How do I know if my unknown contains a fluorine atom(s)? … Part 3

Experiments such as 1H-13C HMQC, HSQC, or HETCOR can be used to suspect the presence of fluorine but not necessarily rule out the absence of fluorine. The stipulation behind this assessment is that a carbon from either a CH, CH2 or CH3 group must experience 13C-19F coupling(s).

The spectrum below is a region of an 1H -13C HSQC for the CH group belonging to the steroid-type fragment. The F1 trace is a projection of all the 13C slices. A 1D 1H NMR spectrum is attached to the F2 domain, hence the better resolution. The CH carbon resonances at 71 pm are split due to 13C-19F coupling. To confirm this, the 13C resonances correlate to a 1H at 4.1 ppm, which integrates to 1. A processed 1H NMR spectrum is shown on a previous blog.

TIP: Once again, the pattern to look out for is ‘doubling up tilt’ of correlations along F1.

How do I know if my unknown contains a fluorine atom(s)? … Part 3

Experiments such as 1H-13C HMQC, HSQC, or HETCOR can be used to suspect the presence of fluorine but not necessarily rule out the absence of fluorine. The stipulation behind this assessment is that a carbon from either a CH, CH2 or CH3 group must experience 13C-19F coupling(s).

The spectrum below is a region of an 1H -13C HSQC for the CH group belonging to the steroid-type fragment. The F1 trace is a projection of all the 13C slices. A 1D 1H NMR spectrum is attached to the F2 domain, hence the better resolution. The CH carbon resonances at 71 pm are split due to 13C-19F coupling. To confirm this, the 13C resonances correlate to a 1H at 4.1 ppm, which integrates to 1. A processed 1H NMR spectrum is shown on a previous blog.

TIP: Once again, the pattern to look out for is ‘doubling up tilt’ of correlations along F1.

How do I know if my unknown contains a fluorine atom(s)? … Part 2

Without a set routine to acquire a 19F NMR spectrum for every single sample, an elucidator must resort to routine NMR experiments for clues to the presence or absence of fluorine.

For the elucidator who routinely acquires a proton decoupled 13C NMR, the spectrum can provide some clues into the presence of fluorine. Carbons in the vicinity of a fluorine atom(s) will show up as split resonances due to 13C-19F couplings.

The segmented 13C NMR spectrum below illustrates four carbons resonances with splitting patterns. The couplings constants are as follows: CF (101 ppm) at 175.4 Hz, CH (70 ppm) at 37.2 Hz, C (48 ppm) at 22.9 Hz, CH (33 ppm) at 19.2 Hz, and CH3 (23 ppm not shown) at 6.0 Hz. The coupling constants themselves are clues to the proximity of the carbon atom to fluorine.

TIP: On a first pass, there may appear to be extra carbons present in the spectrum. It is important to look for patterns such a ‘doubling up’ of carbons. Secondly, it is wise to compare the spectral carbon count to the molecular weight and see if anything is amiss.

How do I know if my unknown contains a fluorine atom(s)? … Part 2

Without a set routine to acquire a 19F NMR spectrum for every single sample, an elucidator must resort to routine NMR experiments for clues to the presence or absence of fluorine.

For the elucidator who routinely acquires a proton decoupled 13C NMR, the spectrum can provide some clues into the presence of fluorine. Carbons in the vicinity of a fluorine atom(s) will show up as split resonances due to 13C-19F couplings.

The segmented 13C NMR spectrum below illustrates four carbons resonances with splitting patterns. The couplings constants are as follows: CF (101 ppm) at 175.4 Hz, CH (70 ppm) at 37.2 Hz, C (48 ppm) at 22.9 Hz, CH (33 ppm) at 19.2 Hz, and CH3 (23 ppm not shown) at 6.0 Hz. The coupling constants themselves are clues to the proximity of the carbon atom to fluorine.

TIP: On a first pass, there may appear to be extra carbons present in the spectrum. It is important to look for patterns such a ‘doubling up’ of carbons. Secondly, it is wise to compare the spectral carbon count to the molecular weight and see if anything is amiss.

How do I know if my unknown contains a fluorine atom(s)?

Ideally, identifying whether a fluorine atom(s) is present is as simple as acquiring a 19F NMR. However, running 'uncommon' experiments is not usually my first step in an elucidation (MDE). Imagine a scenario where the elucidator is unsure whether fluorine is present. He/she acquires a 19F NMR and sees no 19F resonances. Therefore the extra experiment can be considered a waste of time especially when other experiments may provide the clues needed.

I resort to routine experiments such as MS, 1H and 13C NMR, and HSQC to gather information for the presence of fluorine. Although a mass spectrum can indicate such losses as CF3, it is usually not the best approach for inferring the presence of a fluorine atom(s). A 1H NMR spectrum may provide some clues for fluorine but on a complicated spectrum, it may not be as obvious that fluorine is present.

Shown below is a portion of a 1H NMR spectrum for a steroid-type compound with a single fluorine atom. Only the vicinal protons to the fluorine atom show any 1H-19F splitting. However, the splitting is not conclusive evidence for the presence of a fluorine. The subsequent blog will illustrate some better clues into ascertaining the presence of fluorine.

Further complicating the matter, the multiplet at 2.4 pppm (CH group) is overlapping with another multiplet and the multiplet at 4.1 ppm (CHOH group) exhibits some hard to discern couplings.

How do I know if my unknown contains a fluorine atom(s)?

Ideally, identifying whether a fluorine atom(s) is present is as simple as acquiring a 19F NMR. However, running 'uncommon' experiments is not usually my first step in an elucidation (MDE). Imagine a scenario where the elucidator is unsure whether fluorine is present. He/she acquires a 19F NMR and sees no 19F resonances. Therefore the extra experiment can be considered a waste of time especially when other experiments may provide the clues needed.

I resort to routine experiments such as MS, 1H and 13C NMR, and HSQC to gather information for the presence of fluorine. Although a mass spectrum can indicate such losses as CF3, it is usually not the best approach for inferring the presence of a fluorine atom(s). A 1H NMR spectrum may provide some clues for fluorine but on a complicated spectrum, it may not be as obvious that fluorine is present.

Shown below is a portion of a 1H NMR spectrum for a steroid-type compound with a single fluorine atom. Only the vicinal protons to the fluorine atom show any 1H-19F splitting. However, the splitting is not conclusive evidence for the presence of a fluorine. The subsequent blog will illustrate some better clues into ascertaining the presence of fluorine.

Further complicating the matter, the multiplet at 2.4 pppm (CH group) is overlapping with another multiplet and the multiplet at 4.1 ppm (CHOH group) exhibits some hard to discern couplings.

Deciphering a crowded region in a 1H NMR spectrum using 2D NMR

When faced with a crowded region in a 1H NMR spectrum, a 2D NMR experiment can assist in removing the ambiguity and in narrowing down the proton count.

For the 1H NMR spectrum below, Multiplet F (the region between 1.4 to 1.8 ppm) displays an integral of 6.71. Although several factors may contrbute to the disparity of the integral as a whole number, the question remains does the integral 6.71 represent 6 or 7 protons assuming Multiplet E corresponds to 1 proton?

A 1H-13C DEPT-HSQC, shown below, illustrates the correlation between a 1H and 13C that are separated by one bond. In addition, the correlations that are negative (commonly displayed in blue) signify a methylene (CH2) group. The 1D projection along the F1 dimension represents 4 carbons at 26, 27, 31, and 39 ppm and each carbon correlates with 2 inequivalent proton resonances.

Based on the information from the DEPT-HSQC spectrum, one can say with a higher degree of certainty that there are 7 protons within the 1H region of 1.4 to 1.8 ppm.