72 research outputs found
Nonadiabatic derivative couplings through multiple Franck-Condon modes dictate the energy gap law for near and short-wave infrared dye molecules
Near infrared (NIR, 700 - 1,000 nm) and short-wave infrared (SWIR, 1,000 -
2,000 nm) dye molecules exhibit significant nonradiative decay rates from the
first singlet excited state to the ground state. While these trends can be
empirically explained by a simple energy gap law, detailed mechanisms of the
nearly universal behavior have remained unsettled for many cases. Theoretical
and experimental results for two representative NIR/SWIR dye molecules reported
here clarify an important mechanism of such nature. It is shown that the first
derivative nonadiabatic coupling terms serve as major coupling pathways for
nonadiabatic decay processes exhibiting the energy gap law behavior and that
vibrational modes other than the highest frequency ones also make significant
contributions to the rate. This assessment is corroborated by further
theoretical comparison with possible alternative mechanisms of intersystem
crossing to triplet states and also by comparison with experimental data for
deuterated molecules
Controlled fabrication of nanoscale gaps using stiction
Utilizing stiction, a common failure mode in micro/nano electromechanical systems (M/NEMS), we propose a method for the controlled fabrication of nanometer-thin gaps between electrodes. In this approach, a single lithography step is used to pattern cantilevers that undergo lateral motion towards opposing stationary electrodes separated by a defined gap. Upon wet developing of the pattern, capillary forces induce cantilever deflection and collapse leading to permanent adhesion between the tip and an opposing support structure. The deflection consequently reduces the separation gap between the cantilever and the electrodes neighboring the point of stiction to dimensions smaller than originally patterned. Through nanoscale force control achieved by altering device design, we demonstrate the fabrication of nanogaps having controlled widths smaller than 15 nm. We further discuss optimization of these nanoscale gaps for applications in NEM and molecular devices.National Science Foundation (U.S.) (Center for Energy Efficient Electronics Science (E3S) Award ECCS-0939514)Natural Sciences and Engineering Research Council of Canad
A Strategy for the Selective Imaging of Glycans Using Caged Metabolic Precursors
Glycans can be imaged by metabolic labeling with azidosugars followed by chemical reaction with imaging probes; however, tissue-specific labeling is difficult to achieve. Here we describe a strategy for the use of a caged metabolic precursor that is activated for cellular metabolism by enzymatic cleavage. An N-azidoacetylmannosamine derivative caged with a peptide substrate for the prostate-specific antigen (PSA) protease was converted to cell-surface azido sialic acids in a PSA-dependent manner. The approach has applications in tissue-selective imaging of glycans for clinical and basic research purposes. Š 2010 American Chemical Society
Reactivity of Biarylazacyclooctynones in Copper-Free Click Chemistry
The 1,3-dipolar cycloaddition of cyclooctynes with azides, also called "copper-free click chemistry", is a bioorthogonal reaction with widespread applications in biological discovery. The kinetics of this reaction are of paramount importance for studies of dynamic processes, particularly in living subjects. Here we performed a systematic analysis of the effects of strain and electronics on the reactivity of cyclooctynes with azides through both experimental measurements and computational studies using a density functional theory (DFT) distortion/interaction transition state model. In particular, we focused on biarylazacyclooctynone (BARAC) because it reacts with azides faster than any other reported cyclooctyne and its modular synthesis facilitated rapid access to analogues. We found that substituents on BARAC's aryl rings can alter the calculated transition state interaction energy of the cycloaddition through electronic effects or the calculated distortion energy through steric effects. Experimental data confirmed that electronic perturbation of BARAC's aryl rings has a modest effect on reaction rate, whereas steric hindrance in the transition state can significantly retard the reaction. Drawing on these results, we analyzed the relationship between alkyne bond angles, which we determined using X-ray crystallography, and reactivity, quantified by experimental second-order rate constants, for a range of cyclooctynes. Our results suggest a correlation between decreased alkyne bond angle and increased cyclooctyne reactivity. Finally, we obtained structural and computational data that revealed the relationship between the conformation of BARAC's central lactam and compound reactivity. Collectively, these results indicate that the distortion/interaction model combined with bond angle analysis will enable predictions of cyclooctyne reactivity and the rational design of new reagents for copper-free click chemistry
Functionalized Poly(3-hexylthiophene)s via LithiumâBromine Exchange
Poly(3-hexylthiophene) (P3HT) is one of the most extensively investigated conjugated polymers and has been employed as the active material in many devices including field-effect transistors, organic photovoltaics and sensors. As a result, methods to further tune the properties of P3HT are desirable for specific applications. Herein, we report a facile postpolymerization modification strategy to functionalize the 4-position of commercially available P3HT in two simple stepsâbromination of the 4-position of P3HT (BrâP3HT) followed by lithiumâbromine exchange and quenching with an electrophile. We achieved near quantitative lithiumâbromine exchange with BrâP3HT, which requires over 100 thienyl lithiates to be present on a single polymer chain. The lithiated-P3HT is readily combined with functional electrophiles, resulting in P3HT derivatives with ketones, secondary alcohols, trimethylsilyl (TMS) group, fluorine, or an azide at the 4-position. We demonstrated that the azide-modified P3HT could undergo Cu-catalyzed or Cu-free click chemistry, significantly expanding the complexity of the structures that can be appended to P3HT using this method.National Science Foundation (U.S.) (ECCS-0939514
Fluorofluorophores: Fluorescent Fluorous Chemical Tools Spanning the Visible Spectrum
âFluoroâ refers to both fluorescent and fluorinated compounds. Despite the shared prefix, there are very few fluorescent molecules that are soluble in perfluorinated solvents. This paucity is surprising, given that optical microscopy is a ubiquitous technique throughout the physical sciences and the orthogonality of fluorous materials is a commonly exploited strategy in synthetic chemistry, materials science, and chemical biology. We have addressed this shortage by synthesizing a panel of âfluorofluorophores,â fluorescent molecules containing high weight percent fluorine with optical properties spanning the visible spectrum. We demonstrate the utility of these fluorofluorophores by preparing fluorescent perfluorocarbon nanoemulsions.National Science Foundation (U.S.) (ECCS-0939514
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Bioorthogonal Chemistries for Labeling Living Systems
Bioorthogonal is defined as not interfering or interacting with biology. Chemical reactions that are bioorthogonal have recently become valuable tools to visualize biomolecules in their native environments, particularly those that are not amenable to traditional genetic modification. The field of bioorthogonal chemistry is rather young, with the first published account of the term bioorthogonal in 2003, yet it is expanding at a rapid rate. The roots of this unique subset of chemistry are in classic protein modification and subsequent bioconjugation efforts to obtain uniformly and site-specifically functionalized proteins. These studies are highlighted in Chapter 1. Chapter 2 opens with a summary of the bioorthogonal chemical reporter strategy, a two-step approach where a bioorthogonal functional group is installed into a biomolecule of interest, most often using endogenous metabolic machinery, and detected through a secondary covalent reaction with an appropriately functionalized chemical partner. It is this chemical reporter strategy that empowers bioorthogonal chemistry and allows for a wide variety of biological species to be assayed. Chapter 2 proceeds to outline the discovery of the Staudinger ligation, the first chemical reaction developed for use in the bioorthogonal chemical reporter strategy. The Staudinger ligation employed the azide as the chemical reporter group and, since its debut in 2000, many laboratories have capitalized on the exquisite qualities of the azide (small, abiotic, kinetically stable) that make it a versatile chemical reporter group. The success of the azide prompted the development of other bioorthogonal chemistries for this functional group. One of these chemistries, Cu-free click chemistry, is the 1,3-dipolar cycloaddition between cyclooctynes and azides. The cycloaddition is promoted at physiological conditions by the ~18 kcal/mol of ring strain contained within cyclooctyne, and further modifications to the cyclooctyne reagents have lead to increased reactivity through augmentation of the ring strain or optimization of orbital overlap. When I began my graduate work, a difluorinated cyclooctyne (DIFO), which was 60-fold more reactive than other existing bioorthogonal chemistries, had just been synthesized and employed for labeling azides on live cells and within living mice. DIFO performed very well on cultured cells, but it was outperformed by the slower Staudinger ligation in the more complex environment of the mouse. We hypothesized that DIFO was too hydrophobic to be effective in mice and designed a more hydrophilic cyclooctyne reagent, a dimethoxyazacyclooctyne (DIMAC). DIMAC was synthesized in nine steps in a 10% overall yield (Chapter 3). As predicted, DIMAC displayed reaction kinetics similar to early generation cyclooctynes, but exhibited improved water-solubility. Consequently, DIMAC labeled cell-surface azides with comparable efficiencies to the early generation cyclooctynes but greater signal-to-noise ratios were achieved due to minimal background staining. Encouraged by these results, we assayed the ability for DIMAC to label azides in living mice and found that DIMAC was able to modify azides in vivo with moderate signal over background. However, the Staudinger ligation was still the superior bioorthogonal reaction for labeling azides in vivo. Our results collectively indicated that both hydrophilicity and reactivity are important qualities when optimizing the cyclooctynes for in vivo reaction with azides (Chapter 4).We were also interested in modifying DIMAC so that it would become fluorescent upon reaction with an azide. Previous work in the lab had established that fluorogenic reagents could be easily created if a functional group was cleaved from the molecule upon reaction with an azide. We envisioned a leaving group could be engineered into the azacyclooctyne scaffold by strategically positioning a labile functional group across the ring from a nitrogen atom. The cyclooctyne structure should be stable, as it is rigid and intramolecular reactions are not favorable. However, upon reaction with an azide, a significant amount of strain is liberated and the intramolecular reaction should readily occur. Efforts toward the synthesis of this modified DIMAC reagent are chronicled in Chapter 5.Chapter 6 is a very short account of our early work to use DIFO-based reagents for proteomics. The results contained in this chapter are preliminary and further endeavors towards this goal are underway by others within the group.Chapters 7, 8 and 9 are devoted to strategies to increase the second-order rate constant of Cu-free click chemistry. In Chapter 7, various routes toward a tetrafluorinated cyclooctyne are outlined, although none of them successfully yielded this putatively highly reactive cyclooctyne. Chapter 8 describes the synthesis of a difluorobenzocyclooctyne (DIFBO), which is more reactive than DIFO, but unstable due to its propensity to form trimer products. However, DIFBO can be kinetically stabilized by encapsulation in beta-cyclodextrin. Only beta-cyclodextrin and not the smaller (alpha) or larger (gamma) cyclodextrins were able to protect DIFBO. We did observe an intriguing result when complexation with the larger gamma-cyclodextrin was attempted. It appears as though two DIFBO molecules can fit inside the gamma-cyclodextrin and dimeric products, which were not apparent in the absence of gamma-cyclodextrin, were observed. We hypothesized that all oligomer products of DIFBO were derived from a common cyclobutadiene intermediate. While DIFBO was chemically interesting, it was not a useful reagent for labeling azides in biological settings. Thus, Chapter 9 is devoted to the modification of DIFBO, with the aim of identifying a reactive yet stable cyclooctyne. The data from Chapter 9 suggest we are rapidly approaching the reactivity/stability limit for cyclooctyne reagents. The results contained within Chapters 7-9 indicated that it was time to explore other bioorthogonal chemistries. When embarking on the development of a new bioorthogonal chemical reaction, we aimed to explore unrepresented reactivity space, such that the new reaction would be orthogonal to existing bioorthogonal chemistries. We became attracted to the highly strained hydrocarbon quadricyclane and performed a screen to find a suitable reactive partner for this potential chemical reporter group (Chapter 10). Through this analysis, we discovered that quadricyclane cleanly reacts with Ni bis(dithiolene) reagents and this transformation appeared to be a good prototype for a new bioorthogonal chemical reaction. After a thorough mechanistic investigation and many rounds of modification to the Ni bis(dithiolene) species, a nickel complex with suitable reaction kinetics, water-solubility, and stability was obtained (Chapter 11). Gratifyingly, this Ni bis(dithiolene) reagent selectively modified quadricyclane-labeled bovine serum albumin, even in the presence of cell lysate (Chapter 12). Other results in Chapter 12 highlight that this new bioorthogonal ligation reaction is indeed orthogonal to Cu-free click chemistry as well as oxime ligation chemistry. Additionally, quadricyclane-dependent labeling is observed on live cells, although further optimization is necessary.The final chapter of this dissertation outlines the current state of the field. There are now many methods to modify biomolecules including several new, although relatively untested, bioorthogonal chemistries. The rapid pace of this field makes it an exciting time to be pursuing bioorthogonal chemistry
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