Unambiguous evaluation of the relative photolysis rates of nitro indolinyl protecting groups critical for brain network studies

AbstractNitrated indolinyl photoprotecting groups are crucial tools extensively used in the study of neuronal signal transduction. Mononitrated photolabile protecting groups have been used effectively, however, recent advances in the introduction of a second nitro group have shown improvement in the photo efficiency of neurotransmitter (agonist) release, albeit, to varying extents, depending on the assessment methods employed. An unambiguous method is discussed based on Nuclear Magnetic Resonance (NMR), which is shown to be an effective technique in the relative overall rate comparison amongst varying nitrated protecting groups. Mononitrated and dinitrated photolabile protecting groups such as CDNI-Glu and MNI-Glu are used as an example to assess the relative value of adding a second nitro group in photoactive cage designs. Using this technique, it was shown that the second nitro group in CDNI systems enhances the overall relative rate of photocleavage by a factor of 5.8. This reported method can also be used to unambiguously determine relative rate of agonist photorelease

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

The Binding of Cocaine to Cyclodextrins

AbstractÐCocaine binds into b-cyclodextrin, but not detectably into a-or g-cyclodextrin, in water solution. NMR studies indicate the geometry of the complex, which is con®rmed by molecular mechanics calculations and binding studies on cocaine analogues and cyclodextrin dimers. # 2000 Elsevier Science Ltd. All rights reserved. Cocaine 3,4 As a ®rst step, we have examined the binding of cocaine into the cyclodextrins, which are convenient units for binding hydrophobic substrates. We ®nd that indeed cocaine binds with reasonable anity to b-cyclodextrin (b-CD, cycloheptaamylose All binding studies except those speci®cally described as using NMR were conducted by calorimetric titration, using a MicroCal OMEGA instrument. More concentrated solutions of the cyclodextrins and their derivatives were 0960-894X/00/$ -see front matter # 2000 Elsevier Science Ltd. All rights reserved. P I I : S 0 9 6 0 -8 9 4 X ( 0 0 ) 0 0 3 7 1 -

Cyclodextrin retinylidene: A biomimetic kinetic trap model for rhodopsin

Abstract-All trans retinal was attached to both the primary face and the secondary face of b-cyclodextrin via a Schiff base linkage, analogous to that in rhodopsin. The new models were evaluated and compared with n-butylamine retinylidene Schiff base for their rates of hydrolysis, and factors that influence such rates. Competition studies using adamantane carboxylate demonstrated the kinetic trap theory by diminishing the binding of retinal in the cyclodextrin, thereby augmenting the rate of hydrolysis. NMR experiments indicate that the retinylidene is most probably bound in the form of a dimer

Transition‐Metal‐Free Catalytic C─H Bond Silylation

Herein, we provide a detailed look at the state of transition‐metal‐free catalytic C–H silylation with select examples to highlight specific advances during the field's recent development. The reactions are categorized by type of catalyst (i.e. Lewis acid, Brønsted acid, Brønsted base, and radical initiation catalysts). For each catalyst system presented, an overview of the substrate scope, mechanism (if known), and significant limitations is discussed

Competition Between Cyclization and Unusual Norrish Type I and Type II Nitro-Acyl Migration Pathways in the Photouncaging of 1-Acyl-7-nitroindoline Revealed by Computations

The 7-nitroindolinyl family of caging chromophores has received much attention in the past two decades. However, its uncaging mechanism is still not clearly understood. In this study, we performed state-of-the-art density functional theory calculations to unravel the photo-uncaging mechanism in its entirety, and we compared the probabilities of all plausible pathways. We found competition between a classical cyclization and acyl migration pathways, and here we explain the electronic and steric reasons behind such competition. The migration mechanism possesses the characteristics of a combined Norrish Type I and a 1,6-nitro-acyl variation of a Norrish Type II mechanism, which is reported here for the first time. We also introduced a computational procedure that allows the estimation of intersystem crossing rate constants useful to compare the relative quantum yield of substituted cages. This procedure may pave the way for improved cage designs that possess higher quantum yields and a more efficient agonist release.<br /

Competition between cyclization and unusual Norrish type I and type II nitro-acyl migration pathways in the photouncaging of 1-acyl-7-nitroindoline revealed by computations

Abstract The 7-nitroindolinyl family of caging chromophores has received much attention in the past two decades. However, its uncaging mechanism is still not clearly understood. In this study, we performed state-of-the-art density functional theory calculations to unravel the photo-uncaging mechanism in its entirety, and we compared the probabilities of all plausible pathways. We found competition between a classical cyclization and an acyl migration pathway, and here we explain the electronic and steric reasons behind such competition. The migration mechanism possesses the characteristics of a combined Norrish type I and a 1,6-nitro-acyl variation of a Norrish type II mechanism, which is reported here for the first time. We also found negligible energetic differences in the uncaging mechanisms of the 4-methoxy-5,7-dinitroindolinyl (MDNI) cages and their mononitro analogues (MNI). We traced the experimentally observed improved quantum yields of MDNI to a higher population of the reactants in the triplet surface. This fact is supported by a more favorable intersystem crossing due to the availability of a higher number of triplet excited states with the correct symmetry in MDNI than in MNI. Our findings may pave the way for improved cage designs that possess higher quantum yields and a more efficient agonist release

Transition‐Metal‐Free Catalytic C─H Bond Silylation

Herein, we provide a detailed look at the state of transition‐metal‐free catalytic C–H silylation with select examples to highlight specific advances during the field's recent development. The reactions are categorized by type of catalyst (i.e. Lewis acid, Brønsted acid, Brønsted base, and radical initiation catalysts). For each catalyst system presented, an overview of the substrate scope, mechanism (if known), and significant limitations is discussed