EUROISMAR - (EUROMAR, ISMAR, GDCh FGMR Joint Conference), August 25-30, 2019 | ACD/Labs
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EUROISMAR - (EUROMAR, ISMAR, GDCh FGMR Joint Conference)

August 25-30, 2019
Henry Ford Building, Freie Universität Berlin, Berlin, Germany

Poster Schedule

A New Method for the Reliable Detection of 13C Multiplets of Fluorine Containing Compounds
Dimitris Argyropoulos, Rostislav Pol, Vladimir Mikhailenko and Sergey Golotvin
View Abstract

A New Method for the Reliable Detection of 13C Multiplets of Fluorine Containing Compounds

Dimitris Argyropoulos, Rostislav Pol, Vladimir Mikhailenko and Sergey Golotvin

Advanced Chemistry Development, Toronto, Canada

In modern organic and medicinal chemistry, fluorine is commonly used to enhance the chemical properties of molecules in many desirable ways: it may delay the metabolism of the molecule due to the increased stability of the C-F bond, reduce the toxicity of aromatic groups by forbidding the formation of poisonous peroxides during metabolism, or increase the bioavailability due to the higher lipophilicity of the C-F bond vs the C-H bond. As a result, it is estimated that more than 20% of commercial pharmaceutical APIs and 30% of agrochemicals contain at least one fluorine atom [1,2].

In contrast to these benefits, the 13C NMR spectra of fluorinated organic compounds are highly susceptible to interpretation errors. This is because 13C spectra are commonly recorded using only 1H broadband decoupling and the 13C-19F couplings are still present. The 13C-19F coupling constants can be very large (up to 250 Hz or more), which may result in multiplets severely overlapping with other peaks in the spectrum. Additionaly, since 13C spectra inherently have low S/N, it is not uncommon that the lower (outer) parts of a multiplet are below the noise level and not visible. On top of these the carbon atoms connected to fluorine do not benefit from NOE signal enhancement from 1H broadband decoupling as much as those connected to protons are, reducing even further the observed signal intensity. To mitigate this, it is possible to record 13C spectra broadband decoupled from both 1H and 19F but this requires specialized NMR probes and decoupling techniques. Moreover the very broad range of 19F chemical shifts could pose a danger of damage to the probe due to the very high RF power that would be required. Consequently, this approach is not considered practical for general, routine use.

Expansion of the 1H decoupled 13C spectrum of 1,2,3-Trichloro-5-(trifluoromethyl)benzene, indicating the overlapping multiplets due to the 19F-13C couplings.

Figure 1: Expansion of the 1H decoupled 13C spectrum of 1,2,3-Trichloro-5-(trifluoromethyl)benzene, indicating the overlapping multiplets due to the 19F-13C couplings.

Here we present an analysis method that reliably peak-picks and identifies multiplets in the 13C spectra of organic compounds. This technique is based on accurately predicting the 19F coupled 13C spectrum of the proposed compound. Following prediction, we examine the regions of the experimental spectrum where the 19F coupled carbons are expected in order to identify multiplets by peak position and the agreement in the predicted and observed coupling constants, in essence pattern-matching the experimental to the predicted spectrum. Provisions are taken if only part of a multiplet is observed. We show that regardless of whether the final results contain multiple, overlapping multiplets, the expected carbon resonances are reliably identified and assigned for each spectrum. Typical examples from common fluorine containing compounds are shown.

[1] Emsley, John, “Nature's building blocks: An A–Z guide to the elements (2nd ed.)”, Oxford University Press, p. 178, 2011.

[2] Swinson, Joel, "Fluorine – A vital element in the medicine chest", PharmaChem. Pharmaceutical Chemistry: 26–27, 2005.