalytic converters and generate polluting sulfur dioxides when combusted. Hydrodesulfurization (HDS) is the industrial process by which sulfur impurities are removed from petroleum fractions prior to their use as fuels. Currently, HDS is performed by treating petroleum with H_2 at high pressures and temperatures (that is, 150–2,250 psi and 400 °C) over heterogeneous catalysts such as cobalt-doped molybdenum sulfide supported on alumina (that is, CoMoS_x∕γ-Al_2O_3; Fig. 1a). However, certain organosulfur species, in particular dibenzothiophenes alkylated at positions 4 and 6, are not efficiently removed. Homogeneous strategies employing sophisticated, well-defined transition metal complexes—including those based on platinum, nickel, tungsten, molybdenum, palladium, ruthenium, rhodium, iron, cobalt, and others—have been extensively investigated. While these studies have provided valuable mechanistic insights, several fundamental issues, such as the formation of stable organometallic S–M species upon C–S bond activation by the metal centre (Fig. 1b), generally restrict industrial implementation of such methods. Rare examples of desulfurization of dibenzothiophenes alkylated at the 4 and 6 positions by homogeneous transition metal catalysis utilized either Ni compounds in combination with superstoichiometric alkyl Grignard reagents or Ni or Co phosphoranimide complexes in the presence of superstoichiometric KH. These issues pose a formidable challenge for the development of new HDS methods. Moreover, increasingly strict governmental regulations require limiting the sulfur content in diesel fuel and gasoline (in the US: typically <15 and <30 ppm, respectively) as well as other fuels, rendering the development of new powerful HDS methods a primary global concern. In 2013, Grubbs and co-workers reported the KO^tBu mediated cleavage of aryl C–O bonds in lignin models in the absence of transition metals using hydrosilanes. Careful inductively coupled plasma mass spectrometry (ICP-MS) analyses of the reagents and reaction mixtures ruled out catalysis with transition metals. We thus became interested in extending this method to sulfur heterocycles of relevance in oil and gas refining applications. Herein, we report that the robust KOtBu/silane-based (that is, KOSi) system is a powerful and effective homogeneous HDS method, which desulfurizes HDS-resistant dibenzothiophenes in good yield and reduces the sulfur content in diesel fuel to remarkably low levels (Fig. 1c)

Sodium Hydroxide Catalyzed Dehydrocoupling of Alcohols with Hydrosilanes

An O–Si bond construction protocol employing abundantly available and inexpensive NaOH as the catalyst is described. The method enables the cross-dehydrogenative coupling of an alcohol and hydrosilane to directly generate the corresponding silyl ether under mild conditions and without the production of stoichiometric salt byproducts. The scope of both coupling partners is excellent, positioning the method for use in complex molecule and materials science applications. A novel Si-based cross-coupling reagent is also reported

Potassium tert-Butoxide-Catalyzed Dehydrogenative C–H Silylation of Heteroaromatics: A Combined Experimental and Computational Mechanistic Study

We recently reported a new method for the direct dehydrogenative C–H silylation of heteroaromatics utilizing Earth-abundant potassium tert-butoxide. Herein we report a systematic experimental and computational mechanistic investigation of this transformation. Our experimental results are consistent with a radical chain mechanism. A trialkylsilyl radical may be initially generated by homolytic cleavage of a weakened Si–H bond of a hypercoordinated silicon species as detected by IR, or by traces of oxygen which can generate a reactive peroxide by reaction with (KOt-Bu)_4 as indicated by density functional theory (DFT) calculations. Radical clock and kinetic isotope experiments support a mechanism in which the C–Si bond is formed through silyl radical addition to the heterocycle followed by subsequent β-hydrogen scission. DFT calculations reveal a reasonable energy profile for a radical mechanism and support the experimentally observed regioselectivity. The silylation reaction is shown to be reversible, with an equilibrium favoring products due to the generation of H_2 gas. In situ NMR experiments with deuterated substrates show that H_2 is formed by a cross-dehydrogenative mechanism. The stereochemical course at the silicon center was investigated utilizing a ^2H-labeled silolane probe; complete scrambling at the silicon center was observed, consistent with a number of possible radical intermediates or hypercoordinate silicates

Alkali metal hydroxide–catalyzed C(sp)–H bond silylation

Disclosed is a mild, scalable, and chemoselective catalytic cross-dehydrogenative C–H bond functionalization protocol for the construction of C(sp)–Si bonds in a single step. The scope of the alkyne and hydrosilane partners is substantial, providing an entry point into various organosilane building blocks and additionally enabling the discovery of a number of novel synthetic strategies. Remarkably, the optimal catalysts are NaOH and KOH