Genius: a genetic algorithm for automated structure elucidation from 13C NMR spectra

The automated structure elucidation of organic molecules from experimentally obtained properties is extended by an entirely new approach. A genetic algorithm is implemented that uses molecular constitution structures as individuals. With this approach, the structure of organic molecules can be optimized to meet experimental criteria, if in addition a fast and accurate method for the prediction of the used physical or chemical features is available. This is demonstrated using 13C NMR spectrum as readily obtainable information. By means of artificial neural networks a fast and accurate method for calculating the 13C NMR spectrum of the generated structures exists. The method is implemented and tested successfully for organic molecules with up to 18 non-hydrogen atoms.     

Novel methods of automated structure elucidation based on 13C NMR spectroscopy

Three new approaches for automated structure elucidations of organic molecules using NMR spectroscopic data were introduced recently. These approaches apply a neural network 13C NMR chemical shift prediction method to rank the results of structure generators by their agreement of the predicted and experimental chemical shifts. These three existing implementations are compared using realistic example molecules. The applicability and reliability of such approaches is addressed.     

Proximity effect in the 13C NMR spectra of alkylpyridines: An aid in structure elucidation

The structures of seven polysubstituted alkylpyridines, recently isolated from coal tar, were elucidated using their ¹³C NMR spectra. For tri- and tetra-substituted derivatives the correct isomeric structure was found from their conformity with the proximity effect, i.e. the deviations from additivity when calculating chemical shifts from substituent increments (SCS) for sterically crowded molecules. This effect manifests itself both on the ring and on the alkyl carbon signals, and in most cases shifts their position upfield.     

Computer methods of structure elucidation by1H and13C NMR spectra using factographic databanks

Computer methods have been developed for structure elucidation by ¹ H and ¹³ C NMR spectra using factographic databanks containing spectral and structural data of many organic compounds (44,000 for ¹ H NMR and 27,000 for ¹³ C NMR). Information about the structure of compounds under study is obtained from the analysis of reference structures whose spectra are the best matches of the query spectra. This procedure identifies linked fragments composed of the nodes assigned to signals of the query spectrum when comparing it with reference spectra, and of inactive nodes separated from the former by one bond at most. Using many examples, it has been shown that this approach allows one to determine sufficiently large structural fragments of unknowns both by ¹ H and ¹³ C NMR spectra. The most reliable structures are obtained from the combined analysis of ¹ H and ¹³ C NMR spectral search results. Thus the relative occurrences of correct fragments among the n-first (n=1, 3, 5) fragments of the ranked list of candidates, output to the user, are 80, 93, and 96%, respectively.Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences. Translated fromZhurnal Strukturnoi Khimii, Vol. 34, No. 3, pp. 51–60, May–June 1993.Translated by L. Smolina     

A mainly NMR-based structure elucidation of a surprising vindoline trimer with the aid of non-uniform sampled 1H-13C HSQC and HMBC spectra

Structural Chemistry - Two unexpected and unusual vindoline trimers, a ketone and a methyl ether cation, were isolated from a reaction aimed at producing new, synthetically modified vinca...     

Mutual assignment of subspectra and substructures—A way to structure elucidation by 13C NMR spectroscopy

A novel approach to utilising digital computers and a collection of reference data for the interpretation of ¹³CNMR spectra is outlined. Because of the almost unlimited possibilities of molecular structures in organic chemistry, a matching of subspectra with substructures seems most appropriate, followed by an iterative confirmation of the suggested structures. For this purpose the possibility of a search for structure increments and the accompanying chemical shifts is provided by linking the spectroscopic and structural information using a formulae reading machine and generating the topological connectivity table. Three practical examples demonstrate the application of this set of programs and some of the experiences gained during operation.     

Sequential arrangement of gamma-valerolactone enantiomers enclathrated in cholic acid channels as studied by 13C solid-state NMR: elucidation of the optical resolution mechanism

The mechanism of the optical resolution of gamma-valerolactone (VAL) enantiomers by enclathration in cholic acid (CA) channels was investigated. 13C cross-polarization magic-angle spinning spectra of CA/VAL inclusion compounds show four methyl 13C peaks of VAL with different intensities depending on the enantiomeric ratios. The four peaks were assigned to the inner and end (S)-(-)-enantiomers (S) in the S domain and the inner and end (R)-(+)-enantiomers (R). The relative intensities of the four methyl 13C peaks cannot be explained by the random process model for inclusion but are successfully reproduced by assuming the first-order Markov process, in which the inclusion probabilities of S and R depend on which enantiomer has precedingly entered the CA channel. The probability p(S/S) that two S enantiomers successively enter a channel is thus found to be 83%, and p(R/R) is 50%. The large probability of p(S/S) indicates that once an S enantiomer enters a channel, it become easy for other S enantiomers to successively enter the channel, and thus the large enantiomeric excess of S is obtained. The inclusion probabilities of S and R were confirmed by 1D 13C-13C polarization-transfer experiments among the four methyl carbons of VAL in the CA channel. Further, we found that the 13C line widths and peak positions of the CA tail group change depending on the enantiomeric ratio. We concluded that once S is included, it changes the conformation of the CA tail group so that other S enantiomers become easy to successively enter the channel.     

Suppressing one‐bond homonuclear 13C,13C scalar couplings in the J‐HMBC NMR experiment: application to 13C site‐specifically labeled oligosaccharides

Site‐specific ¹³C isotope labeling is a useful approach that allows for the measurement of homonuclear ¹³C,¹³C coupling constants. For three site‐specifically labeled oligosaccharides, it is demonstrated that using the J‐HMBC experiment for measuring heteronuclear long‐range coupling constants is problematical for the carbons adjacent to the spin label. By incorporating either a selective inversion pulse or a constant‐time element in the pulse sequence, the interference from one‐bond ¹³C,¹³C scalar couplings is suppressed, allowing the coupling constants of interest to be measured without complications. Experimental spectra are compared with spectra of a nonlabeled compound as well as with simulated spectra. The work extends the use of the J‐HMBC experiments to site‐specifically labeled molecules, thereby increasing the number of coupling constants that can be obtained from a single preparation of a molecule. Copyright © 2014 John Wiley & Sons, Ltd.     

High resolution 13C NMR spectroscopy V—structure dependence of the 13C,H coupling constants in aceheptylene,azulene and 5-azaazulene

In order to study the structure dependence of the ¹³C,H coupling constants in polycyclic conjugated π electron systems with 5-and 7-membered rings, the ¹H coupled ¹³C NMR spectra of aceheptylene, azulene and 5-azaazulene have been analysed. The results are discussed, including published data of monocyclic reference compounds, and are compared to theoretical values calculated by the FPT-INDO method. It is shown that, first, the geminal ¹³C,H couplings in the unsaturated 5-membered carbocycles are predominantly dependent on CC bond lengths. Second, the vicinal ¹³C,H coupling constants in 5- as well as in 7-membered unsaturated carbocyclic rings can be linearly related to the lengths of the central CC bonds. Third, the vicinal inter-ring couplings show a large variation and give information on ring junction, thus being of special value in structure determination and are governed mainly by the bond angles. Fourth, the calculated ¹³C,H couplings across one and two bonds are totally useless for practical purposes; those across three bonds, however, at least reflect the experimental trends.     

Quinuclidine complex with alpha-cyclodextrin: a diffusion and 13C NMR relaxation study

The stability of an inclusion complex of quinuclidine with alpha-cyclodextrin in solution was investigated by NMR measurements of the translational diffusion coefficient. A 1:1 stoichiometry model yielded an association constant of 35 +/- 3 M(-1). The guest molecules exchange rapidly between the host cavity and the bulk solution. The reorientational dynamics of the guest and host molecules was studied using carbon-13 NMR relaxation at two magnetic fields. The relaxation of the host nuclei showed very little dependence on the guest-host concentration ratio, while the 13C spins in quinuclidine were sensitive to the solution composition. Using mole-fraction data, it was possible to extract the relaxation parameters for the bound and free form of quinuclidine. Relaxation rates of the guest molecule, free in solution, were best described by an axially symmetric model, while the data of the complex species were analyzed using the Lipari-Szabo method. Applying the axially symmetric model to the complexed quinuclidine indicated that the anisotropy of its reorientation in the bound form was increased.     

Automated structure elucidation of organic molecules from (13)c NMR spectra using genetic algorithms and neural networks.

The automated structure elucidation of organic molecules from experimentally obtained properties is extended by an entirely new approach. A genetic algorithm is implemented that uses molecular constitution structures as individuals. With this approach, the structure of organic molecules can be optimized to meet experimental criteria, if in addition a fast and accurate method for the prediction of the used physical or chemical features is available. This is demonstrated using (13)C NMR spectrum as readily obtainable information. (13)C NMR chemical shift, intensity, and multiplicity information is available from (13)C NMR DEPT spectra. By means of artificial neural networks a fast and accurate method for calculating the (13)C NMR spectrum of the generated structures exists. The approach is limited by the size of the constitutional space that has to be searched and by the accuracy of the shift prediction for the unknown substance. The method is implemented and tested successfully for organic molecules with up to 20 non-hydrogen atoms.     

Computer supported structure elucidation of polymethoxy- and polyacetoxyxanthones. V—13C NMR spectroscopy of substituted xanthones

A procedure for developing ¹³C NMR chemical shift additivity rules for all 136 polymethoxyxanthones and all 136 polyacetoxyxanthones, based on multiple linear regression analysis, is reported. The influence of steric interactions between the substituents on the chemical shifts of the carbon atoms in the xanthone ring system is discussed and included in the calculations of the additivity rules for the polymethoxyxanthones. The derived chemical shift increments are implemented into the computer program SEOX 1. The extended program, SEOX 2, allows an automated structure elucidation of polyhydroxy-, polymethoxy- and polyacet-oxyxanthones. The increments are tested using the leave-one-out method in conjunction with SEOX 2, and have been found to be very suitable for this purpose.     

Computer-assisted structure elucidation of organic compounds III: Automatic fragment generation from13C-NMR spectra

The interpretation of carbon-NMR spectra is mainly based on the comparison with suitable reference data taken from literature. The whole information contents of¹³C-NMR spectra cannot be utilized by manual interpretation. Therefore a network of interactive computer programs has been developed, which simulates the strategy of the spectroscopist in generating structural fragments from the spectral data. The most important knowledge source for this process is a carbon-NMR data base containing some 17,500 spectra. Structural fragments are generated automatically from this data file and assembled by a model builder to complete chemical structures using constraints derived from the spectral data. A comparison of the experimental carbon-NMR spectrum with the estimated ones allows the generation of a sorted hitlist.For part II see: H. Kalchhauser, W. Robien,J. Chem. Inf. Comput. Sci. 1985,25, 103.     

Characterization of organic substrates bound to cross-linked polystyrenes by 13C NMR spectroscopy

The ¹³C NMR spectra of a wide variety of organic substrates bound to 2% cross-linked polystyrenes may be obtained routinely, provided the resins can be sufficiently swollen. The ¹³C chemical shifts of polymer-bound trityl alcohol, polymer-bound monotrityl ethers of the symmertrical diols HO (CH₂)_nOH (n=2, 4, 6, 7, 9 and 10), and some related intermediates in the solid phase synthesis of insect pheromones are presented. ¹³C shift additivity correlations, differing little from those in free trityl ethers, are drawn.     

Spec2D: a structure elucidation system based on 1H NMR and H-H COSY spectra in organic chemistry

A system for structure elucidation based on proton NMR spectra has been developed. The system, named Spec2D (system for spectra from 2D-NMR), incorporates 1H NMR and H-H correlation spectroscopy (COSY) spectral information obtained from 2D-NMR experiments. 2D-NMR is important for the structure elucidation because it provides information about the relationships among differently situated protons in the structures of unknown compounds. The system uses the concepts of molecular graphs. The improved representation of substructures as well as several novel algorithms for structure generation have been devised to solve the combinatorial problem and to reduce the processing time. Spec2D consists of a knowledge base, an analysis module, and a candidate structure generator module. Spec2D proposes candidate structures from only 1H NMR and H-H COSY spectral information of an unknown compound without any 13C NMR spectral or structural information, such as molecular formulas. Spec2D has the capability to propose the "new" structure of an unknown compound, if the corresponding substructures are included in the knowledge base.     

Investigation of the structure of aminodicarboxylic acids by 13C NMR method

The protonation of ethylenediaminedisuccinic acid was investigated over a wide range of pH by the ¹³C NMR method. The degrees of protonation of the donor groups and the fractions of the trans and gauche conformers in the partially and fully protonated forms of this complexone were determined. A comparison is made of the conformational states of aspartic, iminosuccinic, and ethylenediaminedisuccinic acids. It is shown that complication in the structure has an effect on the conditions of the trans-gauche transitions, which determine the form of the ligand most favorable for combination with the metal ion.Translated from Teoreticheskaya i Éksperimental'naya Khimiya, Vol. 25, No. 4, pp. 499–504, July–August, 1989.     

Structural elucidation of a new delta2-pyrazoline derivatives using 1H and 13C NMR spectroscopy

This paper describes the unequivocal structural elucidation of a new kind of Delta2-pyrazoline derivatives carried out by means of monodimensional 1H and 13C NMR spectroscopies, bidimensional ones such as HMBC and HMQC experiments, and NOEDIFF effects. Conformational analysis of this molecule agrees very well with the experimentally NOEDIFF effects found.     

13C NMR spectra of benzodiazepinones: Application to isomeric structure determination

A ¹³C NMR study of a number of substituted 1,5-benzodiazepin-2-ones has been carried out, and shows that this technique is one of the rare spectroscopic methods which allows an unambiguous identification of the number and nature of the isomers formed in the condensation of a β-ketoester with a substituted O-phenylenediamine.     

Hydrogen bonding structure and stability of alpha-chitin studied by 13C solid-state NMR

The structure and stability of hydrogen bonds in alpha-chitin were investigated by (13)C solid-state NMR measurements at different temperatures. Splitting of the carbonyl carbon signal for alpha-chitin was interpreted as two types of hydrogen bonding; the peaks at 173.5 and 175.8 ppm were assigned, respectively, to a carbonyl carbon hydrogen bonded exclusively to the NH group and a carbonyl carbon hydrogen-bonded to both NH and C(6)-OH groups. Approximately 60% of carbonyl groups exclusively contributed to the intermolecular hydrogen bonding and ca. 40% of them to the combination of intermolecular and intramolecular hydrogen bonding. Internal rotation around the C(5)-C(6) bond was detected at 55 degrees C.