Experimental and Theoretical Exploration of the Kinetics and Thermodynamics of the Nucleophile-Induced Fragmentation of Ylidenenorbornadiene Carboxylates.

Ylidenenorbornadienes (YNDs), prepared by [4 + 2] cycloadditions between fulvenes and acetylene carboxylates, react with thiol nucleophiles to yield mixtures of four to eight diastereomers depending on the symmetry of the YND substrate. The mixtures of diastereomers fragment via a retro-[4 + 2] cycloaddition with a large variation in rate, with half-lives ranging from 16 to 11,000 min at 80 °C. The diastereomer-enriched samples of propane thiol adducts [YND-propanethiol (PTs)] were isolated and identified by nuclear Overhauser effect spectroscopy (NOESY) correlations. Simulated kinetics were used to extrapolate the rate constants of individual diastereomers from the observed rate data, and it correlated well with rate constants measured directly and from isolated diastereomer-enriched samples. The individual diastereomers of a model system fragment at differing rates with half-lives ranging from 5 to 44 min in CDCl3. Density functional theory calculations were performed to investigate the mechanism of fragmentation and support an asynchronous retro-[4 + 2] cycloaddition transition state. The computations generally correlated well with the observed free energies of activation for four diastereomers of the model system as a whole, within 2.6 kcal/mol. However, the observed order of the fragmentation rates across the set of diastereomers deviated from the computational results. YNDs display wide variability in the rate of fragmentation, dependent on the stereoelectronics of the ylidene substituents. A Hammett study showed that the electron-rich aromatic rings attached to the ylidene bridge increase the fragmentation rate, while electron-deficient systems slow fragmentation rates.

Intramolecular Diels-Alder Reaction of a Biphenyl Group in a Strained meta-Quaterphenylene Acetylene.

At elevated temperatures, a strained, cyclic meta-quaterphenylene acetylene undergoes an intramolecular cyclization reaction to form benz[e]indeno[1,2,3-hi]acephenanthrylene. This reaction represents an example of a Diels-Alder reaction at the 2-, 1-, 1'-, and 2'-positions of a biphenyl derivative, a region analogous to the bay regions of perylene and other periacenes. The reaction proceeds cleanly with high conversion. Kinetics studies of a methylated derivative reveal that the ΔG‡ for the reaction is ∼40-41 kcal/mol, and computational models predict a similar value of Grel for the transition state of a concerted [4 + 2]-cycloaddition.

Ylidenenorbornadiene Carboxylates: Experimental Kinetic Analysis of a Nucleophile-Induced Fragmentation Reaction.

Ylidenenorbornadienes (YNDs), prepared by [4 + 2] cycloadditions between fulvenes and acetylene carboxylates, react with beta-mercaptoethanol to yield a mixture of four diastereomers. These four diastereomers fragment via a retro-[4 + 2] cycloaddition at differing rates. A simulated kinetics approach extrapolated the rate constants of the diastereomers from the observed rate data. YNDs display wide variability in rate of fragmentation, dependent on the stereoelectronics of the ylidene substituents. A substrate containing one carboxylic ester proved exceptionally stable to fragmentation.

Cavity-based free energy analysis of osmolyte effects on protein denaturation.

Experimental measurements of the thermal effects of the same osmolytes on two different globular proteins, C-reactive protein (CRP) and tumor necrosis factor alpha (TNFα), have shown that quantifying the change in the denaturing temperature leads to some results that are unique to each protein. In order to find osmolyte-dependent parameters that can be applied more consistently from protein to protein, this work considers, instead, the overall free energy change associated with that denaturation using coarse-grained models. This is enabled by using theoretical fluid equations that take into account the exclusion of water and osmolyte from the volume occupied by the protein in both its native and denatured forms. Assuming ideal geometric models of the two protein states whose sizes are based on the protein's surface area in each form, and taking into account the density of the aqueous osmolyte solution, the free energy change due to the change in geometry can be calculated. The overall change in free energy of the system is found from that quantity and other protein- and osmolyte-specific parameters, which are determined using the experimental concentration and temperature results. We find that these fitted parameters accurately reproduce experimental results and also show consistent patterns from protein to protein. We also consider two different model geometries of the denatured protein and find little impact on the use of one or the other. Defining the effects of the osmolyte in terms of free energy also allows for prediction of overall phase change behavior, including cold denaturation.