Philosophy to Chemistry to Elucidation

Teaching and Learning by Spectral Data … Part 2

Part 1 of the series Teaching and Learning by Spectral Data explored the difference between presenting an NMR problem set to a student in the form of an alphanumerical text or as an actual NMR spectrum. Continuing on the same problem set, another issue arises. Is the information on the elements and the 1H NMR spectrum adequate for deducing the unknown?

From the following 1H NMR spectrum, the following fragments can be deduced:

1. the multiplet at 7.24-7.57 ppm (m, 5H) indicates a mono-substituted benzene ring system,

2. the pairing of the J values and the integral information indicates a CH3-CH2 and a CH=CH (trans) fragments (tilting is also evident),

3. the chemical shift for the CH2 at 4.45 ppm indicates an adjacent oxygen atom,

4. the chemical shifts for the CH=CH fragment, 6.49 and 7.83 ppm, indicate an adjacent oxygen atom and/or benzene ring.

The elucidation cannot be completed without additional analytical or spectral data such as elemental analysis, MS, IR, 13C NMR, 2D NMR, etc.

Teaching and Learning by Spectral Example ... Part 1

There are many ways to teach the process of elucidating unknown structures. Offering a student a visual guide, such as seeing firsthand a spectral dataset, can enhance the learning process and better equip the student on future work.

Presented below is a typical elucidation question from a university test. The numerical values have been extracted from a 1H NMR spectrum and the student is basically left to focus on elucidating the unknown.

If a 1H NMR spectrum is presented with the question, as shown below, the student is faced with the tasks of interpreting the spectrum and elucidating the unknown.

Although both approaches can serve a purpose, the latter approach enhances the experience of learning how to elucidate an unknown.

Verifying, Confirming, Making Sure … Part 2

In the constant pursuit of new pharmaceutical drugs, process chemists (sometimes referred to as medicinal or synthetic chemists) must investigate all impurities detected in a new drug manufacturing process. The chemist’s procedure is simple: identify, elucidate and synthesize each and every single impurity.

The chromatogram (UV detector set at 254 nm) below shows three peaks. The large peak at 5.51 min. is the active pharmaceutical ingredient (API). The two small peaks on either side of the API are impurities from the manufacturing process. Depending on the dose and potency of the drug substance, typical regulatory requirements for impurities mandate that any peak with a threshold greater than 0.1% be identified, elucidated and synthesized.

Verifying, Confirming, Making Sure ... Part 1

After a long and arduous attempt at an elucidation, it is quite common to be left with more than one candidate structure. In some cases collecting more data is not an option and an exhaustive database/literature search turns up nothing useful, the alternative approach is to synthesize the proposed candidates and then compare the spectral data to the original unknown.

The example below shows three proposed candidate structure differing in the attachment of the hexopyranoside group. The high degree of similarity between the candidates and the high number of quaternary carbons (11 per structure) makes it very difficult to narrow the list to one candidate.

When data is limited and thus cannot assist in eliminating two out of the three candidates, then the only option left is to synthesize the candidates and compare the spectral data.  

Using a Smaller Structure to Elucidate a Larger Structure

Datasets for large unknown compounds tend to be complicated and typically require a lot of effort in distinguishing one signal from another. Having some background information about the unknown, such as a metabolite, a precursor, a derivative, etc. can be invaluable with the detail work needed to get through an elucidation.

The 13C NMR spectrum below is for an unknown compound with 38 carbons. Several carbons in the spectrum are overlapping with each other, thus, making the interpretation difficult.

To facilitate the process of elucidating the unknown, the 13C NMR spectrum for the unknown (drawn in black) is compared to the 13C NMR spectrum for a pure sample of cholesterol (drawn in red). The signals that line up are part of the same cholesterol scaffold; in all ~25 signals match up. The remaining 13 signals belong to the unknown part that requires further work.

 

The structures for the unknown and cholesterol are shown below.