Robert A. Flowers

Electrochemical investigation of the reducing power of SmI2 in THF and the effect of HMPA cosolvent

Abstract The reduction potential of SmI 2 in THF is reported. The effect of varying concentrations of HMPA on the redox potential was determined employing linear sweep voltammetry (LSV). These data show the utility of electrochemistry in studying synthetically important reducing reagents. The oxidation potentials of SmI 2 in THF and SmI 2 containing increasing amounts of HMPA were examined. The effect of HMPA on the reducing power of SmI 2 is reported.

The effect of cosolvent on the reducing power of SmI2 in tetrahydrofuran

Abstract The influence of additives on the reducing power and reactivity of samarium(II) iodide is presented. Different cosolvents (ligands) employed in SmI2 mediated reactions have different affinities for SmI2 in THF. Cosolvent concentration is an important factor in determining the reducing power of the Sm(II)-cosolvent complex.

Catalytic, Atom‐Economical Radical Arylation of Epoxides

The development of efficient catalytic reactions is one of the central aspects of chemistry and arguably the most important for the invention of novel sustainable processes. Radicalbased transformations are among the most attractive methods for use in catalytic cycles owing to the ease of radical generation, high functional group tolerance, and selectivity in C C bond formation. Herein we present such a process, an atom-economical titanocene-catalyzed intramolecular arylation of epoxide-derived radicals. Our approach exploits the innate capability of the titanocene(III)/(IV) redox couple to undergo reversible electron-transfer reactions. This allows the implementation of both oxidative additions and reductive eliminations in single-electron steps into catalytic cycles. The key step of our method is presumed to be a proton-coupled electron transfer (PCET). It constitutes the pivotal single-electron reductive elimination, provides the driving force for efficient rearomatization of the radical s-complex, and negates the need for sacrificial co-reductants or oxidants necessary in radical-based chain processes or catalytic reactions. This issue is critical in Minisci reactions, radical additions to electron deficient heteroarenes, which often require stoichiometric amounts of metal (Fe, Ag) salts and oxidants (H2O2 or organic peroxides). More recently, significant progress towards more sustainable radical arylation has been reported by Heinrich et al. In these reactions, aryl diazonium salts are employed as radical precursors. Nevertheless, titanium trichloride has to be employed in stoichiometric amounts for radical generation in rather acidic media (aqueous HCl). Our catalytic cycle is shown in Scheme 1. It is initiated by the single-electron oxidative addition of [Cp2TiCl] to the substrate generating radical intermediate A. Addition of the

Studies on the Mechanism, Selectivity, and Synthetic Utility of Lactone Reduction Using SmI2 and H2O

Although simple aliphatic esters and lactones have long been thought to lie outside the reducing range of SmI(2), activation of the lanthanide reagent by H(2)O allows some of these substrates to be manipulated in an unprecedented fashion. For example, the SmI(2)-H(2)O reducing system shows complete selectivity for the reduction of 6-membered lactones over other classes of lactones and esters. The kinetics of reduction has been studied using stopped-flow spectrophotometry. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electron-transfer to the lactone carbonyl. The radical intermediates formed during lactone reduction with SmI(2)-H(2)O can be exploited in cyclizations to give cyclic ketone (or ketal) products with high diastereoselectivity. The cyclizations constitute the first examples of ester-alkene radical cyclizations in which the ester carbonyl acts as an acyl radical equivalent.

THE EFFECT OF LITHIUM BROMIDE AND LITHIUM CHLORIDE ON THE REACTIVITY OF SMI2 IN THF

Lithium bromide and lithium chloride salts have a profound influence on the reactivity of SmI2. These salts increase the reducing power of SmI2 and promote pinacol coupling.

Mechanistic complexity in organo-SOMO activation.

Singly occupied molecular orbital (SOMO) activation provides a pathway for asymmetric α-addition to aldehydes.[1] The scope of SOMO activation includes the allylation, enolation, vinylation, styrenation, chlorination, polyene cyclization, and arylation[2] of a range of aldehydes. This union of organocatalysis with single-electron oxidative coupling is an intricate process involving the complex balance of catalyst, oxidant, radicophile, base, temperature, heterogeneous reaction conditions, and H2O. To examine the role of each component in this complex process, a series of spectroscopic and kinetic studies were carried out to study the asymmetric allylation of 1 shown in Equation (1).[1a] The data described herein show three important features: 1) Oxidation of the intermediate enamine is rapid and preferential to oxidation of the catalyst, 2) H2O concentration is critical for catalytic efficiency, and 3) the kinetic role of ceric ammonium nitrate (CAN) is masked by a physical phase-transfer process.

Uncovering the Mechanistic Role of HMPA in the Samarium Barbier Reaction

The presence of HMPA is critical for the selective coupling of alkyl halides and ketones by SmI2. Although previous rate studies have shown that HMPA dramatically accelerates the reduction of alkyl halides over ketones, the basis of this rate acceleration is unknown. In this communication, we report experimental and computational evidence that demonstrate that the selectivity observed in the samarium Barbier reaction is in part a result of activation of the alkyl halide bond by HMPA.

Mechanistic study of samarium diiodide-HMPA initiated 5-exo-trig Ketyl-Olefin coupling: the role of HMPA in post-electron transfer steps.

The mechanistic importance of HMPA and proton donors (methanol, 2-methyl-2-propanol, and 2,2,2-trifluoroethanol) on SmI2-initiated 5-exo-trig ketyl-olefin cyclizations has been examined using stopped-flow spectrophotometric studies. In the presence of HMPA, the rate order of proton donors was zero and product studies showed that they had no impact on the diastereoselectivity of the reaction. Conversely, reactions were first-order in HMPA, and the additive displayed saturation kinetics at high concentrations. These results were consistent with HMPA being involved in a rate-limiting step before cyclization, where coordination of the intermediate ketyl to the sterically congested Sm(III)HMPA both stabilizes the intermediate and inhibits cyclization. Liberation of the contact ion pair through displacement by an equivalent of HMPA provides a solvent-separated ion pair releasing the steric constraint to ketyl-olefin cyclization. The mechanism derived from rate studies shows that HMPA is important not only in increasing the reduction potential of Sm(II) but also in enhancing the inherent reactivity of the radical anion intermediate formed after electron transfer through conversion of a sterically congested contact ion pair to a solvent-separated ion pair. The mechanistic complexity of the SmI2-HMPA-initiated ketyl-olefin cyclization is driven by the high affinity of HMPA for Sm(III), and these results suggest that simple empirical models describing the role of HMPA in more complex systems are likely to be fraught with a high degree of uncertainty.

Ethylammonium nitrate: a protein crystallization reagent

Ethylammonium nitrate (EAN) is a liquid organic salt that has many potential applications in protein chemistry. Because this solvent has hydrophobic and ionic character as well as the ability to hydrogen bond, it is especially well suited for broad use in protein crystallography. For example, EAN may be used as an additive, a detergent, a precipitating agent or to deliver ligands into protein crystals. A discussion of the crystallization of lysozyme using EAN as a precipitating agent is given here.

Dynamic Ligand Exchange in Reactions of Samarium Diiodide

Mechanistic studies show the importance of iodide displacement by additives that accelerate reactions of samarium diiodide. The key feature important for acceleration of reaction rate is the use of proton donors and other additives that have a high enough affinity for Sm(II) to displace iodide yet do not saturate the coordination sphere inhibiting substrate reduction.