The limitations of 19F GARP Decoupling

In a previous post, it was shown that distorted line shapes are obtained for resonances in broadband decoupled NMR spectra when the resonances of the decoupled nuclide are outside of the effective decoupling bandwidth.  This can be a particularly difficult problem when observing ¹H NMR spectra with ¹⁹F decoupling.  ¹⁹F has a large chemicals shift range so, if there are multiple widely spaced ¹⁹F resonances, it will be difficult or impossible to decouple all ¹⁹F sites at once, particularly at higher magnetic field strengths.  If one is not aware of this problem, data misinterpretation may be an issue as distorted line shapes will  lead incorrect splittings used to measure coupling constants.  The figure below illustrates this problem.  The top three panels of the figure show the 300 MHz ¹H[¹⁹F] NMR spectra for the three ¹H resonances of 1,2-difluoropyridine as a function of the ¹⁹F decoupler offset.  The GARP decoupling scheme was used with 90° pulses of 80 µsec.  The decoupler offsets, depicted in the bottom panel of the figure, were varied in 5 ppm increments.

Of the 11 decoupler offsets used, only offset 6 (at -116 ppm) effectively decoupled both ¹⁹F sites.  Varying the decoupler offset by only ± 5 ppm leads to distorted line shapes, which are particularly pronounced for the H₃ resonance.  These distorted line shapes could easily lead to data misinterpretation and erroneous coupling constants.  In this case, the ¹⁹F decoupling bandwidth is 55 ppm.  Since the chemical shift difference between the two  ¹⁹F resonances is 52 ppm, one is able to obtain a fully ¹⁹F decoupled ¹H spectrum with the careful choice of the decoupler offset frequency however, there will be cases where the decoupling bandwidth would not be sufficient to decouple all ¹⁹F resonances in some molecules.  How then can one generally evaluate all of the coupling constants in fluorine containing molecules?  The ¹⁹F-¹⁹F couplings can be evaluated in a ¹⁹F[¹H] spectrum (not shown).  Specific ¹H-¹⁹F coupling constants can be determined by measuring a ¹H PSYCHE spectrum or be collecting ¹H spectra with selective ¹⁹F continuous wave (CW) decoupling  for each of the¹⁹F resonances.  The latter is shown in the figure below.  The bottom panel shows a standard ¹H spectrum.  The middle two panels show the ¹H spectra for each of the ¹⁹F sites decoupled separately using CW decoupling.  The top panel shows the fully ¹⁹F decoupled spectrum.

Using these data, all of the coupling constants can be evaluated and are shown in the figure below.

In conclusion, one must be careful in interpreting ¹H[¹⁹F] spectra and understand the limits of the ¹⁹F decoupling scheme used.

Boron Isotope Effects in Fluorine NMR Spectra

In previous posts on this BLOG, examples of  ¹H/²H and ¹²C/¹³C isotope effects were discussed.  The figure below shows an example of a ¹⁰B/¹¹B isotope effect observed in the ¹⁹F NMR spectrum of tetrabutyl ammonium tetrafluorobarate.

The spectrum clearly shows two resonances separated by 0.05 ppm with an intensity ratio of approximately 20:80 corresponding to the natural abundances of  ¹⁰B and ¹¹B, respectively.  The low frequency resonance is due to ¹¹BF₄^-.  Since  ¹¹B is a spin I = 3/2 nuclide we observe a 1:1:1:1 quartet with J = 1.25 Hz corresponding to the one bond ¹⁹F - ¹¹B coupling.  The high frequency resonance is due to ¹⁰BF₄^-.  Since  ¹⁰B is a spin I = 3 nuclide we observe a very poorly resolved 1:1:1:1:1:1:1 septet with J ~ 0.4 Hz corresponding to the one bond ¹⁹F - ¹⁰B coupling.  

PSYCHE to Evaluate 1H-19F Coupling Constants

Even small molecules can yield very complex ¹H NMR spectra as the result of spin - spin coupling.  This is particularly true for small molecules that contain fluorine.  It can sometimes be challenging to determine which splittings are due to ¹H-¹H coupling and which are due to ¹H-¹⁹F coupling.  One can collect a ¹H spectrum with ¹⁹F decoupling to give a spectrum with only ¹H-¹H coupling present.  Even with this data, it may be difficult to evaluate the ¹H-¹⁹F coupling constants by comparing the ¹H[¹⁹F] spectrum to the ¹H spectrum due to the complexity of the multiplets.  The ¹H-¹⁹F coupling constants can however be read directly from a ¹H PSYCHE spectrum.  The PSYCHE spectrum provides a ¹H decoupled ¹H spectrum, leaving only the ¹H-¹⁹F coupling behind.  The bottom trace of the figure below shows the 300 MHz ¹H NMR spectrum of 2,3-difluoro pyridine.  The spectrum is quite complex, making it difficult to assign ¹H-¹H and ¹H-¹⁹F couplings.  The middle trace shows the ¹H[¹⁹F] spectrum which allows the evaluation of all of the ¹H-¹H coupling constants (³J_H5-H4 = 4.8 Hz, ⁴J_H5-H3 = 1.6 Hz and ³J_H4-H3 = 8.0 Hz.  The top trace shows the ¹H PSYCHE spectrum which allows one to evaluate all of the ¹H-¹⁹F coupling constants.  For this compound, ⁴J_H3-F1 = ³J_H3-F2 = 9.8 Hz, ⁴J_H4-F2 = 3.2 Hz and ⁴J_H5-F1 = 1.8 Hz.

19F NOESY

Two-dimensional ¹H NOESY data are routinely used to assign specific stereo-isomers based on the proton nuclear Overhauser effects (NOE's) which are strongly correlated to inter-proton distances through space.  For example, NOE's may be observed for cis- protons across a double bond but not observed for trans- protons.  The same technique can be used with ¹⁹F in fluorinated compounds to gauge the inter-fluorine distance and assign stereochemistry.  The figure below shows the ¹⁹F NOESY spectrum of a fluorine containing cobalt complex.

From the 1D-¹⁹F NMR spectrum, it is not clear which fluorine atoms are on the same or opposite sides of the four membered cobalt containing ring.  The 2D-¹⁹F NOESY spectrum, on the other hand, shows strong NOE cross peaks between fluorine C and both A and E indicating that C, A and E are on the same side of the ring.  There are also strong cross peaks between fluorine D, and both B and F indicating that D, B anf F are on the same side of the ring.

Thank you to Graham Lee (of Dr. R.T. Baker's research group at the University of Ottawa) for kindly providing the sample and sharing his data. 

Isotope Effects and the 19F - 13C HMQC Spectrum of Trifluoroacetic Acid

The ¹⁹F - ¹³C HMQC spectrum of trifluoroacetic acid is shown in the figure below.

The data were collected with a delay appropriate for a ¹⁹F - ¹³C J  coupling constant between the ¹J_F-C coupling constant of 284 Hz and the ²J_F-C coupling constant of 44 Hz.  The top and side traces are the one-pulse ¹⁹F and ¹³C spectra, respectively.  Why are the HMQC responses not at the same ¹⁹F chemical shift and why aren't they correlated to the peak in the ¹⁹F spectrum?  In order to answer these questions one must take into consideration the ¹⁹F - ^{12, 13}C isotope effects.  The chemical shift of the fluorine depends on whether it is bound to a ¹²C or a ¹³C.  The effect is largest across one bond and gets smaller over multiple bonds.  The ¹⁹F NMR spectrum for trifluoroacetic acid is shown in the figure below with and without ¹³C broadband decoupling in the upper and lower traces, respectively.

Approximately 98% of the trifluoroacetic acid is the ¹²CF₃-¹²COOH isotopomer, giving rise to a large singlet plotted off-scale in the figure. Approximately 1% of the signal is from the ¹³CF₃-¹²COOH isotoponer giving rise to a doublet with ¹J_F-C = 284 Hz and approximately 1% of the signal is from the ¹²CF₃-¹³COOH isotoponer giving rise to a doublet with ²J_F-C = 44 Hz.  All of these signals are clearly present in the lower trace of the figure.  When ¹³C broadband decoupling is applied, the doublets collapse into singlets.  The singlets from each of the isotopomers are resolved in the top trace.  The one-bond ¹⁹F - ^{12, 13}C isotope effect is 0.13 ppm and the two-bond effect is 0.02 ppm.  The figure below shows the same HMQC data with the spectrum from the top trace used as a projection.

One can see that the HMQC responses are correlated to their respective isotopomers.  These effects are also present in ¹H - ¹³C HMQC spectra, but the ¹H - ^{12, 13}C isotope effect is much smaller than the ¹⁹F - ^{12, 13}C isotope effect.