Darstellung und Reaktionen des 2,2,4-Trimethylimidazolin-5-thions

Zusammenfassung 2,2,4-Trimethylimidazolin-5-thion (1) entsteht in guter Ausb. bei der gemeinsamen Einwirkung eines großen Überschusses sowohl an Schwefel als auch an Ammoniak auf Aceton bei Temperaturen von etwa –60° C in Gegenwart bestimmter reaktionsbeschleunigender Zusätze. 1 bildet ein Cu(I)-Salz und läßt sich mit H₂O₂ in alkal. Lösung zum 2,2,4-Trimethylimidazolin-5-on (3) umsetzen.1 reagiert in guten bis sehr guten Ausbeuten mit primären und sekundären Aminen zu 2,2,5-Trimethyl-4-alkylamino-2H-imidazolen (4–12).

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Preparation and reactions of 2.2.4-trimethylimidazoline-5-thion (joint action of sulfur and ammonia upon ketones, LXX. Action of sulfur and ammonia upon acetone, II)

2.2.4-Trimethylimidazoline-5-thione (1) is obtained in good yields by the joint action of a large excess of sulfur and ammonia upon acetone at temperatures around –60° C in presence of certain accelerators. 1 gives a Cu(I)-salt and is converted by alkaline H₂O₂ to 2.2.4-trimethylimidazoline-5-one (3).1 reacts fairly smoothly with primary and secondary amines to yield 2.2.5-trimethyl-4-alkylamino-2H-imidazoles (4–12).

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69. Mitt.:F. Asinger, A. Saus, H. Offermanns undF. Abo Dagga, Ann. Chem.723, 119 (1969).

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1. Mitt.:M. Thiel undF. Asinger, Ann. Chem.610, 17 (1957).

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Teil der DissertationF. Abo Dagga, Techn. Hochschule Aachen 1968.     

Meilenstein Salicylsäuresynthese

In early Christian times treating the sick was considered as blasphemy, and it had only to be in the hands of the Almighty alone (“Do not meddle in the Almighty's creation”). But by and by people did not take diseases as god‐given, and tried and learned to combat them. For some millenniums only natural “remedies” like herbs, animal, and inorganic products were available. Finally, at the beginning of the 19th century it became possible to isolate pure natural substances from herbs, characterize, and modify them by partial synthesis, in order to optimize efficacy, resorption and side effects.On January 2nd 1874 the total chemical synthesis of drugs in industrial scale began in a mansion in the city of Dresden, when Hermann Kolbe jointly with Rudolf Schmitt and Friedrich von Heyden produced Salicylic acid from phenol and carbon dioxide.Until then this drug substance could only be made from willow bark or the plant Spirea ulmaria. Today many substances of natural origin as well of completely newly structured compounds can be made by total synthesis. Biotechnology, and Gene technology are broadening the methods to prepare new drugs.     

Computational studies of darunavir into HIV-1 protease and DMPC bilayer: necessary conditions for effective binding and the role of the flaps

Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the main targets toward AIDS therapy. We have selected the potent drug darunavir and a weak inhibitor (fullerene analog) as HIV-1 PR substrates to compare protease's conformational features upon binding. Molecular dynamics (MD), molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), and quantum-mechanical (QM) calculations indicated the importance of the stability of HIV-1 PR flaps toward effective binding: a weak inhibitor may induce flexibility to the flaps, which convert between closed and semiopen states. A water molecule in the darunavir-HIV-1 PR complex bridged the two flap tips of the protease through hydrogen bonding (HB) interactions in a stable structure, a feature that was not observed for the fullerene-HIV-1 PR complex. Additionally, despite that van der Waals interactions and nonpolar contribution to solvation favored permanent fullerene entrapment into the cavity, these interactions alone were not sufficient for effective binding; enhanced electrostatic interactions as observed in the darunavir-complex were the crucial component of the binding energy. An alternative pathway to the usual way of a ligand to access the cavity was also observed for both compounds. Each ligand entered the binding cavity through an opening between the one flap of the protease and a neighboring loop. This suggested that access to the cavity is not necessarily regulated by flap opening. Darunavir exerts its biological action inside the cell, after crossing the membrane barrier. Thus, we also initiated a study on the interactions between darunavir and the DMPC bilayer to reveal that the drug was accommodated inside the bilayer in conformations that resembled its structure into HIV-1 PR, being stabilized via HBs with the lipids and water molecules.     

Theoretical investigation of the (hyper)polarizabilities of pyrrole homologues C4H4XH (X = N, P, As, Sb, Bi). A coupled-cluster and density functional theory study

Geometries, inversion barriers, static and dynamic electronic and vibrational dipole polarizability (alpha), and first (beta) and second (gamma) hyperpolarizability of the pyrrole homologues C(4)H(4)XH (X = N, P, As, Sb, Bi) have been calculated by Hartree-Fock, M?ller-Plesset second-order perturbation theory, coupled-cluster theory accounting for singles, doubles, and noniterative triple excitations methods, as well as density functional theory using B3LYP and PBE1PBE functionals and Sadlej's Pol and 6-311G basis sets. Relativistic effects on the heavier homologues stibole and bismole have been taken into account within effective core potential approximation. The results show that the electronic (hyper)polarizabilities monotonically increase with the atomic number of the heteroatom, consistent with the decrease in the molecular hardness. Ring planarization reduces the carbon-carbon bond length alternation of the cis-butadienic unit, enhancing the electronic polarizability values (alpha(e)) by 4-12% and the (hyper)polarizability values (and gamma(e)) by 30-90%. Pure vibrational and zero-point vibrational average contributions to the (hyper)polarizabilities have been determined within the clamped nucleus approach. In the static limit, the pure vibrational hyperpolarizabilities have a major contribution. Anharmonic corrections dominate the pure vibrational hyperpolarizabilities of pyrrole, while they are less important for the heavier homologues. Static and dynamic electronic response properties of the pyrrole homologues are comparable to or larger than the corresponding properties of the furan and cyclopentadiene homologue series.     

Electric field polarization in conventional density functional theory: from quasilinear to two-dimensional and three-dimensional extended systems

The large overshoot in (hyper)polarizabilities of quasilinear (1D) chains calculated by applying density functional theory with conventional functionals is investigated for several 2D and 3D extended systems. These systems include arrays of molecular hydrogen chains, as well as 2D coronene-type structures and LiF in 1D, 2D, and 3D. Contrary to a recently proposed model it is found that the overshoot persists in all of these cases. A simple explanation is provided by an analysis of the field-induced charges for molecular hydrogen, which shows an excessive buildup at the chain ends regardless of where the chain is located within the 2D and 3D array.