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A novel heterosubstituted carbene spontaneously binds CO2 in a tunneling reaction under cryogenic conditions.

We present an experimental and computational study to investigate noncovalent interactions between silyl groups that are often employed as "innocent" protecting groups. We chose an extended cyclooctatetraene (COT)-based molecular balance comprising unfolded (1,4-disubstituted) and folded (1,6-disubstituted) valance bond isomers that typically display remote and close silyl group contacts, respectively. The thermodynamic equilibria were determined using nuclear magnetic resonance measurements. Additionally, we utilized Boltzmann weighted symmetry-adapted perturbation theory (SAPT) at the sSAPT0/aug-cc-pVDZ level of theory to dissect and quantify noncovalent interactions. Apart from the extremely bulky tris(trimethylsilyl)silyl "supersilyl" group, there is a preference for the folded 1,6-COT valence isomer, with London dispersion interactions being the main stabilizing factor. This makes silyl groups excellent dispersion energy donors, a finding that needs to be taken into account in synthesis planning.

We present a combined experimental and computational study on the thermodynamic stability of cis- and trans-alkenes substituted with dispersion energy donor (DED) groups. To investigate the role of noncovalent interactions on equilibrium of cis- and trans-alkenes we utilized hydrochlorination reactions. While the general assumption is that increasing steric bulk favors the trans-alkene, we observe an equilibrium shift towards the more crowded cis-alkene with increasing substituent size. With the aim to quantify noncovalent interactions, we performed a double mutant cycle to experimentally gauge the attractive potential of bulky substituents. Additionally, we utilized local energy decomposition analysis at the DLPNO-CCSD(T)/def2-TZVP level of theory. We found LD interactions and Pauli exchange repulsion to be the most dominant components to influence cis- and trans-alkene equilibria.

The Marcus dissection of the Gibbs activation energy (barrier height) into intrinsic and thermodynamic contributions, which successfully models the interplay of rate and driving force, has led to a crucial general phenomenological consequence: the well-known two reactivity paradigms of “kinetic versus thermodynamic control”. However, concepts analogous to the Marcus’ dissection for barrier widths are absent. Here we define and outline the barrier-width- counterpart of the Marcus dissection: the concept of intrinsic barrier width and driving force effect on the barrier width, and report experimental as well as theoretical studies to demonstrate their distinct roles. We present the idea of changing the barrier widths of conformational isomerizations of some simple aromatic carboxylic acids as models and use quantum mechanical tunneling (QMT) half-lives as a read-out for these changes. This sheds light on resolving conflicting trends in chemical reactivities where barrier widths are relevant, and allows us to draw some important conclusions about the general relevance of barrier widths, their qualitative definition, and the consequences for more complete descriptions of chemical reactions based on one-dimensional reaction coordinates.

Simple Summary Pro-androgenic substances such as testosterone are often used to treat muscle- or bone-related disorders. Their interactions with the classical androgen receptor, however, can trigger a number of undesirable effects. It would therefore be of great benefit if the positive androgenic effects could be obtained by circumventing the classical androgen receptor. ZIP9 is a recently identified membrane-bound androgen receptor of physiological significance. Using in silico methods, we identified and verified the extracellular localization of its androgen binding site and designed small peptides that fit in it that do not interact with the AR. All peptides were found to be pro-androgenic; they stimulate mineralization in osteoblastic cells and myogenesis in myoblasts. Thus, these peptides might serve as testosterone surrogates in the treatment of osteogenic or myogenic disorders. Abstract ZIP9 is a recently identified membrane-bound androgen receptor of physiological significance that may mediate certain physiological responses to androgens. Using in silico methods, six tetrapeptides with the best docking properties at the testosterone binding site of ZIP9 were synthesized and further investigated. All tetrapeptides displaced T-BSA-FITC, a membrane-impermeable testosterone analog, from the surface of mouse myogenic L6 cells that express ZIP9 but not the classical androgen receptor (AR). Silencing the expression of ZIP9 with siRNA prevented this labeling. All tetrapeptides were found to be pro-androgenic; in L6 cells they stimulated the expression of myogenin, triggered activation of focal adhesion kinase, and prompted the fusion of L6 myocytes to syncytial myotubes. In human osteoblastic SAOS-2 cells that express AR and ZIP9, they reduced the expression of alkaline phosphatase and stimulated mineralization. These latter effects were prevented by silencing ZIP9 expression, indicating that the osteoblast/osteocyte conversion is exclusively mediated through ZIP9. Our results demonstrate that the synthetic tetrapeptides, by acting as ZIP9-specific androgens, have the potential to replace testosterone or testosterone analogs in the treatment of bone- or muscle-related disorders by circumventing the undesirable effects mediated through the classical AR.

1,2-Ethenediols are deemed key intermediates in prebiotic and interstellar syntheses of carbohydrates. Here we present the gas-phase synthesis of these enediols, the high-energy tautomers of glycolaldehyde, trapped in cryogenic argon matrices. Importantly, upon photolysis at ʎ = 180–254 nm, the enols rearrange to the simplest sugar glycolaldehyde.

We have conducted an experimental and computational study of cyclooctatetraene-1,4/1,6-dimethanol (

Accurate thermochemistry is essential in many chemical disciplines, such as astro-, atmospheric, or combustion chemistry. These areas often involve fleetingly existent intermediates whose thermochemistry is difficult to assess. Whenever direct calorimetric experiments are infeasible, accurate computational estimates of relative molecular energies are required. However, high-level computations, often using coupled cluster theory, are generally resource-intensive. To expedite the process using machine learning techniques, we generated a database of energies for small organic molecules at the CCSD(T)/cc-pVDZ, CCSD(T)/aug-cc-pVDZ, and CCSD(T)/cc-pVTZ levels of theory. Leveraging the power of deep learning by employing graph neural networks, we are able to predict the effect of perturbatively included triples (T), that is, the difference between CCSD and CCSD(T) energies, with a mean absolute error of 0.25, 0.25, and 0.28 kcal mol

We present an experimental and computational study on the conformers of N,N'-diphenylthiourea substituted with different dispersion energy donor (DED) groups. While the unfolded anti-anti conformer is the most relevant for thiourea catalysis, intramolecular noncovalent interactions counterintuitively favor the folded syn-syn conformer, as evident from a combination of low-temperature nuclear magnetic resonance measurements and computations. In order to quantify the noncovalent interactions, we utilized local energy decomposition analysis and symmetry-adapted perturbation theory at the DLPNO-CCSD(T)/def2-TZVPP and sSAPT0/6-311G(d,p) levels of theory. Additionally, we applied a double-mutant cycle to experimentally study the effects of bulky substituents on the equilibria. We determined London dispersion as the key interaction that shifts the equilibria towards the syn-syn conformers. This preference is likely a factor why such thiourea derivatives can be poor catalysts.

Although N-heterocyclic carbenes have been well-studied, the simplest aminocarbene, aminomethylene H−C−NH2, has not been spectroscopically identified to date. Herein we report the gas-phase preparation of aminomethylene by high-vacuum flash pyrolysis of cyclopropylamine and subsequent trapping of the pyrolysate in an inert argon matrix at 12 K. Aminomethylene was characterized by matching matrix IR and UV/Vis spectroscopic data with ab initio coupled cluster computations. After UV irradiation of the matrix aminomethylene rearranges to its isomer methanimine (formaldimine) H2C=NH. Based on our experimental results and computations aminomethylene has a singlet ground state with a reaction barrier of almost 46 kcal mol−1 to methanimine so that H-tunneling is excluded.

This work presents the first detailed study on a series of cyclic hydrocarbon enediynes showing that the cyclization barrier depends upon the ground state energy differences of the biradical products, and that pure density functional methods can be used reliably to estimate the activation enthalpies of the Bergman reaction.