Philosophy to Chemistry to Elucidation

How to deal with ambiguity in an HMBC spectrum? … Part 2

The best approach when dealing with severe ambiguity in assigning a correlation(s) to a 1D resonance(s) in a 1H-13C HMBC spectrum is to take into account all possible assignments. The drawback to this approach is it adds to the complexity of the structure elucidation process rather than simplifying it.

The HMBC spectrum below illustrates a severe case of ambiguity in assigning a correlation to a single 13C resonance. The spectrum exhibits a correlation that can be assigned to a 13C resonance at 129.10 and/or 129.13 ppm.

The elucidator will take the first possible assignment (3.52, 129.10 ppm) and attempt to construct a set of structures (or fragments). Subsequently, the elucidator will take the alternate assignment (3.52, 129.13 ppm) and build a second set of structures. This approach of using multiple assignments will ensure no possibility is overlooked.

TIP: The curved arrows, used to track what nuclei are coupled to each other, are drawn as dotted lines to indicate an ambiguous assignment. Visually, the elucidator can differentiate this ambiguous assignment from curved arrows with solid lines used for definite assignments.

How to deal with ambiguity in an HMBC spectrum? … Part 1

Generally, a 1H-13C HMBC experiment offers a wealth of connectivity information about an unknown structure(s). However, an elucidator may be faced with the issue of ambiguity in assigning a correlation(s) to a 1D resonance(s).

A correlation with an ambiguous assignment may be assessed in one of 5 ways:

-reprocess the HMBC data using a different weighing function to try and narrow down an assignment,

-look for additional information among the other experiments to confirm one assignment over an other,

-ignore the ambiguous correlation and see if there is adequate HMBC data to continue the elucidation,

-make an assumption and assign the correlation to a 1D resonance at the risk of being incorrect, or

-consider multiple assignments at the risk of complicating the elucidation process.

The case below illustrates a mild form of ambiguity in an HMBC spectrum. (A subsequent blog will demonstrate how to deal with a severe case of ambiguity.) The HMBC spectrum exhibits 2 adjacent CH2 resonances, at 41 and 42 ppm, whereby one or both carbons are correlated to the 1H resonance at 2.37 ppm. From afar, the correlation appears to be linked to both carbons. However, upon closer examination of the correlation, the carbon at 42 ppm seems to be the better choice.

TIP: Zooming-in on a correlation can sometimes help resolve the uncertainty associated with the assignment.

Fulvene versus Benzene

Failures, as are successes, are an integral part of a structure elucidator’s role. What differentiates a good elucidator from a bad one is the capability of an elucidator to learn from his/her failures. The most common obstacle that can hold a structure elucidation process from becoming a success is structural bias. (This is based on my experiences with elucidators worldwide.)

A good stance to best avoid structural bias is to be aware of different alternative structures especially those not commonly encountered during a routine structure elucidation. Below is a case in point. The unknown is comprised of two fragments such that the hybridization states of all the carbons are sp2 and the ring size is restricted to 5 or 6. For clarity reasons, the carbon atoms in red are the ones to be arranged.

Two candidate structures are shown below. A common structural bias is to take the 6 sp2 carbons and complete a benzene ring (right structure). The alternative structure is work out a fulvene group (left structure). References are included for both structures.

Stuck on a Structure Elucidation problem? You need Out of the Box thinking, right?

Attempting a challenging structure elucidation of an unknown and being unable to solve the problem can put a damper on a hectic workload and possibly on your skills as an elucidator. Emotionally, the excitement of working on a challenging elucidation problem leads into frustration, as results are what count. Subsequently, the elucidator faces the following choices:

-collect more data,

-question the data or the instrument or the instrument operator,

-discard everything and start from scratch,

-leave it alone for a few days and then come back to it with a clear mind,

-hand it off for someone else to do,

-forget about it and pretend it never existed, or

-file it in the cabinet under the X-file for another day.

The diagram below presents the situation whereby an elucidator is fixated on a core fragment and thus unable to budge from the enclosed Structural Bias box. A classic example is the elucidation of a synthetic product whereby the chemist synthesized an unknown compound far from he/she intended. The elucidator then falls for the bias of a specific fragment upon seeing the synthetic route.

How to avoid the Structural Bias box? There is no easy answer (or answers) other than to simply broadening your scope of knowledge. Definitely, the willingness and enthusiasm to never give up is a plus while ensuring every idea is panned out to its fullest. Also, be sure to be open to more than one solution as you venture outside of your comfort zone. Explore the literature and databases in search of that elusive tidbit that could unlock the missing piece. Finally, focus on piecing the data together in new and creative ways.

t-Butyl group towers over other 1H resonances

Like a methoxy group, a t-Butyl group stands out over other 1H resonances. For organic compounds, the 1H resonance for a t-Butyl group generally towers over other 1H resonances because it integrates to ~9 protons (assuming the presence of 1 t-Butyl group and no overlap with other resonances). The basic 1H NMR pattern of the CH3 groups is a typical singlet, although not always the case, and ranging in chemical shift between 0.5 and 2.0 ppm. The 13C NMR spectrum shows the CH3 resonances between 20 and 42 ppm.

The 1H NMR spectra below illustrates the 3 patterns for a t-Butyl group to be on the lookout for.