Nmr spectroscopy of fluorine 19

nmr f19 spectroscopy

1. NMR SPECTROSCOPY OF FLUORINE-19 PRESENTATION BY ZAKIA AFZAL PhD STUDENT 2013

2. Fluorine-19 nuclear magnetic resonance Fluorine-19 nuclear magnetic resonance is an analytical technique used to identify fluorine-containing compounds. 19 F is one of the most important nuclei for NMR spectroscopy 19 F has a nuclear spin of 1/2 and a high magnetogyric ratio, which means that this isotope is highly responsive to NMR measurements. Furthermore, 19 F comprises 100% of naturally-occurring fluorine.

3. Because of its favorable nuclear properties and high abundance, 19 F NMR measurements are very fast, comparable with 1 H NMR spectroscopy. The reference compound for 19 F is CFCl 3 . Other reference standard are given below.

4. 19 F NMR Reference Standards: Compound: δ( ppm ) vs. CFCl 3 CFCl 3 ( trichloro - fluoro -methane) 0.00 CF 3 COOH ( trifluoro acetic acid) -76.55 C 6 F 6 ( hexafluorobenzene ) -164.9 C 6 H 5 F ( monofluorobenzene ) -113.15 CF 3 Cl ( trifluoro - chloro -methane) -28.6 F 2 (elemental fluorine) +422.92 CH 2 FCN ( monofluoro acetonitrile ) -251 CFCl 2 CFCl 2 ( difluoro , tetrachloroethane ) -67.80 C 6 H 5 CF 3 ( trifluoro -toluene) -63.72 SiF 4 ( tetrafluorosilane ) -163.3 SF 6 (sulfur hexafluoride) +57.42 S 2 O 5 F 2 +47.2 (CF 3 ) 2 CO ( hexafluoro acetone) -84.6 p-FC 6 H 4 F ( para-difluorobenzene ) -106.0 BF 3 -131-3 HF ( aq ) -204.0 CF 4 -62.5 Aqueous F - (KF) -125.3 Positive (+) values indicate downfield shifts, lower-shielding, or higher frequency Negative (-) values correspond to upfield shifts, higher-shielding, or lower frequency. Note: Most literature references historically reverse the sign convention (i.e. negative  

5. CHEMICAL SHIFT Variation of the effective value of Bo experienced by nuclei because of their different electromagnetic environments in the molecule. Usually reported in parts per million of applied field or frequency relative to a resonance in a reference compound (eg.,CFCl 3 ).

6. Chemical Shift of fluorine-19 19 F NMR spectra can be performed in a way equal to 1 H NMR. Chemical shifts of organofluorine compounds using CFCl 3 as standard range from 50 to -250 ppm , a maximum range is as wide 900ppm, much wider than proton NMR. Which ranges 10 to 20 ppm at best. 19 F spectra is very much more sensitive to the structural and environmental changes of molecules.

7. TYPICAL NMR SPECTRA OF ORGANIC FLURO COMPOUND

8. Typical fluorine functional groups and their chemical shift ranges are given in fig.1.15

9. FACTORS AFFECTING CHEMICAL SHIFTS OF FLUORINE Solvent effect on fluorine chemical shift Isotopic effect on fluorine chemical shift Steric de-shielding of Fluorine.

10. Solvent effect on fluorine chemical shift There will usually not be much variation observed in fluorine chemical shifts for the three most common solvents used for obtaining NMR spectra, that is CDCl 3 , DMSO- d 6 and acetone- d 6 , as can be seen in the data presented in table for spectra of a series of typical fluorine containing compounds in various solvents.

11. Table showing solvent effect on chemical shift of fluorine The variation in fluorine chemical shift for these three solvents is not more than + or - 1ppm.Vast majority of spectra are measured in CDCl 3 .

12. Isotopic effect on fluorine chemical shift Because fluorine is relatively sensitive to environment and has such a larger range of chemical shifts, considerable changes in chemical shift can be observed when a nearby atom is replaced by an isotope For example replacement of C-12 by C-13 for the atom to which the fluorine is attached , give rise to a quite measurable shift, usually to lower frequency.

13. DEUTRIUM SUBSTION EFFECT Shifts due to either alpha or beta deutrium substitution is also quiet significant, usually leading to well resolved signals for the deutrated and undeutrated species, which can be useful in charaterization of deutrium labeled fluorinated compounds. An example of alpha effect is shown in Fig below

14. 19F NMR spectrum of 1,6-difluorohexane-1,1 –D2, demonstrating the deuterium isoptopic effect on the fluorine chemical shift

15. STERIC DE-SHIELDING OF FLOURINE Another significant and not infrequently encountered impact on fluorine chemical shift is the deshielding influence of alkyl or arlyl group attached with it This deshielding occur only when there is direct overlap of the van der Waals radii of alkyl group and that of the fluorine , and the deshielding is thought to be result of vander Waals forces of the alkyl group restricting the motion of electrons on the fluorine and thus making the fluorine nucleus respond to the magnetic field as if the electron density were lowered. The most common situation where this effect is seen is in comparison of E and Z isomers of trifluromethyl or difluoromethyl substituted alkenes,

16. Coupling constant of fluorine Fluorine like hydrogen gives characteristic coupling constants depending on the spacial displacement and number of bonds between a coupling partner atom. In particular a long range coupling J 5 is observed in an olefinic system. As shown in Fig.1.16

17. FLUORINE-FLUORINE COUPLING Homonuclear coupling constants between fluorine atoms are usually relatively large compared with those between hydrogen atoms, Coupling between germinal fluorines ( 2 J F-F ) also give a large value of 250 to 300Hz but varying greatly depending on environment of the fluorines . Three bond coupling 3 J F-F in saturated aliphatic hydrocarbons are usually 15-16Hz range.but F-F coupling constant usually decreases as we increase the nuber of proximate fluorines or other electronegative substients . The coupling costant 3 J F-F of trans- vic - difluoroolefin is larger than that of cis -olefin. The largest 3 J F-F are observed between trans-vinyl fluorines where the coupling constant is larger than 35Hz

18. Table showing coupling J-3

19. Other long range and through space homonuclear and hetronuclear couplings also observed

20. HETRONUCLEAR COUPLING H-F COUPLING A typical coupling of organofluorine compounds is observed in a geminal coupling ( 2 J H-F ) with a geminal hydrogen , being as large as 50Hz. This coupling can also be observed by proron NMR

21. HETRONUCLEAR COUPLING F-C COUPLING Coupling between fluorine and carbon is also unique in 13 C NMR 1 J C-F ranges from 250 to 300 Hz Generally coupling costants of 1 J C-F , 2 J C-F , 3 J C-F , and 4 J C-F are respectively, 16-370, 30-45, 5-25, and 1-5Hz. This fact is reliable criterion for the determination of fluoroolefin configurations.

22. Typical coupling costants of n J H -F and n J F -F of fluoroalkanes and alkenes are summarized in Fig.1.18

23. How to calculate the value of J. A typical example of a trifluromethy ether is shown in Fig.1.17 A trifluromethyl carbon splits into a quartet. To obtained such well resolved spectra, high concentration of sample and long term accumulation is necessary.

24. Spin System Like proton we can also assign spin system to compounds containing fluorine on the bases of their chemical and magnetic equivalence by using pople notation And by this way we can predict the type of spectra that is that spectra is first order or second order

25. Some Example of spin system of fluorine containing compounds

26. ABC SPIN SYSTEM

27. FLUORINE nmr spectra is not first order in some cases it shoes virtual coupling

28. VIRTUAL COUPLING The term "virtual coupling" refers to an NMR phenomenon in which apparently first-order multiplets contain false coupling information. In extreme cases, that are not actually coupled will show splitting. More commonly, the magnitude of coupling constants obtained by first-order analysis is incorrect. All virtual coupling effects arise when protons, well isolated from other protons in chemical shift, are coupled to a group of other protons which are strongly coupled to each other . By strongly coupled we mean that these protons are both close in chemical shift and coupled to each other with J > Δν .

29. Example of 2 nd order spectra

30. MULTIDIMENTIONAL F-19 NMR In contrast to carbon and hydrogen 2D NMR methods are not common for fluorine-19. Following are the some example of compounds that can be identified through multidimensional NMR.

31. Secondary alkyl Fluorides Secondary alkylhalides exhibit a downfield shieft of about +35 ppm from their primary analogues , their fluorines typically absorbs at about -183ppm and such fluorines will also experience the usual considerable shielding as a result of branching. Fluorine spectrum of typical secondry fluoride, 2-fluropentane is shown in Fig below

32. Fluorine NMR of 2-fluropentan

33. C-13 NMR of 2-fluropentane

34. Proton NMR of 2-fluropentane

35. Tertiary Alkyl Fluorides Tertiary alkyl fluorides exhibit an additional downfield shift of about +25ppm, which is also very sensitive to branching The signal at -131ppm is split into 10 peaks with a three bond H-F coupling constant of 21 Hz as shown below

36. F-19 NMR spectra of t-butyl fluoride

37. COMPOUNDS OF FLUORINE Elemental fluorine (F 2 ) is the most reactive element. Fluorine combines directly with all other elements, except nitrogen and the lighter noble gases. It form compounds of following type. Ionic salts. Covalent compounds

38. IONIC SALTS OF FLOURINE A wide range of fluoride complexes may be prepared from both metal (FeF 6 3- , RuF 6 - , PtF 6 2- , and SnF 6 2- ) and non-metal (BF 4 - , SiF 6 2- , and PF 6 - ) fluorides. While many fluorides are salts, when the metal is in its higher oxidation states (e.g., OsF 6 and WF 6 ), the formation of an ionic lattice with the appropriate cation (i.e., Os 6+ and W 6+ respectively) is energetically unfavorable

39. COVALENT COMPOUNDS OF FLUORINE Organofluorine compounds that have the carbon–fluorine bond are diverse in their types. They can be fluorocarbons, fluorocarbon derivatives, fluorinated pharmaceuticals and agrichemicals, or mono-fluorinated biologically synthesized compounds, among others. Fluorocarbons are compounds that contain only carbon and fluorine, while other molecules that contain many carbon–fluorine bonds are commonly referred to as fluorocarbons. Pharmaceuticals and agrichemicals commonly contain only one fluorine or a trifluoromethyl group. However, some are more highly fluorinated, such as hexaflumuron , which has six fluorines , in large part to a tetrafluoroethoxy functional group. All known biologically synthesized organofluorines contain only one carbon–fluorine bond.

40. TYPES OF ORGANO FLUORINE COMPOUNDS Fluorocarbons Fluorocarbons are molecules that only contain carbon and fluorine. They can be gases, liquids, waxes, or solids, depending upon their molecular weight. The simplest fluorocarbon is the gas tetrafluoromethane (CF 4 ). Liquids include perfluorooctane and perfluorodecalin . The fluoropolymer polytetrafluoroethylene (PTFE/Teflon) is a solid. While fluorocarbons with single bonds are stable, unsaturated fluorocarbons are more reactive, especially those with triple bonds. Perfluorinated compounds Perfluorinated compounds are fluorocarbon derivatives, as they are closely structurally related to fluorocarbons. However, they also possess new atoms such as nitrogen, iodine, or ionic groups, such as perfluorinated carboxylic acids. Alkyl fluorides Alkyl monofluorides can be obtained from alcohols and Olah reagent or another fluorinating agents.

41. Biological role of organofluorine compounds Biologically synthesized organofluorines have been found in microorganisms and plants, but not animals. The most common example is fluoroacetate , which occurs as a plant defence against herbivores in at least 40 plants in Australia, Brazil and Africa. Other biologically synthesized organofluorines include ω- fluoro fatty acids, fluoroacetone , and 2-fluorocitrate which are all believed to be biosynthesized in biochemical pathways from the intermediate fluoroacetaldehyde . Adenosyl -fluoride synthase is an enzyme capable of biologically synthesizing the carbon–fluorine bond. Man made carbon–fluorine bonds are commonly found in pharmaceuticals and agrichemicals because it adds stability to the carbon framework; also, the relatively small size of fluorine is convenient as fluorine acts as an approximate bioisostere of the hydroxyl group. Introducing the carbon–fluorine bond to organic compounds is the major challenge for medicinal chemists using organofluorine chemistry, as the carbon–fluorine bond increases the probability of having a successful drug by about a factor of ten.An estimated 20% of pharmaceuticals, and 30–40% of agrichemicals are organofluorines , including several of the top drugs.Examples include 5-fluorouracil, fluoxetine (Prozac), paroxetine (Paxil), ciprofloxacin ( Cipro ), mefloquine , and fluconazole .

42. Environmental and health issues Abiotic processes can also result in organofluorines considered as "problem molecules." Fluorocarbon based CFCs and tetrafluoromethane have been reported in igneous and metamorphic rock. However, environmental and health issues still face many organofluorines . Because of the strength of the carbon–fluorine bond, many synthetic fluorocarbons and fluorcarbon -based compounds are persistent in the environment. Others, such as CFCs, participate in ozone depletion. Fluoroalkanes , commonly referred to as perfluorocarbons , are potent greenhouse gases. The fluorosurfactants PFOS and PFOA, and other related chemicals, are persistent global contaminants. PFOS is a persistent organic pollutant and may be harming the health of wildlife; the potential health effects of PFOA to humans are under investigation by the C8 Science Panel.

43. Refrences Guide to Fluorine NMR for Organic Chemists W. R. Dolbier Organofluorine Compounds: Chemistry and Applications by TAMEJIRO HIYAMA www.Chem 605 - Structure Determination Using Spectroscopic Methods www.Instructor: Hans J. Reich www.Wikipidea Organic spectroscopy by William Camp