Our previous work found that canonical forms of transition state theory incorrectly predict the regioselectivity of the hydroboration of propene with BH3 in solution. In response, it has been suggested that alternative statistical and nonstatistical rate theories can adequately account for the selectivity. This paper uses a combination of experimental and theoretical studies to critically evaluate the ability of these rate theories, as well as dynamic trajectories and newly developed localized statistical models, to predict quantitative selectivities and qualitative trends in hydroborations on a broader scale. The hydroboration of a series of terminally substituted alkenes with BH3 was examined experimentally, and a classically unexpected trend is that the selectivity increases as the alkyl chain is lengthened far from the reactive centers. Conventional and variational transition state theories can neither predict the selectivities nor the trends. The canonical competitive nonstatistical model makes somewhat better predictions for some alkenes but fails to predict trends, and it performs poorly with an alkene chosen to test a specific prediction of the model. Added nonstatistical corrections to this model make the predictions worse. Parameterized RRKM-master equation calculations correctly predict the direction of the trend in the selectivity versus alkene size but overpredict its magnitude, and the selectivity with large alkenes remains unpredictable with any parameterization. Trajectory studies in explicit solvent can predict selectivities without parameterization but are impractical for predicting small changes in selectivity. From a lifetime and energy analysis of the trajectories, “localized RRKM-ME” and “competitive localized noncanonical” rate models are suggested as steps toward a general model. These provide the best predictions of the experimental observations and insight into the selectivities.
Several formal heteroborylative cyclization reactions have been recently reported, but little physical-organic and mechanistic data is known. We now investigate the catalyst-free formal thioboration reaction of alkynes to gain mechanistic insight into B-chlorocatecholborane (ClBcat) in its new role as an alkynophilic Lewis acid in electrophilic cyclization/dealkylation reactions. In kinetic studies, the reaction is second order globally; first order with respect to both the 2-alkynylthioanisole substrate and the ClBcat electrophile, with activation parameters of ΔG‡ = 27.1 ± 0.1 kcal mol−1 at 90 °C, ΔH‡ = 13.8 ± 1.0 kcal mol−1 and ΔS‡ = −37 ± 3 cal mol−1 K−1, measured over the range of 70–90°C. Carbon kinetic isotope effects supported a rate-determining AdE3 mechanism wherein alkyne activation by neutral ClBcat is concerted with cyclative attack by nucleophilic sulfur. A Hammett study found a ρ+ of −1.7, suggesting cationic charge buildup during the cyclization and supporting rate-determining concerted cyclization. Studies of the reaction with tris(pentafluorophenyl)borane (B(C6F5)3), an activating agent capable of cyclization but not dealkylation, resulted in the isolation of a post-cyclization zwitterionic intermediate. Kinetic studies via UV-vis spectroscopy with this boron reagent found second order kinetics, supporting the likely relevancy of intermediates in this system to the ClBcat system. Computational studies comparing ClBcat with BCl3 as an activating agent showed why BCl3, in contrast to ClBcat, failed to mediate the complete the cyclization/demethylation reaction sequence by itself. Overall, the results support a mechanism in which the ClBcat reagent serves a bifunctional role by sequentially activating the alkyne, despite being less electrophilic than other known alkyne-activating reagents, then providing chloride for post-rate-determining demethylation/neutralization of the resulting zwitterionic intermediate.
The aromatic amino acid hydroxylases tyrosine hydroxylase (TyrH) and phenylalanine hydroxylase (PheH) have essentially identical active sites, but PheH is nearly incapable of hydroxylating tyrosine, while TyrH can readily hydroxylate both tyrosine and phenylalanine. Previous studies have indicated that Asp425 of TyrH is important in determining the substrate specificity of that enzyme (Daubner, S. C., Melendez, J., and Fitzpatrick, P. F. (2000) Biochemistry 39, 9652–9661). Alanine scanning mutagenesis of amino acids 423-427, a mobile loop containing Asp425, shows that only mutagenesis of Asp425 alters the activity of the enzyme significantly. Saturation mutagenesis of Asp425 results in large (up to 104) decreases in the Vmax and Vmax/Ktyr values for tyrosine hydroxylation, but only small decreases or even increases in the Vmax and Vmax/Kphe values for phenylalanine hydroxylation. The decrease in the tyrosine hydroxylation activity of the mutant proteins is due to an uncoupling of tetrahydropterin oxidation from amino acid hydroxylation with tyrosine as the amino acid substrate. In contrast, with the exception of the D425W mutant, the coupling of tetrahydropterin oxidation and amino acid hydroxylation is unaffected or increases with phenylalanine as the amino acid substrate. The decrease in the Vmax value with tyrosine as substrate shows a negative correlation with the hydrophobicity of the amino acid residue at position 425. The results are consistent with a critical role of Asp425 being to prevent a hydrophobic interaction that results in a restricted active site in which hydroxylation of tyrosine does not occur.
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