1H NMR Studies of Intramolecular OH/OH Hydrogen Bonds via Titratable Isotope Shifts.

Methanol titrations of partially deuterated 1,4- and 1,3-diols dissolved in nonpolar solvents such as CD2Cl2 and benzene-d6 have provided 1H NMR measurements of OH/OD isotope shifts, diagnostic for intact intramolecular hydrogen bonds, under conditions of increasing protic solvent concentration. 1,4- and 1,3-diols with conformationally favored intramolecular OH/OH hydrogen bonds can be titrated to constant isotope shift values, albeit with variable sign, in the presence of excess methanol equivalents, providing evidence for intact intramolecular hydrogen bonds under these conditions. Conversely, the isotope shift in a 1,3-diol with a conformationally labile intramolecular hydrogen bond titrated to zero when in the presence of excess equivalents methanol, consistent with intramolecular hydrogen bond rupture under these conditions. Additionally, the titration behavior of hydroxyl chemical shifts in diols and protected derivatives has revealed significant OH/OD isotope shifts in the absence of chemical shift differences (δOHin = δOHout) that are necessary for an equilibrium isotope effect, lending evidence for an intrinsic contribution to the isotope effect. OH/OD isotope shift titration thus provides a means for understanding the origins of these isotope effects and for probing the intact or nonintact nature of intramolecular OH/OH hydrogen bonds in response to intermolecular hydrogen bonds provided by a protic solvent.

Competing Interactions of Fatty Acids and Monoglycerides Trigger Synergistic Phospholipid Membrane Remodeling.

Using quartz crystal microbalance-dissipation and time-lapse fluorescence microscopy, we demonstrate that adding mixtures of lauric acid (LA) and glycerol monolaurate (GML), two of the most biologically active antimicrobial fatty acids and monoglycerides, to a supported lipid bilayer triggers concurrent tubule and bud formation, which unexpectedly results in synergistic phospholipid membrane remodeling that far exceeds the effects of GML or LA alone. Together, GML and LA drive pearling instability, dynamic transformation of buds into tubules and vice versa, and extensive membrane lysis. The most pronounced effects occurred with equimolar concentrations of GML and LA, highlighting that synergistic membrane disruption arises from competition for the lipid supply to buds and tubules and an inability to relieve membrane strains. These findings offer a conceptually new model to explain how fatty acid and monoglyceride interactions can trigger phospholipid membrane remodeling events relevant to various biophysical and biological systems.

Visible-light mediated carbonyl trifluoromethylative amination as a practical method for the synthesis of ß-trifluoromethyl tertiary alkylamines.

We report the development of an operationally straigtforward, visible-light-mediated multicomponent strategy for the construction of ß-trifluoromethylated tertiary alkylamines from feedstock aldehydes, secondary amines and a convenient source of trifluoromethyl iodide. The new process does not require a photocatalyst, is metal-free, displays a broad functional group tolerance and offers rapid, one-pot access to trifluoromethylated drug-like compounds that will be of interest in medicinal chemistry.

Influence of NaCl Concentration on Bicelle-Mediated SLB Formation.

The deposition of two-dimensional bicellar disks on hydrophilic surfaces is an emerging approach to fabricate supported lipid bilayers (SLBs) that requires minimal sample preparation, works at low lipid concentrations, and yields high-quality SLBs. While basic operating steps in the fabrication protocol mimic aspects of the conventional vesicle fusion method, lipid bicelles and vesicles have distinct architectural properties, and understanding how experimental parameters affect the efficiency of bicelle-mediated SLB formation remains to be investigated. Herein, using the quartz crystal microbalance-dissipation and localized surface plasmon resonance techniques, we investigated the effect of bulk NaCl concentration on bicelle-mediated SLB formation on silicon dioxide surfaces. For comparison, similar experiments were conducted with vesicles as well. In both cases, SLB formation was observed to occur rapidly provided that the NaCl concentration was sufficiently high (>50 mM). Under such conditions, the effect of NaCl concentration on SLB formation was minor in the case of bicelles and significant in the case of vesicles where it is expected to be related primarily to osmotic pressure. At lower NaCl concentrations, bicelles also formed SLBs but slowly, whereas adsorbed vesicles remained intact. These findings were complemented by time-lapsed fluorescence microscopy imaging and fluorescence recovery after photobleaching measurements that corroborated bicelle-mediated SLB formation across the range of tested NaCl concentrations. The results are discussed by comparing the architectural properties of bicelles and vesicles along with theoretical analysis of the corresponding adsorption kinetics.

Optimizing the Formation of Supported Lipid Bilayers from Bicellar Mixtures.

Supported lipid bilayers (SLBs) are widely studied model membrane platforms that are compatible with various surface-sensitive measurement techniques. SLBs are typically formed on silica-based materials, and there are numerous possible fabrication routes involving either bottom-up molecular self-assembly or vesicle adsorption and rupture. In between these two classes of fabrication strategies lies an emerging approach based on depositing quasi-two-dimensional lamellar, bicellar disks composed of a mixture of long-chain and short-chain phospholipids to promote the formation of SLBs. This approach takes advantage of the thermodynamic preference of long-chain phospholipids to form planar SLBs, whereas short-chain phospholipids have brief residence times. Although a few studies have shown that SLBs can be formed on silica-based materials from bicellar mixtures, outstanding questions remain about the self-assembly mechanism as well as the influence of the total phospholipid concentration, ratio of the two phospholipids (termed the "q-ratio"), and process of sample preparation. Herein, we address these questions through comprehensive quartz crystal microbalance-dissipation, fluorescence microscopy, and fluorescence recovery after photobleaching experiments. Our findings identify that optimal SLB formation occurs at lower total concentrations of phospholipids than previously used as short-chain phospholipids behave like membrane-destabilizing detergents at higher concentrations. Using lower phospholipid concentrations, we also discovered that the formation of SLBs proceeds through a two-step mechanism involving a critical coverage of bicellar disks akin to vesicle fusion. In addition, the results indicate that at least one cycle of freeze-thaw-vortexing is useful during the sample preparation process to produce SLBs. Taken together, the findings in this work identify optimal routes for fabricating SLBs from bicellar mixtures and reveal mechanistic details about the bicelle-mediated SLB formation process, which will aid further exploration of bicellar mixtures as tools for model membrane fabrication.