NMR SPECTROSCOPY OF FLUORINE-19

PRESENTATION BY ZAKIA AFZAL PhD STUDENT

2013

Fluorine-19 nuclear magnetic resonanceFluorine-19 nuclear magnetic resonance is

an analytical technique used to identify fluorine-containing compounds. 19F is one of the most important nuclei for NMR spectroscopy

19F has a nuclear spin of 1/2 and a high magnetogyric ratio, which means that this isotope is highly responsive to NMR measurements. Furthermore, 19F comprises 100% of naturally-occurring fluorine.

Because of its favorable nuclear properties and high abundance, 19F NMR measurements are very fast, comparable with 1H NMR spectroscopy.

The reference compound for 19F is CFCl3.

Other reference standard are given below.

19F NMR Reference Standards: Compound: δ(ppm) vs. CFCl3

CFCl3 (trichloro-fluoro-methane) 0.00

CF3COOH (trifluoro acetic acid) -76.55

C6F6 (hexafluorobenzene) -164.9

C6H5F (monofluorobenzene) -113.15

CF3Cl (trifluoro-chloro-methane) -28.6

F2 (elemental fluorine) +422.92

CH2FCN (monofluoro acetonitrile) -251

CFCl2CFCl2 (difluoro, tetrachloroethane) -67.80

C6H5CF3 (trifluoro-toluene) -63.72

SiF4 (tetrafluorosilane) -163.3

SF6 (sulfur hexafluoride) +57.42

S2O5F2 +47.2

(CF3)2CO (hexafluoro acetone) -84.6

p-FC6H4F (para-difluorobenzene) -106.0

BF3 -131-3

HF (aq) -204.0 CF4

-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  

CHEMICAL SHIFTVariation 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.,CFCl3).

Chemical Shift of fluorine-1919F NMR spectra can be performed in a way

equal to 1H NMR. Chemical shifts of organofluorine compounds using CFCl3 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.

19F spectra is very much more sensitive to the structural and environmental changes of molecules.

TYPICAL NMR SPECTRA OF ORGANIC FLURO COMPOUND

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

FACTORS AFFECTING CHEMICAL SHIFTS OF FLUORINE

Solvent effect on fluorine chemical shiftIsotopic effect on fluorine chemical shiftSteric de-shielding of Fluorine.

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 CDCl3, DMSO-d6 and acetone-d6, as can be seen in the data presented in table for spectra of a series of typical fluorine containing compounds in various solvents.

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 CDCl3.

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.

DEUTRIUM SUBSTION EFFECTShifts 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

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

F

H H

F

HH

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,

Coupling constant of fluorineFluorine 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 J5 is observed in an olefinic system. As shown in Fig.1.16

FLUORINE-FLUORINE COUPLING Homonuclear coupling constants between fluorine atoms are

usually relatively large compared with those between hydrogen atoms,

Coupling between germinal fluorines (2JF-F) also give a large value of 250 to 300Hz

but varying greatly depending on environment of the fluorines. Three bond coupling 3JF-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 3JF-F of trans-vic-difluoroolefin is larger than that of cis-olefin.

The largest 3JF-F are observed between trans-vinyl fluorines where the coupling constant is larger than 35Hz

Table showing coupling J-3

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

HETRONUCLEAR COUPLINGH-F COUPLING

A typical coupling of organofluorine compounds is observed in a geminal coupling (2JH-F) with a geminal hydrogen , being as large as 50Hz.

This coupling can also be observed by proron NMR

HETRONUCLEAR COUPLINGF-C COUPLINGCoupling between fluorine and carbon is

also unique in 13C NMR 1JC-F ranges from 250 to 300 Hz

Generally coupling costants of 1JC-F, 2JC-F, 3JC-F, and 4JC-F are respectively, 16-370, 30-45, 5-25, and 1-5Hz.

This fact is reliable criterion for the determination of fluoroolefin configurations.

Typical coupling costants of nJH-F and nJF-F of fluoroalkanes and alkenes are summarized in Fig.1.18

How to calculate the value of J.A typical example of a trifluromethy

ether is shown in Fig.1.17A trifluromethyl carbon splits into a quartet.

To obtained such well resolved spectra, high concentration of sample and long term accumulation is necessary.

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

Some Example of spin system of fluorine containing compounds

ABC SPIN SYSTEM

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

VIRTUAL COUPLINGThe 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.

Example of 2nd order spectra

MULTIDIMENTIONAL F-19 NMRIn 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.

Secondary alkyl FluoridesSecondary 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

Fluorine NMR of 2-fluropentan

C-13 NMR of 2-fluropentane

Proton NMR of 2-fluropentane

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

F-19 NMR spectra of t-butyl fluoride

COMPOUNDS OF FLUORINE

Elemental fluorine (F2) 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

IONIC SALTS OF FLOURINEA wide range of fluoride complexes may be

prepared from both metal (FeF63-, RuF6

-, PtF62-,

and SnF62-) and non-metal (BF4

-, SiF62-, and

PF6-) fluorides.

While many fluorides are salts, when the metal is in its higher oxidation states (e.g., OsF6 and WF6), the formation of an ionic lattice with the appropriate cation (i.e., Os6+ and W6+ respectively) is energetically unfavorable

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.

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 (CF4). 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.

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.

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.

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. Reichwww.WikipideaOrganic spectroscopy by William Camp