Development of studies devoted to design of polymer-immobilized catalysts

The state of the art in the field of designing metal-complex catalysts for olefin polymerization immobilized on polymer supports is analyzed. The types of polymers used for binding transition-metal compounds and organoaluminum components and the topochemistry of their distribution and transformations in the course of catalyzed reactions are considered. Polymer-immobilized bimetallic catalysts show promise in the catalysis of the polymerization process in which the key role of a macroligand is to unite active centers of various kinds. It has been shown that, in metallocene and postmetallocene catalysts, the same construction principles of immobilization are preserved as in the case of first-generation metal-complex catalysts. The possibility of isolating and studying active intermediates offered by the polymer support and the effect of immobilization on the molecular design of polymer systems are discussed.     

Modeling the allosteric effect: modification of the tautomerism by intermolecular interactions and extension to molecular wires

B3LYP/6−31G(d) and B3LYP/6−311++G(d,p) calculations were carried out on quinolone and its four azaderivatives (15 tautomers), five wire models (10 tautomers) for proton transfer formed of anthracenol and azaacridines and the corresponding five crown ethers (ten tautomers) in the anthracenol part. The wires are formed by four carbon atoms existing either as cumulenes (pentaene) or polyynes (diyne). On these structures the effect of hydrogen bonds with HF as hydrogen bond donor, protonation on the aza N atoms and coordination with Li⁺ on the same positions were studied. The resulting energies were analyzed taking into account proximity effects.     

Ab initio molecular dynamics study of the keto-enol tautomerism of acetone in solution.

We have studied the keto-enol interconversion of acetone to understand the mechanism of tautomerism relevant to numerous organic and biochemical processes. Applying the ab initio metadynamics method, we simulated the keto-enol isomerism both in the gas phase and in the presence of water. For the gas-phase intramolecular mechanism we show that no other hydrogen-transfer reactions can compete with the simple keto-enol tautomerism. We obtain an intermolecular mechanism and remarkable participation of water when acetone is solvated by neutral water. The simulations reveal that C deprotonation is the kinetic bottleneck of the keto-enol transformation, in agreement with experimental observations. The most interesting finding is the formation of short H-bonded chains of water molecules that provide the route for proton transfer from the carbon to the oxygen atom of acetone. The mechanistic picture that emerged from the present study involves proton migration and emphasizes the importance of active solvent participation in tautomeric interconversion.     

Ab initio molecular orbital study of the tautomerism of 4-hydroxy-2-pyridinone

Ab initio calculations were performed on 2,4-pyridinediol, 4-hydroxy-2-pyridinone, and 2hydroxy-4-pyridinone at the HF /3-21G level with full geometry optimization. Two conformations of the hydroxyl group were considered for each tautomer. Corrections for polarization functions, electron correlation, and zero point energy were made by comparison with previous calculations on 2- and 4-pyridinone tautomerism which included these contributions. The most stable structure is 4-hydroxy-2-pyridinone, in agreement with experiment. Relative to 4-hydroxy-2-pyridinone, the energies of the other tautomers are estimated to be 1.9 kcal/mol for 2,4-pyridinediol and 8.9 kcal/mol for 2-hydroxy-4-pyridinone. These are in accord with the experimental values 0.3 ± 1.9 and 10.6 ± 1.9 kcal/mol, respectively, deduced from equilibration studies of the tautomeric methyl derivatives.     

Quantum chemical calculations of the molecular structure of diphenylguanidine and experimental studies of its tautomerism in solution

MNDO-PM3 and AM1 quantum chemical calculations of the molecular structure of N,N′-diphenyl-guanidine (DPG) prove that the molecule preferably exists as an asymmetric tautomer with a basic center C = N−. IR and UV spectral data, dipole moments, and average molecular weights of DPG solutions in nonpolar and low-polar solvents confirm the results of calculations, indicating formation of hydrogen-bonded cyclic self-associates of DPG in solution. Translated fromZhumal Strukturnoi Khimii, Vol. 39, No. 4, pp. 618–625, July–August, 1998.     

NH tautomerism in the natural chlorin derivatives

The NH tautomerism of five Mg-free chlorophyll a and b derivatives 2-6 was studied utilizing NMR spectroscopy and molecular modeling. The results from the dynamic NMR measurements of the chlorins revealed that substituent effects contribute crucially to the free energy of activation (DeltaG(double dagger)) in the NH tautomeric processes. An intermediate tautomer for the total tautomeric NH exchange in a chlorin was observed for the first time, when the (1)H NMR spectra of chlorin e(6) TME (3) and rhodin g(7) TME (4) (TME = trimethyl ester) were measured at lower temperatures. The lower energy barriers (DeltaG(1)(double dagger)) obtained for the formation of the intermediate tautomers of 3 and 4, assigned to the N(22)-H, N(24)-H trans-tautomer, were 10.8 and 10.6 kcal/mol, respectively. The energy barrier (DeltaG(2)(double dagger) value) for the total tautomeric NH exchange in the five chlorins was found to vary from 13.6 kcal/mol to values higher than 18 kcal/mol. The lowest DeltaG(2)(double dagger) value (13.6 kcal/mol) was obtained for rhodochlorin XV dimethyl ester (2), which was the only chlorophyll derivative lacking the C(15) substituent. In the case of chlorins 4 and 5, the steric crowding around the methoxycarbonylmethyl group at C(15) raised the DeltaG(2)(double dagger) activation free-energy to 17.1 kcal/mol. However, the highest energy barrier with DeltaG(2)(double dagger) > 18 kcal/mol was observed for the NH exchange of pyropheophorbide a methyl ester (6), possessing the macrocycle rigidifying isocyclic ring E. Our results demonstrate that the steric strain, arising either from the steric crowding around the bulky substituent at C(15) or the macrocycle rigidifying isocyclic ring E, slows down the NH tautomeric process. We suggest that deformations in the chlorin skeleton are closely connected to the NH tautomeric exchange and that the exchange occurs by a stepwise proton-transfer mechanism via a hydrogen bridge.     

On the tautomerism of 5-aminotetrazole

In order to study the connection between the structure of sulfanilamides and their antibacterial action, sulfanilamide derivatives of 1- and 2-methyl-5-aminotetrazoles and of 1,3-dimethyl-5-iminotetrazole have been synthesized. A study of their IR spectra has shown that 1-methyl-5-sulfanilimidotetrazole has the imide structure in the crystalline state and 2-methyl-5-sulfanilamidotetrazole the amide structure. The sulfanilamide derivatives of 1- and 2-methyl-5-aminotetrazoles possess a considerable antibacterial activity, while 1, 3-dimethyl-5-sulfanilimidotetrazole is inactive.For communication V, see [1].     

A gradient-directed Monte Carlo approach to molecular design

The recently developed linear combination of atomic potentials (LCAP) approach [M. Wang et al., J. Am. Chem. Soc. 128, 3228 (2006)] allows continuous optimization in a discrete chemical space, and thus is useful in the design of molecules for targeted properties. To address further challenges arising from the rugged, continuous property surfaces in the LCAP approach, we develop a gradient-directed Monte Carlo (GDMC) strategy as an augmentation to the original LCAP optimization method. The GDMC method retains the power of exploring molecular space by utilizing local gradient information computed from the LCAP approach to jump between discrete molecular structures. It also allows random MC moves to overcome barriers between local optima on property surfaces. The combined GDMC-LCAP approach is demonstrated here for optimizing nonlinear optical properties in a class of donor-acceptor substituted benzene and porphyrin frameworks. Specifically, one molecule with four nitrogen atoms in the porphyrin ring was found to have a larger first hyperpolarizability than structures with the conventional porphyrin motif.     

Reactivity and tautomerism in the azolidine series

A series of 5-benzylidenethiorhodanines was obtained by the reaction of 5-benzylidenerhodanines with P₂S₅. An interpretation of the mechanism for the replacement of an oxygen atom by sulfur is given.See [5] for communication IV.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 192–193, February, 1971.     

A machine learning approach to computer-aided molecular design

Summary Preliminary results of a machine learning application concerning computer-aided molecular design applied to drug discovery are presented. The artificial intelligence techniques of machine learning use a sample of active and inactive compounds, which is viewed as a set of positive and negative examples, to allow the induction of a molecular model characterizing the interaction between the compounds and a target molecule. The algorithm is based on a twofold phase. In the first one — the specialization step — the program identifies a number of active/inactive pairs of compounds which appear to be the most useful in order to make the learning process as effective as possible and generates a dictionary of molecular fragments, deemed to be responsible for the activity of the compounds. In the second phase — the generalization step — the fragments thus generated are combined and generalized in order to select the most plausible hypothesis with respect to the sample of compounds. A knowledge base concerning physical and chemical properties is utilized during the inductive process.     

Information theoretical measures to analyze trajectories in rational molecular design

We develop a new methodology to analyze molecular dynamics trajectories and other time series data from simulation runs. This methodology is based on an information measure of the difference between distributions of various data extract from such simulations. The method is fast as it only involves the numerical integration/summation of the distributions in one dimension while avoiding sampling issues at the same time. The method is most suitable for applications in which different scenarios are to be compared, e.g. to guide rational molecular design. We show the power of the proposed method in an application of rational drug design by reduced model computations on the BH3 motif in the apoptosis inducing BCL(2) protein family.     

On the tautomerism of 5-aminotetrazole

In order to study the connection between the structure of sulfanilamides and their antibacterial action, sulfanilamide derivatives of 1- and 2-methyl-5-aminotetrazoles and of 1,3-dimethyl-5-iminotetrazole have been synthesized. A study of their IR spectra has shown that 1-methyl-5-sulfanilimidotetrazole has the imide structure in the crystalline state and 2-methyl-5-sulfanilamidotetrazole the amide structure. The sulfanilamide derivatives of 1- and 2-methyl-5-aminotetrazoles possess a considerable antibacterial activity, while 1, 3-dimethyl-5-sulfanilimidotetrazole is inactive.     

Conference devoted to the 60th birthday of Academician Yu. A. Ovchinnikov

Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1400–1403, July, 1995.     

PRO_LIGAND: An approach to de novo molecular design. 6. Flexible fitting in the design of peptides

Summary This paper describes the further development of the functionality of our in-house de novo design program, PRO_LIGAND. In particular, attention is focussed on the implementation and validation of the directed tweak method for the construction of conformationally flexible molecules, such as peptides, from molecular fragments. This flexible fitting method is compared to the original method based on libraries of prestored conformations for each fragment. It is shown that the directed tweak method produces results of comparable quality, with significant time savings. By removing the need to generate a set of representative conformers for any new library fragment, the flexible fitting method increases the speed and simplicity with which new fragments can be included in a fragment library and also reduces the disk space required for library storage. A further improvement to the molecular construction process within PRO_LIGAND is the inclusion of a constrained minimisation procedure which relaxes fragments onto the design model and can be used to reject highly strained structures during the structure generation phase. This relaxation is shown to be very useful in simple test cases, but restricts diversity for more realistic examples. The advantages and disadvantages of these additions to the PRO_LIGAND methodology are illustrated by three examples: similar design to an alpha helix region of dihydrofolate reductase, complementary design to the active site of HIV-1 protease and similar design to an epitope region of lysozyme.