Lanthanide shift reagents in nmr

Lanthanide Shift Reagents in Nuclear Magnetic Resonance Spectroscopy

1. Lanthanide Shift Reagents in Nuclear Magnetic Resonance Spectroscopy K.LOGANATHAN

2. Introduction: As is implied in the name, nuclear magnetic resonance is concerned with the magnetic properties of certain atomic nuclei. Analysis of a NMR spectrum provides information on the number and type of chemical entities in a molecule. However, NMR provides much more information than IR.

3. Why Chemical shift reagents? Because the chemical shifts of several groups of protons are all very similar , which shows their proton resonances in the same area of the spectrum and often peak overlap so extensively that individual peaks and splitting cannot be extracted

4. Chemical shift reagents: Chemical shift reagents are organic complexes of paramagnetic rare earth metals from the lanthanide series. Of the lanthanides, europium is probably the most commonly used metal. Two of its widely used complexes are Tris ( dipavalomethanato ) europium and tris -(6,6,7,7, 8,8,8- heptafluoro-2,2-dimethyl-3,5-octanedionato) europium, frequently abbreviated Eu ( dpm )3 and Eu ( fod )3 , respectively 

5. Chemical shift reagents: When such metal complexes are added to the compound whose spectrum is being determined, there is a profound shifts in the various groups of protons. The direction of the shift (up field or downfield) depends primarily on which metal is being used. Complexes of europium, erbium, thulium and ytterbium shift resonances to lower field, while complexes of cerium, praseodymium, neodymium, samarium, terbium, and holmium generally shift resonances to higher field.

6. Interaction of chemical shift reagents: These lanthanide complexes interact with a relatively basic pair of electrons ( an unshared pair ) which can coordinate with Eu+3. Typically, aldehydes, ketones, alcohols, thiols , ethers and amines all interact.

7. Chemical shift reagents: The amount of shift a given group of protons experiences depends on the distance separating the metal (Eu3+)and that group of protons and the concentration of shift reagent in the solution. Hence it is necessary to include the number of mole equivalents of shift reagents used or its molar concentration when reporting a lanthanide shifted spectrum

8. Chemical shift reagents: E.g:The spectra of 1- hexanol : In the absence of shift reagent, the spectrum shown Only the triplet of the terminal methyl group the triplet of the methylene group next to the hydroxyl are resolved in the spectrum. The protons (aside from O-H) are found together in a broad, unresolved group. With the shift reagent added each of the methylene groups is clearly separated and is resolved into proper multiplet structure.

9.  β- Diketone complexes of some of the lanthanides have interesting and useful properties as NMR shift reagents. Lewis acid complexation of the lanthanide atom with basic sites on molecules results in substantial chemical shift effects consistent with the presence of large shielding and deshielding cones around the lanthanide atom. These chemical shift effects are the result of unpaired electrons in the f shell of the lanthanide. The lanthanides are especially effective because there is relatively little delocalization of the unpaired f electrons onto the substrate (Fermi contact interactions), and so the principal effect is usually the anisotropy of the metal. An optimum combination of minimum line broadening by direct Fermi contact interaction with unpaired spins, and maximum downfield and upfield dipolar shifts is provided by Eu and Pr tris -β- diketone complexes. The first widely used shift reagent was Eu ( dpm ) 3  ( tris (2,2,6,6-tetramethylhepta-3,5-dionato)europium(III)) (Hinckley,  J. Amer. Chem. Soc.   1969 ,  91 , 5160). The fluorinated analog   Eu ( fod ) 3  ( tris (7,7,-dimethyl-1,1,2,2,2,3,3-heptafluoroocta-7,7-dimethyl-4,6-dionato)europium(III ) ( Rondeau , Sievers ,  J. Am. Chem. Soc.   1971 ,  93 , 1522) has better solubility and is a stronger Lewis acid

10. The choice of Europium as the main shift reagent and Praseodymium as the alternate reagent of choice was dictated by their properties. Eu shows shifts in the downfield direction, thus usually accentuating the existing shift differences in  1 H NMR spectra. Pr shifts signals mostly up field, often initially making the spectra more complicated. The shifts for some of the later lanthanides ( Dy and Tm) are much larger, but there are also severe line-broadening effects (with the 2-proton of picoline - 200 Hz for Dy and 65 Hz for Tm, versus ca 5 Hz for Eu and Pr )

11. Observed isotropic shifts for the most shifted resonance of 1-hexanol (H-1), 4-picoline-N-oxide (H-2) and 4-vinylpyridine (H-2), in the presence of Ln( dpm ) 3  at 30 °C in CDCl 3

12. The chemical shift effects of dipolar interactions are reasonably predicted by the usual deshielding or shielding cone, as for anisotropic effects of various functional groups.

13. Evidence that the shift effects are primarily due to the magnetic anisotropy of the metal, and not by direct contact interactions with the unpaired spins is provided by the great similarity (in ppm) of the  1 H and  13 C shifts, as in the example of isoborneol below, with Eu ( dpm ) 3

14. Eu reagents cause mainly downfield shifts, Pr reagents cause upfield shifts. The Eu reagents are much more frequently used, because the shift effects enhance the normal chemical shift differences between protons, whereas Pr reagents initially diminish them. That is, protons near functional groups tend to be downfield of the others, and the Eu shift reagents continue to move them further downfield.

15. The LCS reagents work only on molecules with Lewis basic sites. Sequence of complexing strength varies with the nature of the substrate, but is approximately: NH 2  > OH > R 2 O > R 2 C=O > CO 2 R ≈ R 2 S > R-CN.

16. Shift reagents are not used just to simplify spectra. They are especially valuable for distinguishing geometric isomers, such as cis -trans isomers of double bonds. They have sometimes been used for conformational analysis, but this use is constrained by the likelihood that complexation to the lanthanide could cause changes in the conformation of the molecule. In the examples below, the relatively small Δδ values for the beta- hydrogens and large Δδ values of the alpha-substituents of methacrolein and acrolein point to a predominance of the s-trans conformation, whereas the Δδ values for acrylamide suggest an s- cis conformation. However, these conclusions are strictly valid only for the europium complexes, not for the free compounds .

17. Chiral Shift Reagents . One of the most useful applications of lanthanide shift reagents is in the determination of optical purity by the use of chiral ligands on the lanthanide. Some of the more effective reagents developed are  Eu ( facam ) 3  ( tris (3-trifluoroacetyl-d-camphorato)europium(III) and  Eu ( hfbc ) 3  ( tris (3-heptafluorobutyryl-d-camphorato)europium(III). Often sufficient separation between the R and S enantiomers can be obtained so that the enantiomeric purity can be determined directly by NMR integration.

18. Using Lanthanide Shift Reagents . Here are some considerations in the practical use of LIS reagents. The solvent must be non- complexing and dry: CCl 4 , CDCl 3  and CD 2 Cl 2  are excellent. the solution should be filtered to remove paramagnetic particles.  The usual procedure is to prepare a solution of the shift reagent in CDCl 3 , filter it to remove paramagnetic impurities, and then add small increments of this solution to the solution of the substrate, taking NMR spectra after each addition. In this way it is possible to keep track of the individual signals of the substrate, and determine the Δδ values for all protons of interest.

19. Chemical Shift Reagent These are the agents used to cause shift in the NMR spectra. The amount of shift depends on, Distance between the shift reagent and proton, Concentration of shift reagent. • The advantages of using shift reagents are, Gives spectra which are much easier to interpret, No chemical manipulation of sample is required, More easily obtained. • Paramagnetic materials can cause chemical shift, e.g., Lanthanides. Complexes of Europium, Erbium, Thallium and Ytterbium shift resonance to lower field. • Complexes of Cerium, Neodymium and Terbium shift resonance to higher field.

20. Advantages of using chemical shift reagents: Gives spectra which are much easier to interpret. No chemical manipulation of the sample is required with the use of shift reagents. more easily obtained.

21. Disadvantage: Shift reagents cause a small amount of line broadening At high shift reagent concentrations this problem becomes serious, but at most useful concentrations the amount of broadening is tolerable 

22. Conclusion: Thus the chemical shift reagents and solvent induced shifts have their application in resolving the NMR spectra of complex structures by inducing shifts with respect to reference compound. Thus useful in interpretation of structures of complex organic compounds.