Identification and structure elucidation by NMR spectroscopy.
ISBN 13: 9781468482904
Trends in Analytical Chemistry 69 88—97 Contents lists available at ScienceDirect Trends in Analytical Chemistry j o u r n a l h o m e p a g e : w w w. All rights reserved. Contents 1. Development of NMR experiments and instrumentation CASE expert systems NMR chemical-shift prediction Is it possible to avoid an erroneous structure elucidation? Introduction To make clear the issues being discussed in this review, it is nec- essary to consider some basic concepts.
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If the spectrum troscopy in combination with high-resolution mass-spectrometry of the unknown fully coincides with a reference spectrum, it means HRMS makes up a basic set of methods to solve this problem. Given that the structural formula of the unknown is identical to that of the molecular formula of a complex organic molecule that has been the reference. This is termed as structure identification. Given the structure is role in structure elucidation. In this review, we consider applica- elucidated, it is necessary to establish if the compound is new.
The tion of NMR to determine structures of small organic molecules. Structure elucidation is obviously the most complicated task. A single solution is selected by E-mail address: elyas acdlabs. This Heteronuclear correlations which arise as a result of 1JCH couplings goal is achieved as a result of interpretation of 1D- and 2D-NMR Single Quantum between 13C nuclei and protons attached to the spectra, which may admit alternative solutions due to resonance Coherence corresponding atoms.
It is evident that the separated by three bonds 3JHH. If erroneous spin couplings leak into chemical bond. Correlation different sequences of coupled protons in a molecule. There is no routine problem [1,2,13]. Hence, the problem reduces to inferring all plau- approach that would allow determining which intervening sible structures from the set of axioms.
The axioms can be readily 1HC pairs are separated by two bonds and which — by formalized, and provide a theoretical basis for creation of algo- three. This task, as a rule, is impossible for a human expert. These spectra are usually not used during in the following two directions: Spectroscopy structure assembly. For example, This review discusses the state of progress in solving these distinguishing between correlations of coupling constants 2JCH and 3 problems.
Different methods were suggested to reduce the time for spectral acquisition, to increase sensitivity and to simpli- 2. The HSQC For molecules containing nitrogen atoms, resonances of 15N nuclei data may provide some insight into the numbers of possible het- are determined from 1HN heteronuclear single-quantum corre- eroatoms, as well as a partial carbon count.
The most frequently used set of 2D- sible to begin to assemble structural fragments comprising the NMR experiments is presented in Table 1. Then, the HMBC spectrum is acquired, and in principle, dard correlations can also be observed. These correlations are referred allows one to complete assembly of the structure. Low sensitivity also contradictory. The following acquisition times to correlations between a 13C-attached 1H to all other coupled obtain adequate signal-to-noise ratios were determined: COSY — 1 H. The resonances of coupled protons can be seen along a 7 min; rotating-frame Overhauser-effect spectroscopy ROESY — line at the same 13C chemical shift from the carbon atom attached to the primary 1H .
The authors  concluded that, with a 1 mg sample of missing. As a rule, be used to establish the full chemical structure and stereochemis- correlations that are strong in an H2BC spectrum and weak try.
Interpretation of NMR spectra
Using the same equipment as in , high signal-to-noise pure in an HMBC spectrum indicate two-bond correlations. Drawbacks acquired in just over 30 min . Both protonated the number of protons in a molecule to the sum of the heavy atoms and non-protonated adjacent carbons are observed. Method suffers from sensitivity data and molecular formula information. To circumvent this issue, several new ap- small volume high sensitivity and cryogenic NMR probes .
It is to 4-, 5-, and even 6-bond long-range nJCH heteronuclear cou- capable of establishing the identity of adjacent neighbor plings. Major drawbacks of the experiments were optimized. It is expected that such experiments can facilitate the structure eluci- dation of nitrogen-containing molecules, particularly those belonging to heterocyclic compounds and alkaloids. As a result of technical progress, cooled microprobes became available [39,40]. Structure 1. Natural product breitfussin A. As a result, very recently, a new and very general pure shift able degree.
In combination with covariance processing see below , the result is a high-quality, high-resolution TOCSY spectrum with singlets in both dimensions see Fig. This technique Structure 3. For example, to use a single-scan HSQC spectra for re- action monitoring, a 0. Another possibility to accelerate acquiring a spectrum appeared when NMR spectrometers equipped with two or more independent receivers became available, which allowed different types of 2D spectra to be obtained simultaneously .
Long-range heteronuclear single quantum multiple bond correlations LR- Fig. Covariance cidation in a single experiment, but low sensitivity prevents its wide processing involves reprocessing 2D data sets, singly or in pairs, to application. Bruschweiler , are the most useful. The resultant spectrum does not include any new with its assistance, unknown molecules were elucidated by information that was not present in the two original 2D spectra. Nev- two spectroscopists in 6 months . The software for covariance process- unique skeletons were described . A series of advanced graph-theory algorithms The state of the art in this area was extensively reviewed [1,5,66,67].
The 1D- and 2D-NMR spectra can be imported to the program from a spectrometer or input manually from a table prepared by the user. The imported data must be thoroughly checked and edited by the spectroscopist. The strategy of the system rests upon a series of databases containing factual and axiomatic knowl- edge. This easily allows users to investigate the dependence of the structural problem solution on any change in the initial set of axioms. The system is capable of inferring all plausible structures from a com- bination of a molecular formula and 1D- and 2D-NMR data e.
Selection of the most probable structure is performed on the basis of the 13C chemical-shift prediction using three algorithms imple- mented into the system — HOSE code based , neural networks and additivity rules [1,5]. The program is capable of elucidating a structure of an unknown in the presence of an unknown number of non-standard correlations of unknown length.
The software is commercially available and was used for solving many complex an- alytical problems. For example, with its aid, the structure of complex alkaloid quindolinocryptotackieine was determined  in an in- teractive mode, allowing for step-by-step resolution of many ambiguous correlations, which took a spectroscopist a week of work. Structure 3 see Fig. The software was recently applied for structure Atom properties are adjusted to the structure of gymnopalyne to illustrate differ- ent conventional signs: atom hybridization sp3 — blue, sp2 — violet, sp — green, not elucidation of armeniaspirols A—C .
Information about 1H chemical shifts can also be visualized . The three top-ranked structures according to the dA deviation. The correct structure 1 armeniaspirol B is reliably selected as the most probable  in accordance with the criteria suggested . The program produces a correct structure if all the predicted spectra calculated for two to three top-ranked struc- fragments are included in the database. As only one example tures are large or very close, only then should QM predictions be illustrates the suggested approach, no conclusions regarding its ef- performed for those questionable structures.
It can be used for solving having very similar structures . NMR chemical-shift prediction chemical-shift prediction is frequently used due to the possibility of quickly acquiring a spectrum with a small sample size. Proton As mentioned above, NMR chemical-shift prediction plays an in- chemical-shift dependence on, e.
The predictors can be incorporated in expert systems Keyes et al. The programs data. It was 1. The prediction is very fast. For a pharmaceutical company. The novel method developed and tested on several families of structures. For example, Thummala et al. As spectroscopic structure elucidation is a complex logical- Codina et al.
An of reviews [13,—] discussed many structural misassignments. A tures can be noted: multigram quantity of a crude extract was rapidly fractionated by centrifugal partition extraction CPE.
Expert system-based analysis of many cases, when erroneous Pauli and co-workers  comprehensively investigated the pre- structures were inferred, shows [1,13,75,] that application of CASE cision necessary for measuring spectral parameters of 1H-NMR allows the determination of the correct structure and causes of the spectra for their tabulation to be used for structure dereplication human error to be detected. As a manual 1H spectrum assignment is a time consuming, tedious and error-prone procedure, an expert system for the auto- 9. Conclusions matic atom-to-peak or multiplet assignment of 1H-NMR spectra of small molecules has been developed .
Many studies drawback . It should be expected that application of pure shift spectra ity of DOSY. A method of mixture analysis based on 13C- cantly, so facilitating and accelerating the stage of data preparation. The low sensitivity of the approach pre- Acknowledgements vents its wide application.
A standard 5 mm NMR pieces of valuable advice. Elyashberg, A. Williams, K. Williams, Computer-based Structure Elucidation from components from a single experiment . After LC separation, Spectral Data. Bross-Walch, T. Kuhn, D. Moskau, O. Zerbe, Strategies and tools for structure the sample was split, and a small portion sent for MS analysis, while determination of natural products using modern methods of NMR the remainder was directed to SPE cartridges for collection.
Cheatham, M. Kline, E. Williams, G. Halabalaki, K. Vougogiannopoulou, E. Mikros, A. Skaltsounis, Recent  C. Jones, C. Larive, Could smaller really be better? Liu, M. Green, R. Marques, T. Pereira, R. Helmy, R. Williamson, et al. Breton, W. Molinski, B. Reynolds, E. Mazzola, Nuclear magnetic resonance in the structural assignment of marine natural products, Tetrahedron 68 — Kinghorn, Y. Falk, J. Kobayashi Editors ,  L. Gross, F. Mohn, N. Moll, G. Meyer, R.
Catalog Record: The interpretation of NMR spectra | HathiTrust Digital Library
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2. Theory of the magnetic shielding tensor
Kolmer, R. Adams, M. It also contains integral areas, splitting pattern, and coupling constant.
Chemical shift is associated with the Larmor frequency of a nuclear spin to its chemical environment. It is important to understand trend of chemical shift in terms of NMR interpretation. Electronegative groups move to the down field left; increase in ppm. Unsaturated groups shift to downfield left when affecting nucleus is in the plane of the unsaturation, but reverse shift takes place in the regions above and below this plane. Figure 1. Splitting signals are separated to J Hz, where is called the coupling constant.
The spitting is a very essential part to obtain exact information about the number of the neighboring protons. The maximum of distance for splitting is three bonds. Chemical equivalent protons do not result in spin-spin splitting. Spin Multiplicity plays a role in determining the number of neighboring protons. In other word, the proton is only coupled to other protons that are far away in chemical shift.
The spectrum is called first-order spectrum. The splitting pattern depends on the magnetic field. The second-order splitting at the lower field can be resolved into first-order splitting pattern at the high field. The note is that structure system is A 3 M 2 X 2. The signal of Hm is split into six peaks by H x and H a Fig. High-order splitting pattern takes place when chemical shift difference in hertz is much less or the same that order of magnitude as the j coupling. The second order pattern is observed as leaning of a classical pattern.
Fig 4. Here is other system as an example: A 2 B 2 Fig 5. The two triplet incline toward each other. Outer lines of the triplet are less than 1in relative area and the inner lines are more than 1. The center lines have relative area 2. Fig 5. Coupling constant is the strength of the spin-spin splitting interaction and the distance between the split lines. The value of distance is equal or different depending on the coupled nuclei.
The coupling constants reflect the bonding environments of the coupled nuclei. Coupling constant is classified by the number of bonds:. Germinal coupling generates through two bonds Fig 6. Two proton having geminal coupling are not chemically equivalent. This coupling ranges from to 40 Hz. Geminal coupling constant determines ring size. When bond angle is decreased, ring size is decreased so that geminal coupling constant is more positive. If a atom is replace to an electronegative atom, Geminal coupling constant move to positive value.
Fig 6. Geminal coupling. Vicinal coupling occurs though three bonds Fig 7. The Vicinal coupling is the most useful information of dihedral angle, leading to stereochemistry and conformation of molecules. Vicinal coupling constant always has the positive value and is affected by the dihedral angle? Vicinal coupling constant depending on the dihedral angle Fig 8 is given by the Karplus equation. In addition, vicinal coupling constant ranges from 8 to 10 Hz at the and?
Fig 7. Vicinal coupling. The valence angle? Valence angle is related with ring size. Typically, when the valence angle decreases, the coupling constant reduces. The distance between the carbons atoms gives influences to vicinal coupling constant. The coupling constant increases with the decrease of bond length. Electronegative atoms affect vicinal coupling constants so that electronegative atoms decrease the vicinal coupling constants.