No abstract

Most organic and organometallic catalysts have been discovered through serendipity or trial and error, rather than by rational design. Computational methods, however, are rapidly becoming a versatile tool for understanding and predicting the roles of such catalysts in asymmetric reactions. Such methods should now be regarded as a first line of attack in the design of catalysts.

A tris-triphenylphosphinegold oxonium tetrafluoroborate, [(Ph 3 PAu) 3 O]BF 4 , catalyzes the rearrangement of 1,5-allenynes to produce cross-conjugated trienes. Experimental and computational evidence shows that the ene reaction proceeds through a unique nucleophilic addition of an allene double bond to a cationic phosphinegold(I) complexed phosphinegold(I) acetylide, followed by a 1,5-hydrogen shift.

This manuscript describes the role of non-classical hydrogen bonds (NCHBs), specifically C-HO interactions, in modern synthetic organic transformations. Our goal is to point out the seminal examples where C-H···O interactions have been invoked as a key stereocontrolling element and to provide predictive value in recognizing future and/or potential C-H···O interactions in modern transformations.

DFT computations reproduce the surprisingly high regioselectivities in nucleophilic additions and cycloadditions to 4,5-indolynes, and the low regioselectivities in reactions of 5,6-indolynes. Transition state distortion energies control regioselectivities, activating the 5 and 6 positions over 4 and 7 positions, leading to high preferences for 5 and 6-substituted product from 4,5-and 6,7-indolynes, respectively. Orbital and electrostatic interactions have only minor effects, producing low regioselectivities in reactions of 5,6-indolynes. The distortion model predicts high regioselectivities with 6,7-indolynes; these are verified experimentally. The regioselectivities found with other benzynes are explained on the basis of distortion energies that are reflected in reactant geometries.The indole motif is ubiquitous among bioactive natural products and medicinal agents. 1 Indolynes are highly reactive derivatives that have shown promise in the synthesis of indole alkaloids and substituted indole derivatives. [2][3][4] In contrast to the inherent nucleophilic reactivity of indoles, indolynes are electrophilic. This umpolung of the indole heterocycle, coupled with the high reactivity of arynes, render indolyne methodology a powerful tool for the preparation of novel and synthetically challenging indole derivatives. 3 Previous studies have shown that nucleophilic additions to 4,5-indolynes can occur with significant regioselectivity. 3 We now report quantum mechanical calculations that provide a surprising explanation of the origins of this regioselectivity as well as the reported regioselectivities for other substituted arynes, reported in our laboratories and those of Buszek. 4 We have now predicted and verified experimentally the regioselectivities of nucleophilic additions to 5,6-and 6,7-indolynes. We show that control of regioselectivity arises from the unsymmetrical bending distortion of arynes, and the attendant differential distortion energies required to achieve regioisomeric transition state geometries. The intimate relationship between distortion energies 5 and activation barriers has been demonstrated previously in 1,3-dipolar 6 and Diels-Alder cycloadditions. 7 After submission of our manuscript, an experimental and computational study of furan cycloadditions to indolynes from Buszek and Cramer came to a related conclusion. 8 We previously reported that the generation of 4,5-indolynes from silyl triflates produces aryne intermediates that are trapped to give 5-substituted adducts preferentially ( The results of density functional computations (B3LYP/6-31G(d)) 9 are shown in the last column. Transition states were located for a variety of nucleophilic additions. The results are supported by computations with larger basis sets, other functionals (e.g., see SI for MO6-2X results), and MP2 calculations that will be reported in a full paper. The B3LYP results on the competing transition structures (TSs) reproduce the trends in regioselectivity, while the magnitudes are usually exaggerated. Activation...

Efficient syntheses of 4,5-, 5,6-, and 6,7-indolyne precursors beginning from commercially available hydroxyindole derivatives are reported. The synthetic routes are versatile and allow access to indolyne precursors that remain unsubstituted on the pyrrole ring. Indolynes can be generated under mild fluoride-mediated conditions, trapped by a variety of nucleophilic reagents, and used to access a number of novel substituted indoles. Nucleophilic addition reactions to indolynes proceed with varying degrees of regioselectivity; distortion energies control regioselectivity and provide a simple model to predict the regioselectivity in the nucleophilic additions to indolynes and other unsymmetrical arynes. This model has led to the design of a substituted 4,5-indolyne that exhibits enhanced nucleophilic regioselectivity.

The development of catalysts for Mannich-type reactions that afford anti-products with excellent diastereo- and enantioselectivities under mild conditions and low catalyst loadings (1-5 mol %) is reported. Based on principles gained from the study of (S)-proline-catalyzed Mannich-type reactions that afford enantiomerically enriched syn-products, (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid (RR35) has been designed to catalyze the direct enantioselective anti-selective Mannich-type reactions. Computational studies of the above reaction using HF/6-31G* level of theory suggested that this design would be highly effective. The catalyst was subsequently synthesized and studied in organocatalytic Mannich-type reactions between unmodified aldehydes and N-PMP-protected alpha-imino esters. In accord with the design principles and in quantitative agreement with the theoretical predictions, reactions catalyzed by this catalyst afforded anti-products in good yields with excellent diastereo- and enantioselectivities (anti:syn 94:6 to 98:2, >97 to >99% ee).

The selective synthesis and in situ characterization of aqueous Alcontaining clusters is a long-standing challenge. We report a newly developed integrated platform that combines (i) a selective, atomeconomical, step-economical, scalable synthesis of Al-containing nanoclusters in water via precision electrolysis with strict pH control and (ii) an improved femtosecond stimulated Raman spectroscopic method covering a broad spectral range of ca. T he importance of Al (aluminum) in the biosphere and to human civilization is enormous. The scale of mining and production of Al compounds is second only to that of Fe (iron). Our lives are influenced by its use in electronics (1, 2), cooking and eating utensils, and food packaging, and as structural materials in the construction, automotive, and aircraft industries. Its deposition and migration as a mineral ore are controlled by its aqueous chemistry and speciation. Millions of tons of Al compounds are used worldwide each year for water treatment, and it is found in all drinking water (3). The behavior of Al in water plays significant roles in soil chemistry and plant growth (4, 5), for example, governing Al bioavailability, toxicity, and its overall impact in aquatic ecosystems (6). Meanwhile, aqueous Al clusters are gaining importance as solution precursors for the large-area deposition of Al 2 O 3 coatings with broad technological applications (7,8).Despite more than a century of study (9, 10), the complete portrait of aqueous Al chemistry remains unclear. Studies of aqueous Al chemistry are notoriously difficult because of the variety and complexity of the species that can be formed, encompassing monomeric, oligomeric, and polymeric hydroxides (11-17); colloidal solutions and gels; and precipitates. Synthesis is complicated by the fact that the counter-ions and the method and rate of pH change all have dramatic effects on product formation (18,19). Few methods exist for the in situ determination and assignment of molecular-level structures. For instance, 27 Al NMR can only identify certain Al aqueous species (15). Furthermore, unlike organic compounds, systematic spectroscopic signatures of metal hydroxide clusters are less accessible, making interpretation of experimental spectra challenging. We hereby report a combined synthesis, experiment, and theory platform for the study of aqueous metal clusters. Electrolysis is exploited to control the solution pH and counter-ion content precisely during cluster synthesis without using chemical reagents. The evolution of solution species is followed in situ by an improved femtosecond stimulated Raman (FSR) technique (20-22) that can detect weak signals associated with structure-defining vibrational modes. The resulting pHdependent Raman spectra are interpreted by juxtaposition to quantum mechanically computed vibrational modes to assign specific molecular structures. Through this integrated approach, we have discovered a speciation behavior for Al in water that has not previously been observed. We focus here on the synthesis an...