NMR Data for Carbon-13. Part 4: Natural Products
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At the most basic level, it requires functional groups for derivatization or complexation, and these are absent in 1 — 4. Here we provide a solution to the problem of identifying a natural product or other unknown compound by matching its 1D 13 C NMR spectrum with two spectra from a pair of known compounds.
The solution is generally applicable but is specifically designed for the case where the spectra of the two known samples are extremely similar, potentially even identical. Two common complications are addressed: systematic differences in calibration chemical shift referencing between spectra and, importantly, the differential temperature dependence of 13 C chemical shifts.
First, we lay out a stepwise process for comparing pairs of 13 C NMR data sets that allows one to decide whether the spectra are the same or different. If they are different, then the differences are articulated and applied for structure assignment. We claim that the method requires only standard tables of 13 C NMR chemical shifts. Second, to validate this claim, we show that published data sets from Kitching and Breit can be used to assign the structure of 1 without any head-to-head sample comparison.
Third, we provide full details of the synthesis of 2 and 4 , and finally, fourth, we apply the new method to rigorously show without the aid of a natural sample that the natural product is 4 S ,6 R ,8 R ,10 S ,16 S -pentamethyldocosane 2. Remarkably, the method succeeds even though the largest difference in chemical shift in the 13 C NMR spectra of isomers 2 and 4 is only about 10 ppb! When real differences in chemical shifts are this small, it is critical to account for possible differences in sample temperature. The current standard for comparison of 13 C NMR spectra of two similar candidate samples with the spectrum of a natural sample is simply raw subtraction.
The set of chemical shifts of the natural product spectrum is subtracted from each set of chemical shifts of the candidate spectra, resulting in two sets of differences that are typically shown as scatter plots. The two plots are then compared by standard deviation or other means, and then the natural product is assigned the structure of the candidate with the smaller differences. First, it assumes that there are real and reliable differences in the spectra of the two candidate isomers, but there may not be. Second, it assumes without justification that all errors are random and therefore will tend to cancel in the final comparison.
Third, it treats all differences in chemical shifts as equal in importance, regardless of the locations of the carbon atoms involved.
In other words, some chemical shift differences are more valuable than others. But which ones? And how do you know? The goals are to both assign the structure of the unknown compound and to confidently articulate that the assignment is correct. The initial discussion here presents the generalized process, so it is necessarily abstract. However, each of the steps of the processes will be illustrated concretely in the following section on validation.
NMR Spin Coupling
Steps and possible outcomes of a process for comparing different samples whose 13 C NMR spectra are very similar and possibly identical. Samples S and R are two different candidates of known structure that are compared to a natural product NP of unknown structure. To the extent possible, the resonances of the spectra are assigned to their associated carbon atoms by standard means.
The spectra of the synthetic samples must be recorded under the same conditions and at the same nominal probe temperature within about 1 K. The temperature of the NP spectrum is critical but does not need to be known in advance because it emerges from the analysis. Step 1 is to compare the spectra of the candidate samples R and S not to the natural product but to each other.
The goals are to determine whether the candidate spectra are the same or different and, if different, to articulate the differences. Start by subtracting the chemical shifts of R from S or the reverse and gauge the experimental uncertainty in the chemical shift values. Record duplicate spectra if needed to estimate this. If the subtractions are all zero within the expected experimental error, then the spectra are substantially identical.
This means that the two candidate spectra cannot be used to assign the configuration of NP. Further subtraction of S and R from NP is pointless, and another means of assignment is needed. If some subtractions are not zero, then group all resonances into three categories based on their differences in their chemical shifts. The chemical shifts of each pair of resonances in S and R are either 1 the same, 2 uncertain, or 3 reliably different.
Establish chemical shift limits for the three categories based on the estimated error and common sense analysis of the data. Before advancing to step 2, check the carbon atom assignments of the various resonances, which should pass the sniff test of chemical common sense. In steps 2 and 3, we compare the spectra of the candidate samples to that of the NP. This is where standard comparisons usually start; however, we are ahead of the game because we already know that our comparisons are meaningful that is, S and R do not have identical spectra and we know what to compare the reliably different resonances.
In step 2, we control for temperature and calibration differences of the candidate and natural samples.
In principle, the subtractions should all be zero. In practice, there are three possible outcomes: First, if all of the values are zero or close to zero , then both the temperature and calibration errors are small. In that case, proceed directly to step 3 final comparison. Second, if the values are small and constant either positive or negative , then there is a calibration difference between the synthetic and natural samples.
Temperature effects on 13 C NMR spectra of alkanes are variable, ranging from 0 to about 20 ppb per degree K in either direction that is, upfield or downfield with increasing T , reflecting the change in conformation populations with temperature. Clearly the spectra of the candidate samples have to be collected at the same sample temperature as the spectrum of the natural product.
Application of anisotropic NMR parameters to the confirmation of molecular structure
What to do if you identify a temperature difference between your synthetic samples sample temperature known and the natural product sample sample temperature unknown? This process will be illustrated below. If all of the subtraction values equal zero within the experimental uncertainty, then this is the natural product match. If all subtraction values equal the reliably different values identified in step 1, then this is the mismatch.
No other result is possible; there cannot be subtractions that neither match zero nor mismatch reliably different. First, Kitching provided the spectrum of the isolated natural product and assigned the various resonances. This proves a key assumption of our method, that at least some of the carbons in the isomers have identical chemical shifts. Breit concluded that assigning the configuration of 3 by the usual raw subtraction of chemical shifts of synthetic and natural samples was not possible because the spectra of 1 and 3 were too similar.
NMR Spectroscopy - Chemistry LibreTexts
The 16 R ,18 S configuration 1 was assigned to the natural product because no peaks were doubled in the spectrum of the sample of 1 with the natural product capillary inserted, whereas a lone peak was doubled in the corresponding spectrum of 3 with the capillary. The tube-in-tube experiments suggest that the stereoisomers 1 and 3 have 27 chemical shifts that are the same and only one that is significantly different; however, we show presently that more differences can be identified.
Together, the data sets provide an extremely rare perhaps the only case study where spectra of pairs of diastereomers with similar spectra have been collected in three different ways: as individual, pure samples Breit , truly mixed Kitching, but admixed with two other isomers , and artificially mixed Breit, tube-in-tube. Our goal was to do what was not possible by raw subtraction: to confidently assign the structure of the hexamethyldocosane natural product from the data sets of the individual samples alone.
Table 1 shows his complete data lists 2 along with the subtraction results. Breit is correct—the spectra are strikingly similar. Chemical shift differences in ppb and assigned carbon atoms on the structures of the hexamethyldocosane top and pentamethyldocosane bottom candidate isomers. The uncertain resonances are labeled in green, and reliably different resonances are in red.
Notice how the reliably different resonances are not randomly distributed or clustered at the ends. Instead, they cluster in the region C9—C This makes sense given the structural difference between the two isomers. Still, the six reliably different resonances suffice for the analysis.
Strikingly, most of the uncertain and reliably different resonances in the hexamethyldocosane isomers 1 and 3 belong to methylene carbons. In contrast, only one of the six methines C10 RD class and one of the six methyl groups not shown because it was not assigned, UC class lights up in this analysis. These and the remaining subtraction tables are shown in the Supporting Information. The result is a small, constant difference of about 3 ppb.
The 4. Without question, the hexamethyldocosane is 1. Specifically, are the reliably different resonances identified by this method real?
The last column of Table 2 lists the ppb differences in the doubled resonances in Kitching mixture sample. The magnitudes of the differences match within about 2 ppb.margun.savviihq.com/chicas-en-arganda.php
Introduction to C-13 NMR of natural products
This cannot be coincidence. This simply shows that having more reliably different resonances increases the confidence of the method. It is not important to find all of the real differences, only that the differences found are reliable. This success was enabled in no small part by the high quality of the published data sets from both Breit and Kitching. Breit has already assigned 1 securely by the tube-in-tube method, so here it is the validation of the method that counts.
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Strikingly, the new method of controlled subtraction of the data was comparable in effectiveness to recording spectra of true mixtures in identifying different doubled resonances and was considerably better than the tube-in-tube method.