Elucidating ‘undecipherable’ chemical structures using computer‐assisted structure elucidation approaches

Structure elucidation using 2D NMR data and application of traditional methods of structure elucidation are known to fail for certain problems. In this work, it is shown that computer‐assisted structure elucidation methods are capable of solving such problems. We conclude that it is now impossible to evaluate the capabilities of novel NMR experimental techniques in isolation from expert systems developed for processing fuzzy, incomplete and contradictory information obtained from 2D NMR spectra. Copyright © 2012 John Wiley & Sons, Ltd.     

Are deterministic expert systems for computer-assisted structure elucidation obsolete?

Expert systems for spectroscopic molecular structure elucidation have been developed since the mid-1960s. Algorithms associated with the structure generation process within these systems are deterministic; that is, they are based on graph theory and combinatorial analysis. A series of expert systems utilizing 2D NMR spectra have been described in the literature and are capable of determining the molecular structures of large organic molecules including complex natural products. Recently, an opinion was expressed in the literature that these systems would fail when elucidating structures containing more than 30 heavy atoms. A suggestion was put forward that stochastic algorithms for structure generation would be necessary to overcome this shortcoming. In this article, we describe a comprehensive investigation of the capabilities of the deterministic expert system Structure Elucidator. The results of performing the structure elucidation of 250 complex natural products with this program were studied and generalized. The conclusion is that 2D NMR deterministic expert systems are certainly capable of elucidating large structures (up to about 100 heavy atoms) and can deal with the complexities associated with both poor and contradictory spectral data.     

Intermolecular charge transfer in model hydrogen-bonded systems—biological implications

The electronic structure of the model hydrogen-bonded systems has been studied at the all-valence level in relation to the charge transfer mechanism. It is concluded that together with the intermolecular proton transfer an electronic charge transport occurs for hydrogen bonds of 2.70–3.00 Å in length, i.e., when the proton motion within the bond is anticipated. For elucidation of transport properties of one-dimensional hydrogen-bonded systems the tunneling–hopping model is preferred instead of the band theory. The importance of the proposed mechanism of the charge transfer for biological processes has been emphasized.     

New computer-assisted methods for the elucidation of molecular structure from 2-D spectra

General principles of the construction of expert systems for the elucidation of the structure of molecules from their spectra were considered. The principal attention was focused on systems based on the use of 2-D NMR spectra. The structural information extracted from 2D NMR spectra was characterized, and the strategy was outlined for structure elucidation under the conditions when the analyzed spectrostructural information is incomplete, fuzzy, and contradictory. The most advanced expert system ACD/Structure Elucidator, which is capable of determining the structure and stereochemistry of large molecules, in particular, those typical in the chemistry of natural compounds, is described as an example.     

Methodology of using expert systems for structure elucidation of organic molecules by their spectra

Major axioms underlying structure elucidation of molecules by their characteristic spectral data are considered. The amount of information obtained by solving the problem on structure elucidation of molecules serves as a basis to evaluate the quality of solution. Conditions for computer-aided solution of problems using expert systems (ES) are analyzed. Reasons for incorrect or zero solutions and for inconsistencies leading to negative results are examined. The role of additional information as a necessary condition for correct solution is discussed. On the basis of this analysis, a general strategy for structure elucidation of molecules by their spectra using ES is suggested. The principal idea is to use the iteration method, gradually increasing the rigidity of constraints. Strategies named ARCHEOLOGIST and SCULPTOR are discussed. Examples are given. Russian Scientific Research Institute of Organic Synthesis. Translated fromZhurnal Strukturnoi Khimii, Vol. 36, No. 3, pp. 548–558, May–June, 1995. Translated by L. Smolina     

高通量天然产物化学和毛细管核磁共振探头技术的应用

介绍了近几年为高通量药物筛选构建大型天然产物样品库的高通量天然产物化学,即多通道平行高效液相制备和平行液质联用分析技术;详细介绍了核磁共振新技术即体积小和质量灵敏度高的毛细管核磁共振探头技术,该探头技术的成功应用使得天然产物样品库中活性化合物的结构鉴定所需样品量降低到前所未有的微克级水平;展望了源于中药的天然产物作为小分子探针开展脑功能方面的化学基因组学研究。     

Evolutionary-algorithm-based strategy for computer-assisted structure elucidation

An evolutionary algorithm (EA) using a graph-based data structure to explore the molecular constitution space is presented. The EA implementation proves to be a promising alternative to deterministic approaches to the problem of computer-assisted structure elucidation (CASE). While not relying on any external database, the EA-guided CASE program SENECA is able to find correct solutions within calculation times comparable to that of other CASE expert systems. The implementation presented here significantly expands the size limit of constitutional optimization problems treatable with evolutionary algorithms by introducing novel efficient graph-based genetic operators. The new EA-based search strategy is discussed including the underlying data structures, component design, parameter optimization, and evolution process control. Typical structure elucidation examples are given to demonstrate the algorithm's performance.     

Quantum Chemistry-based Molecular Dynamics Simulations as a Tool for the Assignment of ESI-MS/MS Spectra of Drug Molecules

In organic mass spectrometry, fragment ions provide important information on the analyte as a central part of its structure elucidation. With increasing molecular size and possible protonation sites, the potential energy surface (PES) of the analyte can become very complex, which results in a large number of possible fragmentation patterns. Quantum chemical (QC) calculations can help here, enabling the fast calculation of the PES and thus enhancing the mass spectrometry-based structure elucidation processes. In this work, the previously unknown fragmentation pathways of the two drug molecules Nateglinide (45 atoms) and Zopiclone (51 atoms) were investigated using a combination of generic formalisms and calculations conducted with the Quantum Chemical Mass Spectrometry (QCxMS) program. The computations of the de novo fragment spectra were conducted with the semi-empirical GFNn-xTB (n=1, 2) methods and compared against Orbitrap measured electrospray ionization (ESI) spectra in positive ion mode. It was found that the unbiased QC calculations are particularly suitable to predict non-evident fragment ion structures, sometimes contrasting the accepted generic formulation of fragment ion structures from electron migration rules, where the “true” ion fragment structures are approximated. For the first time, all fragment and intermediate structures of these large-sized molecules could be elucidated completely and routinely using this merger of methods, finding new undocumented mechanisms, that are not considered in common rules published so far. Given the importance of ESI for medicinal chemistry, pharmacokinetics, and metabolomics, this approach can significantly enhance the mass spectrometry-based structure elucidation processes and contribute to the understanding of previously unknown fragmentation pathways.     

Study of Electrochemical Processes with Coupled Homogeneous Chemical Reaction in Differential Pulse Voltammetry at Spherical Electrodes and Microhemispheres

Homogeneous chemical reactions coupled to oxidation‐reduction processes at electrode surfaces are very common in electrochemistry. In this paper we cope with the application of Differential Pulse Voltammetry at spherical electrodes and microhemispheres for the study of this kind of systems. Analytical expressions are deduced from which the influence of the different experimental variables is examined. Several diagnostic criteria for elucidation of the reaction mechanism from DPV peak parameters are given, as well as working curves for extraction of the kinetic rate constants of the chemical reaction.     

LONG RANGE ELECTRON TUNNELING IN BIOLOGICAL AND MODEL SYSTEMS

Abstract— This review paper reports the data on the role of long range electron tunneling in photosynthetic and model systems. The main papers concerned with elucidation mechanisms and kinetical peculiarities of electron transfer in reaction centers of bacteria and green plants are considered. The paper reviews the articles on long range electron transfer in reactions of metalloporphyrins—synthetic analogs of the main natural pigment of photosynthesis, chlorophyll. Liquid and solid phase redox reactions of electronically excited porphyrin molecules, intramolecular and photosensitized electron transfer processes are considered.     

Specific deuteration effects on carbon-13 NMR relaxation data of amido-type systems

The effect of deuterium substitution in amido-systems is explored. For benzamide, both positive and negative changes in T^DD₁ are observed. A method for structure elucidation of these and related systems is presented.     

Energetics of electron processes in semiconductor photocatalytic systems

The energetics of electron processes in photocatalytic systems based on dispersed semiconductors, their nanocomposites and heterostructures are examined. Methods for the approximate estimation and quantitative determination of their energetic characteristics are evaluated and energy diagrams of photocatalytic systems based on semiconductor nanocomposites and their heterostructures are plotted. Analysis of the diagrams permits the elucidation of the nature of their photocatalytic effects in redox reactions. L. V. Pisarzhevskii Institute of Physical Chemistry, National Academy of Sciences of Ukraine, 31 Prospekt Nauki, Kiev 03039, Ukraine. Translated from Teoreticheskaya i éksperimental'naya Khimiya, Vol. 36, No. 2, pp. 69–89, March–April, 2000.     

Chemics—ube,a modified system of chemics

Two kinds of contraint have been added to the CHEMICS program system for structure elucidation of organic compounds. One is a limitation on the construction of small ring structures; the other is the introduction of a facility for input of appropriate information at the discretion of the user during the automated analyses of spectral data of unknown compounds. The computation processes for a couple of compounds by the new system are described.     

The detection of hidden proton magnetic resonance signals by means of INDOR

The INDOR technique appears to be a very useful and rapid tool for the detection of hidden proton lines as an aid in the elucidation of the structure of complex organic molecules. The experimental conditions for obtaining optimum results in a limited time are discussed. Analysis of the INDOR spectra of a number of selected spin systems are given; these show the capabilities of this method. Examples are given in which this technique is applied.     

Recent developments in transition metal diaryl chemistry

This Perspective discusses the synthesis and reactivity of low-coordinate transition metal diaryl complexes. The development of sterically demanding ligands, in particular m-terphenyls is facilitating the isolation of complexes featuring two-coordinate open-shell transition metal centres. These coordinatively unsaturated complexes are now being investigated for their reaction chemistry, which is not only contributing to the elucidation of the structure and bonding within these systems but is also leading to the formation of novel compounds.     

Solution structure of quinoline- and pyridine-derived oligoamide foldamers

The unambiguous elucidation of a new folded structure in solution may prove to be a very challenging task. The NMR protocols developed for solving the solution structures of alpha-peptides have been applied to aliphatic beta- and gamma-peptides but are not directly applicable to aromatic oligomers. In particular, the string of spin systems in an aromatic sequence cannot be reconstituted solely from correlations between protons. For aromatic oligomers, it is shown that the assignment of a large part of the 13C NMR spectrum through HMBC and HSQC experiments allows to unambiguously assign proton NMR spectra and in turn to interpret NOE correlations. This has been implemented both with quinoline- and pyridine-derived oligoamide foldamers, and should be applicable to a wide range of oligomers including various combinations of monomers. The NOE correlations allow the unambiguous solution structure elucidation of helical conformations of oligoamides derived from pyridine and quinoline monomers showing that, in these series, the solution structures correspond very well to the structures observed in the solid state.     

智能质谱解释系统的创建

本文五个方面详细讨论了ＡＳＥＳ／ＭＳ系统中的最新发展。ＡＳＥＳ／ＭＳ系统与世界上其它同类系统相比具有三个显著特点：１ 系统所依据的数据库具有可靠的数据质量；２ 系统具有强的学习功能；３ 系统地动用了中性丢失规律。系统具有较强的实用性。