Lanthanide Shift Reagents in Nuclear Magnetic Resonance Spectroscopy By B. C. Mayo DEPARTMENT OF CHEMISTRY, THE POLYTECHNIC OF NORTH LONDON, HOLLOWAY, LONDON N7 8DB 1 Introduction Nuclear magnetic resonance (n.m.r.) spectroscopy is a most valuable technique for structural investigations of complex organic molecules. However, owing to the relatively low sensitivity of proton chemical shifts to changes in the chemical and stereochemical environment, the application of n.m.r. spectroscopy has been severely restricted. Such terms as the ‘methylene, methine envelope’ used fre- quently in connection with the proton n.m.r. spectra of steroids and terpenes illustrate this frequent overlapping of resonance of non-equivalent protons. Shift reagents are used in n.m.r.spectroscopy to reduce the equivalence of nuclei by altering their magnetic environment, and are of two types: aromatic solvents such as benzene or pyridine, and paramagnetic metal complexes. The latter function by co-ordinating to suitable donor atoms in the compound under study, thereby expanding their co-ordination shell and forming a new complex in solution. Apart from effects due to shielding by bonding electrons, the chemical shifts are altered by the paramagnetic metal ion by a transfer of electron spin density, via covalent bond formation, from the metal ion to the associated nuclei (contact shift), or by magnetic effects of the unpaired electron magnetic moment (pseudocontact shift). First-row transition-metal complexes can be used as shift reagents and operate by both contact and pseudocontact mechanisms, although the former predominates owing to the covalent character of these compounds.Unfortunately, these shift reagents exhibit an adverse effect on the resolution of the n.m.r. spectra by causing severe line-broadening. In 1969 Hinckleyl initiated a major advance in this field by introducing the use of a lanthanide-metal complex as a shift reagent and since then it has become established that lanthanide complexes produce far less linewidth broadening and give shifts which are caused virtually exclusively by the pseudocontact mechanism. The complexes found most useful are lanthanide acetylacetonate derivatives, some of which are fluorinated and exhibit greater shifting power. The most common practice is to successively add known amounts of the lanthanide shift reagent (LSR)to the compound under study (substrate) and record the n.m.r.spectrum after each addition. The chemical shift of each proton in the substrate alters, to a greater or lesser degree, with each addition of shift C.C. Hinckley, J. Amer. Chem. SOC.,1969, 91, 5160. Lanthanide Shvt Reagents in Nuclear Magnetic Resonance Spectroscopy reagent and the extent of this lanthanide induced shift (LIS) is measured. A plot of the LIS against the ratio of LSR: substrate is a straight line at low values of this ratio. The slope of this line is characteristic of the compound under study. Apart from spectral clarification, the factors determining pseudocontact shift allow relative distances within the complex to be determined, permitting studies of the stereochemistry of the substrate under examination.The application of LSRs in n.m.r. spectroscopy has permitted the solution of a large number of structural problems and one example of this occurs in the use of chiral lanthanide shift reagents for estimating the composition of mixtures of enantiomers. 2 Substrate-Lanthanide Shift Reagent Interaction The lanthanide shift reagent consists of a six-co-ordinate metal complex which readily expands its co-ordination in solution to accept further ligand~.~~~ The substrate co-ordinates to the LSR by virtue of the requirement that it contains heteroatoms which exhibit some degree of Lewis basicity.Addition of the LSR to a solution of the substrate in a normal n.m.r. solvent leads to the formation of an equilibrium mixture, as shown in equations (1) and (2) K L + s + [LS] KS ES] + s + [LS,] where L and S are the concentrations of the LSR and substrate, respectively, and [LS] the concentration of the complex formed in solution; the ratios of these species depends on K and K2,the binding constants. The latter binding constant K2 is usually assumed negligible (see later), i.e. a 1 : 1 complex is thought to be formed. Owing to the magnetic interactions with the metal ion (Section 3) in the complexed substrate [LS], the n.m.r. positions of associated nuclei in the substrate differ from those in the uncomplexed state. The equilibrium in solution between these species is rapid on the n.m.r.timescale: so that only a single average signal is recorded for each nucleus in the different environments.* This does not mean that the whole spectrum is merely displaced since factors such as the distances of the nuclei from the metal ion cause a differential expansion of the spectrum. Consequently, the foremost use of LSR is in effectively increasing the resolution, in many cases producing first-order spectra. An expression can be derived for the lanthanide induced shift (LIS), denoted by ad,of the nuclei of the substrate before and after addition of the LSR? * Slow chemical exchange is reported5 to occur at -8OOC with a solution of dimethylsulphoxide and the LSR tris-(1,1,1,2,2,3,3-heptafluoro-7,7-dimethyloctane-4,6-dionato)-europium(II1) [Eu(fod),] in deuteriomethylene chloride.R. G. Charles and R. C. Ohlmann, J. Inorg. Nuclear Chem., 1965, 27, 119. J. E.Schwartzberg, D. R. Gere, R. E. Severs, and K. J. Eisentraut, Inorg. Chem., 1969, 6, 1933. * F.A.Hart, J. E. Newbery, and D. Shaw, Nature, 1967,216,261. D. F.Evans and M. Wyatt, J.C.S. Chem. Comm., 1972, 312. D.R.Eaton, Canud.J. Chem., 1969,47,2645. K[LS] AB (3)6A = 1 + K&S] where & is the LIS of the complexed substrate [LS], i.e. the bound chemical shift, and K the equilibrium constant of expression (1). At low concentration of LSR, a linear concentration dependence of LIS is observed, which is used to control the magnitude of the shift.For the purpose of obtaining shift parameters which are independent of concentration of LSR, Demarco et al. have proposed7 a technique used by many whereby the concentration-shift plots are extrapolated to concentrations where the molar ratio of LSR to substrate is 1 : 1. These LISs at such high concentrations can often not be checked directly owing to the limited solubility of the LSR. The chemical shift of the uncom- plexed substrate can be obtained by a graphical method whereby the chemical shift of each nucleus is plotted against the concentration of LSR and the plot extrapolated to zero concentration of LSR,8s1*-16 a technique useful when individual resonances are part of a complex, multiple adsorption band. How- ever, deviations between extrapolated and observed chemical shifts are cited' even at low concentrations of LSR.17 By studying expression (2), it is apparent that as the concentration of LSR is increased, the deviation from linearity should also increase, as shown in Figure 1.Such curves cannot be produced using the dipivalomethanato LSR So is constant) Figure 1 Relationship of LIS (84)with the concentration of added LSR [L,] and added substrate [So] 'P. V. Demarco, T. K. Elzey, R. B. Lewis, and E. Wenkert, J. Amer. Chem. SOC.,1970,92, 5743. a K. K. Anderson and J. J. Uebel, Tetrahedron Letters, 1970, 5253. H. Hart, and G. M. Love, Tetrahedron Letters, 1971, 625. loC. Beaute, Z. W. Wolkowski, and N. Thoai, Tetrahedron Letters, 1971, 817. l1 Z. W.Wolkowski, Tetrahedron Letters, 1971, 821. Z. W. Wolkowski, Tetrahedron Letters, 1971, 825. l3 M. Witanowski, L. Stefaniak, H. Januszewski, and Z. W. Wolkowski, Tetrahedron Letters, 1971, 1653. l4 A. F. Cockerill and D. M. Rackham, Tetrahedron Letters, 1970, 5149. l6 K. C. Yee and W. G. Bentrude, Tetrahedron Letters, 1971,2775. l6 D. R. Crump, J. K. M. Sanders, and D. H. Williams, Tetrahedron Letters, 1970, 4949. l7 J. Goodisman and R. S. Matthews, J.C.S. Chem. Comm., 1972, 127. Lanthanide Shift Reagents in Nuclear Magnetic Resonance Spectroscopy owing to its limited solubility, but they are produced experimentally by: (a) using Eu(N0,),,6D20 in an aqueous solution in a study of 31Pn.m.r. spectra;l* and (b)using Eu(fod), or Pr(fod),, which are fluorinated LSRs having higher solubilitie~.~~ It should be noted that the extrapolation of the linear portions of the curve does not coincide with the line drawn at a 1 : 1 molar ratio.The quantity of LSR needed to reach the flat part of the curve in Figure 1 depends on the Lewis basicity of the substrate, and for weakly basic substrates up to two molar equivalents of the fluorinated LSR are necessary.19 However, when used in a large excess these LSRs give LISs approaching that of the bound substrate. Deviations from the curves expected from expression (3) occur at high con- centrations of LSR, which have been explained by a combination of medium and associated effects.14 The praseodymium complexes are reported to exist as dimers in the solid state,20 varying from 7 to 8 co-ordinate and the consequences of polyfunctional substrates21*22 have yet to be studied in detail.The shift parameters derived by these approaches are somewhat dependent on the initial substrate concentration and an alternative approach has been advocated which provides a method for obtaining quite accurate bound chemical shifts, and also a value for K the binding constant. From the LIS (ad),the uncomplexed chemical shift, and the bound chemical shift dg, the following is derived : From this expression a useful relationship is derived relating K and d~ so(l-z)='T-(;+Lo)SA L~ *& Armitage and co-wo~kers~~ use this expression with an assumption that 6d/& is negligible at low concentration of LSR.Hence: so = Lo AB--($+Lo) 6A In a plot of Soagainst 1/6d the slope equals Lo -d~and the intercept equals 1/K + Lo. Therefore, from the slope, the 'first reliable values' of the bound chemical shift dg are determined. These and other show previous results' to be much too low and provide a more accurate basis for comparison of substrates. As seen from expressions (2) and (4), dilution effects alter the LIS, J. K. M. Sanders and D. H. Williams, Tetrahedron Letters, 1971, 2813. lD R. E. Rondeau and R. E. Sievers, J. Amer. Chem. SOC.,1971, 93, 1522. C. S. Erasmus and J. C. A. Boeyens, Acta Cryst., 1970, B26,1843. p1 H. van Brederode and W. G. B. Huysmans, Tetrahedron Letters, 1971, 1695. 2a I. Fleming, S. W. Hanson, and J. K. M.Sanders, Tetrahedron Letters, 1971, 3733. a3 I. Armitage, G. Dunsmore, L. D. Hall, and A. G. Marshall, Chem. Comm., 1971, 1281. 24 J. Bouquant and J. Chuche, Tetrahedron Letters, 1972.2337. Mayo whereas the bound chemical shift is independent of concentration. The equi- librium constant K can be derived from the intercept, but the values obtained will be upset by the extent of dimerization of the LSR. A twofold advantage exists in measurements at low concentrations of the LSR (a factor favouring the fluorinated LSRs which have greater ‘shifting power’) since (i) this minimizes the possibility of dimerization of the LSR and (ii) that the bulk susceptibility changes caused by the metal ion are minimal. Various papers report values of the equilibrium constants (see Table l), obtained in some cases from slightly different approaches to that described.It is interesting to note that greater values of the equilibrium constant occur with fluorinated as opposed to non- fluorinated LSRs. This phenomenon is the cause of the larger LIS observed Table 1 Equilibrium constants of LSRs and various substrates Substrate LSR Equilibrium Ref. constant (K) Cholestanol Eu(dpm)3 61 24 Neopen t an01 Eu(dpm)3 6* 25 Pyridine Eu(dpm)3 100 26 n-Prop ylamine Wdpm)3 12* 25 Nucleoside phosphates EuIII 4 to 17 27, 28 Neopentanol Eu(fod) loo* 25 t-Butyl alcohol Eu(fod), 280 29 Isopropyl alcohol Eu(f0d)3 97* 30 Tetrahydro furan Eu(fod), 57* 30 But an-Zone Eu(fod)3 32* 30 Isopropeny1 acetate Eu(fod), 27* 30 Ally1 acetate Eu(fod) 26* 30 n-Propylamine Eu(f0d)3 loo* 25 * Values estimated from the technique reported by Armitage and co-~orkers.~~ for the fluorinated reagents and not the value of the bound chemical shift, which is smaller for the dipivalomethanato reagent^.^^^^^ Optically active LSRs, which are used to separate resonances of enanti~mers,~~~~~are thought to distinguish these isomers by forming diastereoisomeric complexes with the LSR which have different binding constants.I. Armitage, G. Dunsmore, L. D. Hall, and A. G. Marshall, Chem. and Ind., 1972, 79. 26 H. Huber and J. Sellig, Helv. Chim. Acta, 1972, 55, 135. 27 C. D. Barry, A. C. T. North, J. A. Glasel, R. J. P. Williams, and A. V. Xavier, Nature, 1971,232,236.as C. D. Barry, A. C. T. North, J. A. Glasel, R. J. P. Williams, and A. V. Xavier, Biochem. Biophys. Acta, 1972, 262, 101. a0 K. Roth, M. Grosse, and D. Rewicki, Tetrahedron Letters, 1972, 435. 30 D. R. Kelsey, J. Amer. Chem. SOC.,1972, 94, 1764. 31 B. L. Shapiro, M. D. Johnston, jun., A. D. Godwin, T. W. Proulx, and M. J. Shapiro,Tetrahedron Letters, 1972, 3233. 38 G. M. Whitesides and D. W. Lewis,J. Amer. Chem. SOC.,1970,92,6979; 1971,93, 5914. 33 H. L. Goering, J. N. Eckenberry, and G. S. Koermer, J. Amer. Chem. Soc., 1971,93, 5913. Lantkanide Shift Reagents in Nuclear Magnetic Resonance Spectroscopy One difficulty in determining the intrinsic LIS parameters, namely the bound chemical shift and the binding constant, is the interference by other substrates and impurities in the solution being examined.A possible method of overcoming this difficulty3* employs a reference substrate having a known bound chemical shift and binding constant. From an expression similar to equation (3) the following is derived: where the subscripts refer to the parameters of the investigated substrate 0) 1 1and the reference substrate (m). In a plot of a -against -, the slope and in- aAm tercept should give AB and K of the investigated substrate (i.e. AB~and Kj). Without the knowledge of d~~and Km for the reference substrate, the slope and intercepts are nevertheless used to characterize the compounds examined. Values of these parameters are not reported, but this approach is illustrated by an analysis of a mixture of four compounds.A similar approach is also referred to,86 which is extended to a mixture of (x) substrates. An internal reference signal of examined substrates can also be used to analyse and compare a solution containing two or more substrates.ao For two protons (m and j) in the same substrate: By plotting adj against aAm, slopes which are independent of substrate or reagent concentrations are obtained, which are applied to the analysis of mix-tures of substrates which contain the same internal standard protons, e.g. acetoxy or methoxy. Results showed that for a similar geometric arrangement in a series of compounds, the slopes of such plots are characteristic. Armitage and co-workers have developed a schemeea for evaluating the stoicheiometry of the complex formed in solution.Thus, modifying equation (1) to: KL + nS + &Snl (9) where n is the number of moles of S that combine with one mole of L, then: log S = (l/n) log [LS/L] -(l/n) log K Combination with expression (3) permits evaluation of S, L,and PSI, which by plotting a graph of log S against log [LS/L] gives a slope equal to l/n. Values of unity are calculated with Eu(dpm), for both n-propylamine and neopentanol, although this method is invalid when the binding constant is large.ea Other ** D. E. Williams, TetrahedronLetters, 1972, 1345. J. K. Sanders and D. H. Williams, J.C.S. Chem. Comm., 1972,436. investigations have been made;zB one in particular concludes that pyridine and Eu(dpm), form a 1 :1 complex,2s although the possibility of n = 2 is seriously considered as the pyridine di-adduct, a solid isolable compound, is known,' and dimethyl sulphoxide is thought to form a di-adduct at low temperatures in deuteriochloroform.6 The lowering of the LIS with different solvents are reported;36 one explanation attributes this to competitive inhibition of weakly complexed substrates, particu- larly with donor solvents such as acetonitrile, pyridine, acetone, and dimethyl sulphoxide. Approximate orders of magnitude of the decrease in LIS are 10,20, and 30 % for deuterio-benzene, -chloroform, and -acetonitrile, respectively, when compared with carbon tetrachloride or carbon disulphide using tris(dipiva1o- methanato)europium(m), Eu(dpm),, on alcohols and amines.,* Therefore, the use of donor competing solvents should be avoided when using the tris-p- diketonate LSR, although alternative reagents are available for use in more highly polar solvents (see Section 7),l8p3' and one has been used in aqueous Finally, as the magnitude of LIS is geometry dependent (see Section 5) and lanthanide complexes are predominantly electrostatic, the solvation spheres can influence this geometry so that different solvents may alter shifts.The presence of other donor substrates as impurities can reduce the effective concentration of the LSR39if they form stronger co-ordination complexes than the substrate under study. The presence of water inhibits the LIS in this ~ay,lO,~O as shown by the 60% reduction in the LIS of cholesterol hydrate protons when compared with the anhydrous form,ls owing to competitive co-ordination by water.The presence of moisture in some LSRs can easily be observed by a change in c~lour,~~ e.g. Pr(dpm), and Eu(dpm), are pale green and pale yellow when anhydrous, but yellow and white, respectively, when hydrated. It appears that extremely small amounts of impurity in the LSR, insufficient to cause a change of melting point, nevertheless cause deviations in the LIS, e.g. 30% difference in the LIS of two batches of LSR.42It has been proposed that a standard sub- strate for measurement of the LIS with the LSR be adopted, which could provide a better criterion for measuring purity than melting point.As the LSR is only a weak Lewis acid, steric hindrance reduces the LIS either because of a smaller value of the equilibrium constant or a greater nucleus- cation distance or both. Steroidal acetals, thioacetals, and methoxy-derivatives have been shown3' to co-ordinate selectively to LSRs according to the degree of steric hindrance, e.g. a 3/?-methoxy-steroid co-ordinates to a greater extent than the more hindered 3a-methoxy-steroid. A further report illustrates the effect of the steric hindrance42 in a study of substituted anilines, which shows that a *IJ. K. M. Sanders and D. H. Williams, J. Amer. Chem. SOC.,1971, 93, 641. *' J. E. Hertz, V. M. Rodriquez, and P. Joseph-Nathan, Tetrahedron Letters, 1971, 2949. a* F. A. Hart, G. P.Moss, and M. L. Staniforth, Tetrahedron Letters, 1971, 3389. 39 L. Tomic, Z. Majerski, M. Tomic, and D. E. Sunko, Chem. Comm., 1971, 719. 40 I. Armitage and L. D. Hall, Canad.J. Chem., 1971,49,2770. 41 D. R. Crump, J. K. M. Sanders, and D. H. Williams, Tetruhedron Letters, 1970,4419. 4a L. Ernst and A. Mannschreck, Tetrahedron Letters, 1971, 3023. Lanthanide Shvt Reagents in Nuclear Magnetic Resonance Spectroscopy linear correlation of basicity in terms of pKa with proton LIS is upset when steric hindrance is present, such as with ortho-and N-substitution. In conclusion, the quoting and comparison of LIS or bound chemical shift with different substrates should be made with caution; as seen later, other parameters such as the geometry of the complexed substrate and the particular LSR affect the magnitude of the LIS.A number of comparisons of co-ordinating ability of different substrates, as indicated by the LIS, are discussed in Section 8. 3 Shift Mechanism In the lanthanide-substrate complex, interaction between the paramagnetic metal ion and the nuclei of the substrate causes changes in the chemical shift of the nuclei. Two types of interaction between metal cation and ligand have been proposed, contact and pseudocontact interactions, and the resulting shifts referred to as the contact and pseudocontact shifts. Pseudocontact shift43 is caused by a dipolar interaction between the nucleus and the electron spin magnetization of the paramagnetic metal ion. Two theories have been developed giving expressions for the magnitude of the pseudocontact shift, both of which can be expressed as follows: 6A = x(3 cos 281 -1) ri3 where Oi is the angle between (a) the distance vector, Ti, joining the metal cation to the particular nucleus, i, in the complexed substrate, and (b)the crystal field axis of the complexed substrate, often assumed as the line joining the metal atom to the lone-pair-bearing atom.Now -ps(s + 1)x= 27 kT f(g) from the theory by McConnell and and from the more recent theory of Bleany:6 where p is the Bohr magneton; S the electron spin; k is Boltzmann’s constant; A,0(r2) the crystal field coefficient; and g the g tensors. The value of x is different for each complex studied as it involves the g tensor, which is split into g1and g,,,the tensors perpendicular and parallel to the molecular axis. According to McConnell and Robertson’s theory, the pseudocontact shift arises from a failure of the dipolar interaction to average zero owing to the metal possessing an anisotropic g tensor.However, Bleany 43 P. J. McCarthy, in ‘Spectroscopy and Structure of Metal Chelate Compounds,’ ed. K. Nakamoto and P. J. McCarthy, Wiley, New York, 1968, p. 346. 44 H. M. McConnell and R. E. Robertson,J. Chem. Phys., 1958, 29, 1361. 46 B. Bleaney, J. Magn. Resonance, submitted for publication. Mayo proposes46 a theory in which x encompasses a different set of parameters Rather than attributing pseudocontact shift to the anisotropic g factors, he suggests that the dipolar shift is caused by anisotropy in the susceptibility which occurs in less than cubic geometries.One difference arising from this approach is the temperature dependance, which is P2(except in the cases of Eu3+and Sm3+), as opposed to T-l expected from McConnell and Robertson’s theory. For europium and samarium, effects of the excited states give a more complex temperature dependence, approximating to T-l. Various temperature relation- ships have been reported which vary from T-* for Yb(d~m)~~~ to T-l using Pr(d~m),.~@The shift 6d is also dependent on the distance ri of the nuclei from the metal cation through space and not via the covalent bonds of the molecules, a distinction important in studying the consequences of the various parameters involving the shifts.Furthermore, the shift is dependent on the geometric term (3 cos2 8i -l), a factor neglected in many studies. The expressions (11) and (12), derived for axially symmetric complexes, may not necessarily be applicable to the wide range of complexes of lower symmetries, although it is reported as adequate for at least systems of C2and C2vsymmetry.43 The crystal structures of Ho(dpm),,2(4-pi~oline)~~and E~(dpm),,2(pyridine)~* are not axially sym- metric with respect to the adduct ligands, but possibly in solution an approach to axiality is achieved by rapid ligand exchange. Contact shiftsa3 occur by direct electron-nucleus magnetic interaction as distinct from the classical dipolar interactions.Consequently, shifts occur by movement of unpaired electron spin density from the metal cation to the ligand by covalent bond formation. Hence, this mechanism operates through the metal cation co-ordinating bond and so depends on the degree of covalency in this bond. This interaction is independent of the 3 cos2& -1 term and falls off rapidly with increasing distance except in conjugated systems, which facilitate delocalization of unpaired electrons. The distinction between contact and pseudocontact shift is important for a better understanding of the factors affecting the LIS. The assumption that lanthanides interact by a pseudocontact mechanism is based on their high electropositive character and the shielding of unpaired electrons of thef0rbitals.4~ As the lanthanides form complexes by electrostatic interaction, this precludes the operation of a contact mechanism of the same order of magnitude as those found with first-row transition-block metal complexes,5o but with even as little as 1% covalency contact shift should be Therefore, even with lanthanides, a small degree of contact interaction is possible51 and is seen in deviations from the expression (1l), particularly for protons attached to the 46 C.Beaute, S. Cornuel, D. Lelandais, N. Thoai, and Z. W. Wolkowski, Tetrahedron Letters, 1972, 1099. 47 W. De Horrocks, jun., K. P. Sipe, and J. R. Luber, J. Amer. Chem. SOC.,1971, 93, 5258. 48 R. E. Cramer and K. Seff, J.C.S. Chem. Comm., 1972, 400. 49 F. A. Cotton and G. Wilkinson, ‘Advanced Inorganic Chemistry’, Wiley, New York, 2nd edn. D.R. Eaton, J. Amer. Chem. SOC.,1965,87, 3097. 81 E. R. Birnbaum and T. Moeller, J. Amer. Chem. SOC.,1969, 91, 7274. Lanthanide Sh$t Reagents in Nuclear Magnetic Resonance Spectroscopy carbons nearest the lone-pair-bearing atoms.sa It has been suggested that contact shift is significant for aromatic aminesySs where the presence of conjugation may increase the electron delocalization, thus increasing the degree of contact con- tribution,' but this view is contradicted in a study of quinoline and isoquino- line.s4 Pseudocontact and contact interactions are distinguished in a graphical analysissa using the log of expression (11) [see later, expression (15)], and contact shift is only reported to occur on the protons vicinal to the lone-pair-bearing atom.A similar deviation from an otherwise linear plot of log ri against log 6d is reported by Dernarc~,~who attributes this to the presence of contact shift. The relative magnitude of the g tensors correlates with the direction of shift, as indicated in electron paramagnetic resonance experiments, which show good agreement of the relative magnitudes of gl and gllwith those observed in the shielding or deshielding of the different lanthanides.s5 However, magnetic susceptibility anisotropy data correlate qualitatively with the observed signs of LISs,g6 and Bleany's theory, which excludes the anisotropic g tensor, still calculates shift data having excellent agreement with observed LISs by use of an expression for pseudocontact shift.67 A detailed analysis of trans-4-t-butylcyclo- hexanol and adamantan-2-01 achieves such good correlation using only the pseudocontact term that contact shift is excluded.s8 However, one investigation of such correlations concludes that no experimental results confirm (or disprove), the pseudocontact expression, owing to the wide deviation in the experimental results dealt with.17 The similarity of x in expression (11) for lH and 13Cn.m.r.spectra of borneolSB and the similarity of LIS ratios of aniline and 2,4,6-tri- fluoroaniline in the lH and lSF n.m.r.60 both indicate that and lSFnuclei are subject to predominaatly a pseudocontact interaction. The 31P n.m.r. results of phosphates and phosphonates indicate a significant contact interaction operating18 and the 14Nn.m.r.studies on mine-M(dpm), systems (M is ytter-bium or europium) indicate a predominance of contact intera~ti0n.l~ Nuclei with lone pair electrons P4N, lSN,and *lP)may be expected to interact pre- dominantly by a contact mechanism. 4 Distance-Shift Relationships Assuming the interaction of the lanthanide complexes is predominantly pseudo- contact, the magnitude of the LIS of the ith nucleus is inversely proportional to the cube of the average distance from the metal ion [expression (1l)]. In fact, this distance parameter is often assumed to be the predominant term as the I* C.C. Hinckley, M. R. Klotz, and F. Patil, J.Amer. Chem. Soc., 1971,93,2417.F. A. Hart, J. E. Newbery, and D. Shaw, Chem. Comm., 1967, 45. I4H. Huber and C. Pascaul, Helv. Chim. Acta, 1971,54,913. 55 G. A. Hutchinson and E. Wong, J. Chem. Phys., 1958, 29, 754. 50 W. De W. Horrocks,jun., and J. P. Sipe, J. Amer. Chem. Soc., 1971, 93, 6800. 67 B. Bleaney, C. M. Dobson, B. A. Levine, R. B. Martin, R. J. P. Williams, and A. V. Xavier, J.C.S. Chem. Cornm., 1972,791. S. Farid, A. Ateya, and M. Maggio, Chem. Comm., 1971, 1285. J. Briggs, F. A. Hart, G. P. Moss, and E. W. Randall, Chem. Comm., 1971, 364. 6~ Z. W. Wolkowski, C.Beaute, and R.Jantzen, J.C.S. Chem. Comm., 1972, 619. Mayo remaining factors, namely the angle term, are regarded as constant. Thus expression (11) is simplified to: SA = b/ra (14) where b is assumed as a constant.The distance-shift relationship is clearly illustrated in the proton n.m.r. spectrum of n-heptanol. As seen in Figure 2,61addition of Eu(dpm)s renders 20 15 10 5 0 PPm Figure 2 Proton (60MHZ)n.m.r. spectra of n-heptanol;(a) 0.3 mol I-' in CDCls; (b) with a molar ratio of 0.78 of Eu (dpm),/n-heptanol (Reproduced with permission from Analyt. Chem., 1971, 43, 1599.) the spectrum amenable to first-order analysis, shifting the resonance nearest the hydroxy-group furthest; on increasing distance the LIS is less. Substantial shifts for protons up to 13a from the site of co-ordination have been measured,l smaller shifts (O.lp.p.m.) for distances up to 27A are also reported.' HincMey reported1 the f%st use of a LSR in distance-shift relationships with the steroid cholesterol.The distances of each nucleus from the co-ordinated metal ion in the complex are estimated from Dreiding models. The inverse cube of this distance term is plotted against the values of the LIS for each nucleus and frequently produces a linear response, substantiating this aspect of the relation- ship for pseudocontact shifts. Consequently this approach enables relative distances of the nuclei from the metal ion to be estimated, which can contribute to structural information. This can be applied by altering the possible structural models of the molecule to obtain the best correlation of.the distance-shift data. The presence of more than one co-ordination site in the organic substrate complicates the interpretativn of the measured shifts since these represent sums of the interactions with the LSR at each site,6a although some groups form stronger co-ordination complexes than others.At each co-ordination site, equi- librium constants, and hence pseudocontacts, contribution differ and so result in D.L.Rabenstein, Analyt. Chern., 1971, 43, 1599. 6% A. Ius, G. Vecchio, and G. Carrea, Tetrahedron Letters, 1972, 1543. Lanthanide Sh ft Reagents in Nuclear Magnetic Resonance Spectroscopy different proportionality constants in expression (14). These complications make straightforward plots of the LIS against the inverse cube of the distance in- effective aids in analysis, but fortunately the log of this expression renders an important simplification: IogSd = -3Iogri + logc (15) A plot of log ad against log ri should be linear irrespective of c, a constant.By assuming expression (15) correct, a graphical analysis by this approach allows a distinction between the relative contributions of co-ordination at each site of a bifunctional steroid.62 This approach is only useful when co-ordination sites are far apart so that some protons are only affected by co-ordination at one site. The slope of -3 would be expected but it is not in fact obtained with these graphs, which is attributed to errors in the distance measurement or geometric factors.' One generalized interpretation suggests that molecules which produce slopes greater than three are flexible, but those of slopes less than three are rigid.17 In many cases good linear relationships between the LIS and the inverse square of the distance parameter have been fo~nd.~*~~~-~~ However, an analysis of these different values of the power of the distance termes concludes that too little is known about the detailed nature of the geometry to allow definite structural conclusions to be drawn and crude approximations may not reflect the complex nature of the interactions involved.Deviations from the distance- shift correlations may be due to over-simplification with respect to the shift mechanism or the geometric terms. The angle term is frequently considered reasonably constant in many substrates and if free rotation occurred about the metal ion-heteroatom bond of the labile complexYs7 the angle term may be averaged out.Measurements of the broadening of resonances, caused by the metal ion increasing the transverse relaxation rate (T2),can also lead to estimates of relative distances within the complexed substrate. A simplified form of an expressionesis used to relate the half bandwidth (hi,,) and the inverse sixth power of the distance term (ri) of the ith nucleus, where C is a constant for the particular complex being investigated. This approach was first used with two transition-metal complexes,eB and has since been applied to LSRs,27~28~70in particular those lanthanides which produce appreciable broadening, e.g. gadolinium(Ir1). 63 M. R. Willcott, J. F. M. Oth, J. Thio, G. Plinke, and G. Schroder, Tetrahedron Letters, 1971, 1579.64 L. W. Morgan and M. C. Bourlas, Tetrahedron Letters, 1972, 2631. 65 A. F. Cockerill and D. M. Rackham, Tetrahedron Letters, 1970, 5153. 66 A. J. Rafalski, J. Barciszewski, and M. Wiewiorowski, Tetrahedron Letters, 1971, 2829. 67 R. F. Fraser and I. Y. Winfield, Chem. Comm., 1970, 1471. 6* H. Sternlicht, J. Chem. Phys., 1965, 42, 2250. 6s E. E. Zaev, V. K. Voronov, M. S. Shvartsberh, S. F. Vasilevesky, Yu. N. Molin, and I. L. Kotljarevsky, Tetrahedron Letters, 1968, 617. 7O J. Reuben and J. S. Leigh, jun., J. Amer. Chem. SOC.,1972, 94, 2789. Mayo 5 Consequences of Geometric Factors Deviations from the distance-shift correlations due to neglect of the geo- metric term as in expression (14) are common and by including the term (3~0s' 8i -l), improved correlations are obtained.In order to measure the angle 8i for each nucleus, the position of the metal ion with respect to the substrate needs to be known. This problem has been avoided by some workers by measuring distances of nuclei from either the heter~atom~~p~~ or the perimeter of the lone pair on this atom.14 These results may be sufficient for the cases in hand, but do not contribute to a more complete understanding of the shift mechanism. The orientation of this lone-pair is more predictable in cases of restricted rotation in the carbon-heteroatom bond, e.g. carbonyl groups, but is less predictable for systems which rotate freely, e.g. hydroxy-groups. Table 2 summarizes the positions postulated for the metal ion with respect to the substrate where some estimates are made by comparison with analogous com- plexes studied by X-ray crystallography, others by modifying values of the metal position and evaluating the most linear response to expression (11).The most successful attempts to locate the metal atom, firstly by Briggs, Hart, and and later by ~ther~,~~@+~~~~~ were achieved by varying the metal-atom position and computing the correlation with minimum deviations from expressions (11) and (16) using the LIS and broadening parameters. The results show that for an accurate positioning of the metal ion a set of calculations needs to be worked out for each molecule studied. This approach may be used to calculate the ratio of conformers by computing the percentage contribution of each conformer required to obtain the best correlation.How- ever, a possible disadvantage of this technique is that the ratio of conformers may be altered on co-ordinating to the LSR. A 13Cn.m.r. study of some phos- phorinans does show that the ratio of conformers is altered by the quantity of LSR Conversely, other report~~lg~~ indicate very little change in the ratio of conformers when complexed to the LSR, but presumably this will depend on the energy barrier between the conformers concerned. In certain cases the angle 8i may be sufficiently large that the direction of 'normal shift' is reversed. A plot of the 3cos2 Bi -1 term against angle, as in Figure 3, shows how the LIS can be varied from positive to negative as the angle is altered.Thus with Eu(dpm), shielding as opposed to the 'normal' de- shielding, shifts are produced when the angle 81 is between 54.7 and 125.3 O, but in most cases the angle appears to be below 54.7". Many reports of europium upfield shifts are rep~rted,~~~~~~~~~~~-~~ most of which enable direct interpretation 71 J. Briggs, F. A. Hart, and G. P. Moss, Chem. Comm.,1970, 1506. M.R. Willcott, tert., R. Lankinski, and R. E. Davis, J. Amer. Chem. SOC.,1972, 94, 1742. 'Is M. Ochiai, E. Mizuta, 0. Aki, A. Morimoto, and T. Okada, Tetrahedron Letters, 1972, 3245. W. G. Bentrude, H. W. Tan, and K. C. Yee, J. Amer. Chem. SOC.,1972,94, 3264. 76 S. G. Levine and R. E. Hicks, Tetrahedron Letters, 1971, 31 1. 76 B.L. Shapiro, J. R.Hlubucek, and G. R.Sullivan,J. Amer. Chem. SOC.,1971, 93, 3281. 77 T. H. Siddall, Chem. Comm., 1971,452. 76 P. H. Mazzocchi, H. J. Tamburin, and G. R. Miller, Tetrahedron Letters, 1971, 1819. 7D S. B. Tjan and F. R.Visser, Tetrahedron Letters, 1971, 2833. '0 M.Kishi, K.Tori, and T. Komeno, Tetraheah Letters, 1971, 3525. o\ h, ETable 2 Postulated positions of the lanthanide ion in the complexed substrate ASubstrate Functional Distance Angle MXC Lanthanide Method of group (heteroatom Jdegrew ion assessing to rnetal)/A kiAdamant-1- or -2-01 OH Radii of 115 Eu Estimate 81 8 op0 plus Eu s4-t -Bu t ylcyclo hexanol OH 2.3 139 Eu Computed optimum 58 c Adamant-2-01 OH 3.0 128 Eu Computed optimum 58 3 Borneo1 OH 3.O 126 Pr Computed optimum 71 5 General OH 2.7-0.4 --Computed optimum 58 % Cyclic ketones c=o 2.8 109 Eu Analogy with RCO-HgCIB 82 8 Halogenovinyl ketones CHO 3.O 150 Yb Best linear fit 83 % Indanone and fluorenone c=o 1.5 120 Yb Best linear fit 11 8itSulphoxides s=o 3.5 I Eu Analogy with La(edta) 67 2.Amines NH* 3.O -Yb Best linear fit 10 h Analogous complexes of kno wn stereochemistry 2 Cyclononanone-HgC1a 2.8 Hg -84 s8Yb(acac),,H zO 2.34 Yb X-Ray crystallography 85 8La(edta) 2.55 La X-Ray crystallography 86 8Eu(dPm)3,2PY 2.65 Eu X-Ray crystallography 48 s *l G. H. Wahl, jun., and M. R. Peterson, jun., Chern. Cumrn., 1970, 1167. sP. Kristiansen and T. Ledaal, Tetrahedron Letters, 1971, 2817. 8a* C.Beaute, Z. W. Wolkowski, J. P. Merda, and D. Lelandais, Tetrahedron Letters, 1971, 2473. 20’ S. Dahl and P. Groth, unpublished results. J. A. Cunningham, D. E. Sands, W. F. Wagner, and M. F. Richardson, Znorg. Chern., 1969, 8, 22. J. L. Hoard, B. Lee, and M. D. Lind, J. Arner. Chern. Suc., 1965,87, 1612. Mayo m Figure 3 The variation of 3 COS20i -1 with the angle 8 of structural problems. By altering the solvent or ligand of the LSR, the direction of the shift is often a1tered,37v38s51~87 as these factors can also affect the geometry of the complexed substrate. An alternative explanation for the reversal of the ‘normal’ direction of the LIS is attributed either to the presence of significant contact interacti~n,~~ to changes in magnetic susceptibility gor (although disagreement has been expressed with this latter reason77) or to changes in the sign of crystal field coefficient^.^^ A further point involves the definition of the angle &,which is derived using the crystal field axis as one vector.This axis need not coincide, as is often assumed, with the metal atom-heteroatom bond;88 the difference is not neces-sarily compensated by free rotation around the bond. 6 Lanthanide Metal Ion Transition-metal complexes could be used as shift reagents in n.m.r. spectroscopy if it were not for the excessive linewidth broadening these metal ions exhibit in This phenomenon is related to similar effects caused by oxygen and free radicals when present in solution in the n.m.r.tube. These species provide a mechanism for shortening the relaxation times (T2)of the protons and, therefore, increasing the bandwidth. Europium(m), the most frequently selected lanthanide, is selected by virtue of its anomalously inefficient nuclear spin-lattice relaxation properties.g0 It has a low-lying Russell-Saunders state and a diamagnetic 7F0 ground state, which gives a very small separation of the highest and lowest occupied metal orbitals and which leads to inefficient relaxation; the excited 7F1state presumably contributes to the pseudocontact shift. Q1Thus the presence of such metal ions as europium(n1) in solution causes very little broadening in n.m.r. spectra. H. Donato, jun., and R. B. Martin, J. Amer. Chem. SOC.,1972, 94, 4129.8B C. L. Honeybourne, Tetrahedron Letters, 1972, 1095. 8s A. Carrington and A. D. McLachlan, ‘Introduction to Magnetic Resonance’, Harper and Row, 1967, p. 225. @O J. H. Van Vleck, ‘The Theory of Electric and Magnetic Susceptibilities’, Oxford UniversityPress, 1932. chap. IX. @l S. I. Weissman, J. Amer. Chem. SOC.,1971, 93, 4928. 63 3 Lanthanide Shut Reagents in Nuclear Magnetic Resonance Spectroscopy Table 3 Comparison of the lanthanide- and transition-metal complex proton n.m.r. bandwidths Lanthnide BandwidthsJHza Half-height band- Relative widthsJHz broadening1 Pr 40 5.6 Hz per Hz of shift= 0.005 Nd 16 4.0 Sm 7 4.4 0.02 Eu 10 5.0 0.003 Gd 1500 - Tb 250 96.00 0.1 DY 180 200.00 - Ho 180 50.00 0.02 Er 250 50.00 Tm 400 65.00 - Yb 60 12.00 0.02 Transition nietal Bandwidth JHzd as MIL' Ti 2000 V 25 Cr lo00 Mn 100 Fe 800 Mo 200 Ru 100 a Lanthanide bandwidthssa of t-butyl in M(dpm), in carbon tetrachloride.b Lanthanide half bandwidthss6 of methyl in 2-picoline using M(dpm)B. C Lanthanide relative broadeninel of t-butyl in M(dpm),. d Transition-metal bandwidthss0 of methyl in M(acac),. Several comparisons of the lanthanides for use as LSRs have been reported and Table 3 shows some comparisons of lanthanide broadening properties along- side those of some first-row transition-block metal complexes. Close comparison of these figures is not possible as different ligands and solvents were used in the measurements.Narrow bandwidths are exhibited by the lanthanides praseodymium (Pr), neodymium (Nd), samarium (Sm),and europium (Eu), and moderate broadening is found with ytterbium (Yb),but a notable exception to these characteristics occurs with gadolinium (Gd), which is used explicitly as a broadening pr~be.~**~~~93 Europium and praseodymium are used most extensively and ytterbium also appears satisfactory for use, although it causes greater broaden- *%N.Ahmad, N. C. Bhacca, J. Selbin, and J. D. Wander, J. Amer. Chem. SOC.,1971, 93, 2564. s3 K. G. Morallee, E. Nieboer, F. J. C. Rossotti, R. J. P. Williams, and A. V. Xavier, Gem. Comm., 1970, 1132. 64 Mayo ing. Further comparison of broadening properties have been investigatedsa using M(NO,),(dbbp), where dbbp is 4,4’-di-n-butyl-2,2’-bipridyl and M are various lanthanides.An investigation of these complexes shows that lanthanum, lutetium, and ytterbium cause extensive broadening; cerium, praseodymium, neodymium, and samarium only cause moderate broadening; and europium is cited as the only metal permitting a distinction between three aromatic protons in the complex. A similar 14N n.m.r. studyn4 of the half bandwidths shows a significantly different situation, with dysprosium (Dy) and holmium (Ho) giving the least broadening. A secondary factor in selection of the correct lanthanide as a LSR is the magnitude of the shift produced. Some comparisons of this factor have been made for the lanthanides, as seen in Table 4.The largest shifts are unfortunately Table 4 Comparisons of lanthanide induced shiftsa Metal Shgt caused Shift caused Shift power Shut by by M(dpm),.by M(dpm),. relative to M {OP(NMe,)a MC104) a-methylene y-methylene Eu(dpm), of MeCN /Hzb /Hzb /Hze /Hzd Pr -11.25 -3.7 -1.1 -3.00 Nd -5.55 -1.8 --1.15 Sm -1.35 -0.6 -0.2 -0.27 Eu 2.95 1.8 1.O 1.33 Gd Tb -26.25 -10.9 -5.5 -19.2 -DY -54.00 --17.9 -Ho -51.45 -18.1 -7.0 -17.0 Er 25.55 8.8 -4.4 Tm -44.65 -14.8 6.9 Yb 12.15 4.4 4.0 6.9 -Lu 0.00 0.0 a A more recent survey gives analogous results.56 * The 01 and y groups refer to the methylene protons of cyclohexanone (0.1 mol 1-I) in a saturated solution of M(d~rn)~in CC14.g* C Shift power relative to Eu(dpm), calculated from ‘representative’ selection of lanthanides refer to slopes of concentration vs.shift plots.41 (I Ref. 95. exhibited by the metals which cause greatest broadening, e.g. terbium to thulium, and, therefore, the metals selected for use as LSRs are necessarily a compromise of these factors, with a greater consideration given to the broadening factor. Consequently, europium produces relatively small but adequate shifts and is the lanthanide used most extensively since the first paper was published by Hinck1ey.l This metal ion produces large enough shifts with sufliciently minimal broadening to allow gross multiplet adsorption bands to be resolved at relatively large shifts. M. Witanowski, L. Stefaniak, and H. Januszewski, Chem.Cornrn., 1971, 1573. 65 Lanthanide Shift Reagents in Nuclear Magnetic Resonance Spectroscopy Furthermore, the t-butyl resonance of Eu(dpm), occurs upfield of TMS in proton n.m.r. and is, therefore, not interfering with the spectra. In 14Nn.m.r., europium causes three times as much shift as ytterbium,13 reversing the relative shift power found in proton n.m.r. spectroscopy (cf: Table 4). Praseodymium follows europium in its popularity, owing to two factors: (i) the shifts are larger than those caused by europium, in proton n.ni.~.,~~ compensating for the slightly poorer broadening properties ; (ii) praseodymium causes upfield shifts and is, therefore, a useful complimentary reagent. A disadvantage of praseodymium and other shielding LSRs, however, is the added complication of crossing over of resonances, which confuses analysis in some cases.A series of papers,10~11~76~ 96 largely by Beaute and Wolkowski, advocates the use of ytterbium and holmiumS7a owing to their relatively greater shifting powers (cf: europium), but these advantages are balanced by their greater bandwidths. Thulium has been used as a LSR,40but although shifts are greater than those caused by europium, drastic broadening again limits its application. In 13C n.m.r. the praseodymium/ europium shift-ratio and the terbium/europium LIS ratios are given as 1.8 and 8.6, resp~ctively,~~but as usual the advantage of terbium has to be balanced against its extensive broadening properties. The reference to a LSR as de- shielding or shielding refers to its use under ‘nornial’ conditions (as a p-di- ketonate complex, in fairly non-polar solvents and with angle 81 outside the 54.7 to 125.3 O limits).Finally, diamagnetic lanthanum is usedD7b in LSR studies although the shifts produced are probably due to changes in shielding by bonded electrons and not indicative of any pseudocontact shift. The main use of lan- thanum may, therefore, lie in taking accurate measurements of the LIS due to pseudocontact shift only, by subtracting shifts caused by the lanthanum complex from the LIS caused by a paramagnetic LSR.67 7 Lanthanide Shift Reagent (LSR) Lanthanide tris(#?-diketonates), often air stable and soluble in organic solvents, are known to expand their co-ordination by accepting further ligand~~~ and have a very simple n.m.r.spectrum, i.e. factors desirable in a shift reagent. The simplest #?-diketonates, the acetylacetonates, are used with first-row transition- block metals as shift reagents, but these ligands are hygroscopic and the co- ordinated water leads to weak complexation with further ligands, giving poor shifts.36 The t-butyl derivative dipivaloylmethanate is a more satisfactory LSR, whose proton n.m.r. spectra in CDC13consists of only one singlet which is shifted to higher field by approximately -0.7 p.p.m. when co-ordinated to a substrate such as an alcoh01.~ Bulky ligands in the LSR are an advantage as this restricts mobility in the complex, preventing the susceptibility tensors being averaged out by a combination of different configurations (see Section 3).47 The dipivaloyl- Or, J.Briggs, G. H. Frost, F. A. Hart, G. P. Moss, and M. L. Staniforth, Chem. Comm., 1970, 749. O6 C. Beaute, Z. W. Wolkowski, and N. Thoai, Chem. Comm.,1971,700. O’aL. Tomic, Z. Majerski, M. Tomic, and D. E. Sunko, Croat. Chem. Acta, 1971, 267. 07bE. Wenkert, D. W. Cochran, E. W. Hagaman, R. B. Lewis, and F. M. Schell, J. Amer. Chem. Soc., 1971, 93, 6271. 66 methanato-complex of europium was first used by Hinckleyl as the dipyridine adduct Eu(dpm),,2py. This was later improved by Sanders and Williamso8 by use without the associated pyridine, rendering the complex more amenable to expanding its co-ordination and accepting substrates, which effects a fourfold increase in shifts. These complexes are available commercially, but they can be prepared in the laboratory from the metal nitrate.Bs The complexes have only a limited solubility in the normal n.m.r.solvents, which prevents a 1 :1 molar ratio being reached. In the absence of the substrate, Eu(dpm), has a maximum concentration of approximately 40mg ml-l in deuteriochloroform,7 and solubi- lity increases with co-ordination to a basic substrate, e.g. concentrations of 200 to 300mg ml-l are obtained with alcohols in chloroform or deuteriobenzene, but only 100 mg ml-l in carbon tetra~hloride.,~ It is probable that the substrates less basic than alcohols will not permit such comparatively high concentration of the LSR.However, the dipivaloylmethanato-complexes are widely used reagents which give quite satisfactory shifts even at the low concentrations governed by their limited solubility. Other similar reagents with no particular advantage over the dipivalomethanates have been reported, e.g. tris(dibenz~ylmethanate)~~~~~~ and t ris-( 1-benzoylace t onate) .lO O The introduction of fluorine atoms on the p-diketonate ligand overcomes the solubility problem and has led to new superior LSRs. One such complex, the 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyloctane~,6-dionato(fod) lanthanide,' apart from having improved solubility (of the order of 400 mg ml when com- plexed to a substrate), has a more acidic metal ion owing to the electron- withdrawing power of the fluorines.This greater Lewis acidity causes a stronger association with the substrate and thus extends its range to less basic groups; although the bound chemical shift is smaller for these fluorinated LSRS,~~the observed LIS is larger because of the stronger binding in the complex. However, an alternative method for comparing the shifting power of LSRs, by measuring their vinylic proton shifts,lol allows a comparison of the shifting power of various fluorinated LSRs with the non-fluorinated reagents,loa Eu(fod), > Eu(pfd), > Eu(fhd), > Eu(dpm)s where (pfd) represents 1,1,1,2,2-pentafluoro-6,6-dirnethylheptane-3,5 and (fhd) represents 1,1,l-trifluoro-5,5-dimethylhexane-2,4-dione.Various LSRs appear to exhibit different degrees of contact interaction with aromatic sub- strates, and a series of the reagents with an increasing degree of contact inter- action operating is reported :loS J.K. M. Sanders and D. H. Williams, Chem. Comm.. 1970,422. O°K. J. Eisentraut and R. E. Severs, J. Amer. Chem. SOC.,1965, 87,5254. looG. V. Smith, W. A. Boyd, and C. C. Hinckley, J. Amer. Chem. SOC.,1971,93, 6319. lol H. E. Francis, Ph.D. Thesis, University of Kentucky, Lexington, Kentucky, 1972. lo*H. E. Francis and W. F. Wagner, Org. Magn.Resonance, 1972,4189. lo9B. F. G. Johnson, J. Lewis, P. M. Ardle, and J. R. Norton, J.C.S. Chem. Comm., 1972, 535. 67 Lanthanide ShiJt Reagents in Nuclear Magnetic Resonance Spectroscopy Pr(fod), < Yb(fod), -c Eu(dpm), < Er(dpm), < Eu(fod)s increasing contact interaction Finally, one disadvantage in using the fluorinated LSR is that the t-butyl resonance occurs in the 1-2 p.p.m. region when complexed, hence interfering with proton resonances in this region.Optically active LSRs such as tris-[3-(t-butylhydroxymethylene)-( + )-cam-phorato]europium(rr~) have been developed for the purpose of determining enantiomeric Once again the idea of using fluorinated ligands to improve the relative shifting power of these LSRs has been applied to these reagents and has led to tris-[3-(trifluoromethylhydroxymethylene)-(+)-cam-ph~rato]-~~and tris- [3-(heptafluoropropylhydroxymethylene)-(+ )-camphoratol-europium- and -praseodymiurn-(~rr)~~~ which are used* to distinguish resonances of a number of enantiomorphs.These LSRs are assumed to distinguish between enantiomorphs by forming diastereoisomeric complexes which have either different stability or just a different magnetic environment.sS Further LSRs used mainly for application in highly polar solvents include europium trichloride, reported to co-ordinate to polyfunctional steroids in dimethyl sulphoxide, causing upfield shifts,37 and praseodymium and europium nitrate hexadeuterium oxide, used successfullyL8 in deuterioacetone for investiga- tion of phosphate and phosphonates by 31Pn.m.r. The use of praseodymium perchlorate in deuterium oxide is reported3* in the study of carboxylic acids, and a poorer reagent, M (N(CH,CO,), )(HzO)3,where M is a lanthanide, is also used in studying carboxylic acids as their sodium salts.Table 5 shows the structures of some lanthanide shift reagents. 8 Organic Functional Groups As already pointed out, greater shifts are caused by functional groups which are most basic, and this aspect has been investigated by Ernst and Mannschreck, who an almost linear correlation of pKa with LIS for a series of substi- tuted anilines. The basicity factor appears a most important criterion on which to judge the effectiveness with which a group will give a LIS, although factors such as steric hindrance cannot be ignored. Alcohols are the most widely used functional group, followed by ketones and esters, which give slightly smaller shifts. These groups, together with quinones,lo6 aldehyde^,^^^*^ acetal~,,~ lactones,1a8 tetrahydrofurans,lO ether^,^^^^^epoxide~,6~~~~~ carboxylicparticularly rnethoxide~,~~~~~~~~~ and a number of phos- * A simple method for the preparation of these reagents is reported.lo6 lo4R.R. Fraser, M. A. Petit, and J. K. Sanders, Chem. Comm., 1971, 1450. loSV. Schurig and R. Israel, Tetrahedron Letters, 1972, 3297. loBJ. Grandjean, Chem. Cumm., 1971, 1060. lo' L. H. Keith, Tetrahedron Letters, 1971, 3. lo8F. I. Carroll and J. T. Blackwell, Tetrahedron Letters, 1970,4173. looA.F. Bramwell, G. Riezebos, and R.D. Wells, Tetrahedron Letters, 1971, 2489. Maya Table 5 Lanthmide shgt reagents Acetylacetone (acac) Tris(acety lacetonato) europium(HI) IEU(acac ) 1 r 1 r 1 30 0 L '3 Tris(dipival0ylmethanato Tris(dibenzoylmethanato) europium(111) IEu(dpm)3l europium(111) IEu(dbm) I 1 Eu F,$T 1 F F 3 -13 Tris -( 1,l,1,2,2,3,3 -heptaf luoro Tris -W(t-butylhydroxymethylene)-7,7-dimenthyloctane-4,6--(+)-camphoratoleuropium(rr~)dionato)europium(111) IE~(fod)~l (continired overleaf) Lanthanide Shvt Reagents in Nuclear Magnetic Resonance Spectroscopy Table 5 continued . ;Eu -Eu/ F--tFF$F FF 'F 3 3 Tris -I 3-( heptafluoro-n-propyl-Tris -I3 -(trifIuoromethyIhydroxy-hydroxymethylene)-.(+) -methyhe) -(+ camphorat01camphoratoleuropium (111) europium(III) phorous oxides,15~1s~74~110-113 all give LISs useful for spectral clarification.A wide range of comments and comparative investigations have been made on the preferred selective co-ordination of oxygen-containing groups, which necessarily involves either a comparison of LISs in different monofunctional molecules or a study in polyfunctional molecules.These observations are largely empirical and the factors which affect the shift should be considered in each case (steric hindrance, geometry, etc.). Only the alcohol in a difunctional hydroxy-ester is reported22 to co-ordinate at low concentrations of LSR, as expected. By increas- ing the LSR concentration, co-ordination eventually occurs at the carbonyl of the acid group, presumably only at a stage when co-ordination is complete at the hydroxyl-function. A detailed graphical analysis of a hydroxy-keto-~teroid~~ separates the relative contribution of the shift from co-ordination at each group, a method which could be developed for a wider range of polyfunctional mole- cules.Conversion of carbohydrates into the 5-O-acetate and 5-deoxy-analogues of methyl-2,3-O-isopropylidene-p-~-ribofuranosideshows a decrease in shift by 40 to 50 % and 10 to 20 %, respectively.llS Ketones are reported to co-ordinate better than ethers and esters, although only 35 to 40% as well as alcohols.B8 Quinones also give a satisfactory LIS, the carbonyl group being regarded as the preferred site of co-ordination in com- parison with an aromatic methoxy-group.loe A wide range of oxygen compounds are compared in a variety of intra- and inter-molecular competition experiment^,^ where tetrahydrofuran-acetone co-ordinate comparatively in a ratio of 8 :1; dimethyl ether-acetone, 7 :3; dioxanxyclohexane-1 ,4-dioneY 6 :4; and dioxan-methyl acetate or -acetone, 5 : 1.The presence of conjugation decreases T. M. Ward, I. L. Allcox, and G. H. Wahl, jun., Tetrahedron Letters, 1971,4421. l11 B.D.Cuddy, K. Treon, and B. J. Walker, Tetrahedron Letters, 1971,4433. 11s J. R.Corfield and S. Trippett, Chem. Comm.,1971,721. 11* R.F.Butterworth, A. G. Pernet, and S. Hanessian, C~mad.J. Chem., 1971,49,981. co-ordination in an up-unsaturated ether, and if oxygen is part of a furan ring, co-ordination is very Investigations of esters in polymers indicates preferred co-ordination to the carbonyl and not the ether ~xygen.~~~~~~~ In the case of functional groups consisting of two possible donor atoms, co-ordination is thought to occur mainly with the oxygen atom when present.As amides protonate preferentially at the o~ygen,~~~~~~~ the nitrogen lone pair being delocalized, preferential co-ordination of the LSR to the oxygen is ex- pected. This is found with amidess6~11s s6 azoxyben~enes,’~~and also oxime~,’~~ trimethylene sulphites,120 sulph~xides,~~ hemithioacetalsYs7 thiadecalones,lZ1 phosphate^,^^^^^ and the phosphoryl oxygen in pho~phorinans.~~~~~ However, the converse is thought to occur with oximes,12z where results indicate preferred co-ordination to the nitrogen lone pair. The carboxylate ion gives a greater shift to associated protons than the basic amine group when in an aqueous solvent?a Phenols, hydroxy, and, particularly, carboxylic compounds can be studied with normal LSRs, but these may decompose the complexed substrate on standing.Together with sulpho~ides,~~~~ which co-ordinate 25 to 30% less than alcohol^,^ thioamide~,~~~J~~ and thiocarbamate all give appreciable s~lphinyls,~~~ LISs, as well as hemithi~acetals,~~ which co-ordinate via the oxygen. The sulphonyl oxygen (R,SO,) co-ordinates less than the sulphinyl oxygen (R,SO), which is analogous to the nitro (RNO2) and amine oxide (RzNO) systems.80 Aminesl0JZ6 give larger shifts than alcohols;z3 and amides,l18Ja7 oximes,1aS1z2 q~inolines,~~ all give pyrazines,loB pyridines,1° and nitroso-amino-carbanions1z8 reasonable LISs; N-oxides give slightly smaller shifts;66~103~1zB pyrroles and nitriles96 only give small shifts and imines, azobenzenes, and nitro-compounds remain ~nperturbed~~~~~ by LSRs.In I4Nn.m.r., a survey13of nitrogen substrates shows that largest shifts are caused by alkylamines and pyridines; acetonitrile has less interaction with LSRs owing to its poorer basicity. Surprisingly, co- ordination is reportedlsO to occur preferentially with a phosphine in a phosphine- amine compound. The effect of deuteriating the substrate is shown to increase J. E. Guillet, I. R. Peat, and W. F. Reynolds, Tetrahedron Letters, 1971, 3493. A. R. Katritzky and A. Smith, Tetrahedron Letters, 1971, 1765. n6T. Birchall and R. J. Gillespie, Canad. J. Chem., 1963,41, 148. 11’ R. L. Middaugh, R. S.Drago, and R. J. Niedzielski,J. Amer. Chem. SOC.,1964,86,388. 118 L. R. Isbrandt and M. T. Rogers, Chem. Comm., 1971,1378. IIOR. E. Rondeau, M. A. Berwick, R. N. Steppel, and M. P. Serve, J. Amer. Chem. Soc., 1972,94,1096. laoG. Wood, G. W. Buchanan, and M. H. Miskow, Canad.J. Chem., 1970,50,521. A. van Bruijnsvoort, C. Kruk, E. R. de Waurd, and H. W. Huisman, Tetrahedron Letters, 1972, 1737. la5K. D. Berlin and S. Rengaraju,J. Org. Chem., 1971,36,2912. Ia3 W. Walter, R. F. Becker, and J. Thiem., Tetrahedron Letters, 1971, 1971. lZ4J. L. Greene, jun., and P. B. Shevlin, Chem. Comm.,1971, 1092. lZ6 R. A. Bauman, Tetrahedron Letters, 1971,419. la6 H. Burzynska, J. Dabrowski, and A. Krowczynski, Bull. Acad. polon. Sci., S&r.Sci.chim., 1971, 587.la’ A. H. Lewin, Tetrahedron Letters, 1971, 3583. lasR. R. Fraser and Y. Y. Wigfield, Tetrahedron Letters, 1971, 2515. lZ8R. A. Fletton, G. F. H. Green, and J. E. Page, Chem. and Ind., 1972, 167. laoR.C. Taylor and D. B. Walters, Tetrahedron Letters, 1972, 63. 71 Lanthanide Sh$t Reagents in Nuclear Magnetic Resonance Spectroscopy the ~hift,~~J~~~~~~-~~~ possibly owing to an increase in base strength caused by the deuterium. Alkyl halides, olefins. and saturated hydrocarbons. as expected. co-ordinate weakly or not at Some general conclusions have been made concerning comparisons of co-ordinating ability of different functional groups. The co-ordinating power of thiols, thio-ethers, and arylphosphines are generally much less than their oxygen and nitrogen analogues.lS The following series of functional groups have been put in order of their ability to co-ordinate and cause a LIS: phosphoryl > carbonyl > thiocarbonyl > thiophosphoryPO ethers > thioethers > ketones > esters@ amines > hydroxyls > ketones > aldehydes > ethers > esters > nit rile^^^ (for RCH,X) (Note: there are contradictions with respect to relative shifts, e.g.ketones and ethers) 9 Application of Lanthanide Shift Reagents By applying the principles outlined in the review, apart from spectral simplifica- tion, a great deal of information can be gained by using LSRs. This varies from producing spectra amenable to first-order analysis to configurational and *82s83conformational analysisll ,21+v3 9 lo8#134a using the dis tance-shift and distance-broadening relationships.A unique application is apparent when, for example, upfield shifts are produced by Eu(dpm), in fairly non-polar solvents, which is peculiar to structures which are often described as ‘f~lded’~~~~* and have the angle 81 between 54.7 and 125.3’. Shift reagents are used in spectral simplification of aliphatic systemsB5, and are also applied to their configuration and conformational analysis, e.g.oximes,lz thioarnide~,~~~,~~~and thiocarbamate Monocyclic systems are studied either in order to clarify spec tra7 9 36 9 or in c~nfigurational~~ @ 639 76 9 lS69 137 and conformational analysi~.~~.~~~~ The proton n.m.r. of heterocyclic systems are also simplified, e.g.pyrazines,lo@ pyridine~,~~~ pyridine N-oxides,12@ carbo-hydrate~,~~~J~~b~~~~ and examples of conformational and alky1idenefuranonesy7@ elucidation are cited with valerolactones,108 dioxaphosphorinan~,~~~~~and thia- decalones.12‘ Bicyclic systems, bicyclononanes in partic~lar,~~J~~~~~~ are studied alongside other rigid molecules chosen to simplify analysis of the distance and lalA. M. Grotens, C. W. Hilbers, and E. de Boer, Tetrahedron Letters, 1972, 2067. A. M. Grotens, J. Smid, and E. de Boer, Tetrahedron Letters, 1971, 4863. 133 D. A. Lightner and G. D. Christiansen, Tetrahedron Letters, 1972, 879. lsaaM.R. Vegar and R. J. Wells, Tetrahedron Letters, 1971, 2847. lsrbD. Horton and J. K. Thomson, Chem.Comm., 1971, 1389. 136 P. Belanger, C. Freppel, D. Tizane, and J. C. Richer, Chem. Comm., 1971, 266. 136 C. Casey and R. A. Boggs, Tetrahedron Letters, 1971, 2455. 13’ C. Freppel, D. Tizane, and J. C. Richer, Cunad. J. Chern., 1971, 49, 1984. 13* K. E. Stensio and U. Ahlin, Tetrahedron Letters, 1971,4729. 13@I. Armitage and L. D. Hall, Chem. and Ind., 1970, 1537. lrOL.F. Johnson, J. Chakravaty, R. Dasgupta, and U. R. Ghatak, Tetrahedron Letters, 1971, 1703. 72 Mayo geometric factors and allow correlation of the LIS with the pseudocontact shift expression. Thus the LIS of all protons in the n.m.r. spectra of adamant-1-01~~ and -2-01,~~J' 2-hydroxy-l-(2-hydroxyethyl)adamantane,6sborne~l,~.~~and iso- bomeo17 have been reported, as well as that for the methyl resonances of (+)-camphor.141 The 13Cn.m.r.spectra of borne01,~~ is~borneol~~~, cycl~pentanols,~~~ have been similarly assigned using and rib0-5-phosphatel~~ LSRs. Stereochemical problems have been solved in a wide range of compounds including pe~ticides~~~~~~~ Inone such structural elucida- and natural prod~cts.~~J~~ tion of a new diterpene, trachyl-oban-19-01,~~~ 32 proton resonances were assigned with the aid of LSRs. Steroids are another group of compounds ~t~died;~~~~~~~~~J~~,~~~one result indicates the position of the C17 side-chain in solution.86 References on the application of LSRs to conformational analysis are numerous.63~7s~82~83~108Detailed investigation of polyfunctional substrates are less common, although an example of a satisfactorily assigned spectrum of a di-functional sys tem is reported for 2-hydr ox y- 1-(2-hydrox ye t hy1)adaman t ane.65 However, complicated molecules can be simplified before using the LSR by reducing the number of functional groups available; one paper suggests the conversion of an alcohol into a trifluoroacetic ester, a group with very poor basicity, as an effective blocking group.16 Formation of first-order spectra with LSRs permits the measurement of coupling constant^,^^^^^^^^^ although com- plexation of the substrate with the LSR is reported to alter this parameter.150a Lanthanide shift reagents have been used as structural probes in studying co-ordination sites of enzymes by observing the shifts of acetamido and glyco- sidic methyl groups.93 The distinction of the resonances of iso-, hetero-, and syno-tactic polymers with LSRs has been applied in an analysis of poly(methy1 metha~rylate),ll~,~~~and is even used in molecular weight determinations.160b The optically active LSRs are used to distinguish enantiorn~rphs;~~ the fluorinated reagents appear to have a wider appli~ation~~J~~-one case cites the separation of enantiotropic protons at a prochiral centre.151 Application of LSRs to 14N n.m.r.spe~froscopy~~~~~is restricted by the large extent of broadening, but it is 141 C. C. Hinckley, J. Org. Chem., 1970,35,2834. 14a 0.A. Gansow, M. R. Willcott, and R. E. Lenkinski, J. Amer. Chem. SOC.,1971,93,4295. 143 W. B. Smith and D.L. Deavenport, J. Magn. Resonance, 1972, 6,256. lP4M. Christl, H. J. Reich, and J. D. Roberts, J. Amer. Chem. SOC.,1971, 93, 3463. 146 B. Birdsall, J. Feeney, J. A. Glasel, R. J. P. Williams, and A. V. Xavier, Chem. Comm., 1971,1473. lIe J. D. McKinney, L. H. Keith, A. Alford, and C. E. Fletcher, Cunad. J. Chem., 1971, 49, 1992. 147 0.Achmatowiez,jun., A. Ejchart, J. Jurczak, L. Kszerski, and J. St. Pyrek, Chem. Comm., 1971, 98. 14* P. V. Demarco, T. K. Elzey, R. B. Lewis, and E. Wenkert, J, Amer. Chem. Soc., 1970, 92, 5737. 14* D. G. Buckley, G. H. Green, E. Ritchie, and W. C. Taylok, Chem. and Ind., 1971, 298. laoaF. Floyd and L. Ho, J. Polymer Sci., Part B, Polymers Letters, 1971,9,491. lsobB.L. Shapiro, M. D. Johnston, jun., and R.L. R. Towns, J. Amer. Chem. Soc., 1972, 94, 4381. lS1 M. R. Frazer, M. A. Petit, and M.Miskow, J. Amer. Chem. Soc., 1972, 94, 3253. Lunthanide Shvt Reagents in Nuclear Magnetic Resonance Spectroscopy useful to use the LIS to characterize the mode of nitrogen bonding. More useful is 31P n.m.r.,f8 and as aHn.m.r. has been used with transition-metal reagents,162 there is a further possible application of LSRs with this nucleus. 10 Practical Aspects A widely used method for studying shifts is by addition of portions of LSR, as a solid or a solution, so that the gradual shifts of each resonance can be followed. This permits identification of peaks, initially part of a complex adsorption band, by reverse extrapolation to zero concentration of LSR, and is also one method of measuring the shift parameter. However, an alternative approach23 gives more accurate shift parameters or bound chemical shifts, by starting with a solution of the LSR in the n.m.r.tube and adding portions of the substrate. A plot of substrate concentration against the inverse of the LIS gives a slope equal to (L~B),where dg is the bound chemical shift;2a see Section 2. The internal standard from which chemical shifts are measured is also displaced by the LSR, albeit a fairly small shift. This is a consequence of changes in the bulk magnetic susceptibility of the solution, which shifts the TMS signal by up to 1.4 p.p.m. in one case.37 However, these shifts are linear, with respect to the LSR concentration, so that no drastic errors in structural conclusions should arise, noting that the magnitude of these shifts is invariably smaller than the shifts of the substrate.Acetonitrile has been used as an internal standard; the lack of broadening at high concentration of LSR indicates a minimal shift;l* benzene1l5 and cyclohexanes have also been used, the latter being shifted 3 Hz in the concentrations studied. Alternative standards such as chloroform are proposed to avoid interference by the LSR resonances in the 1 p.p.m. region.14 The effect of changes in bulk magnetic susceptibility may also cause displacement of the nucleus being studied, but such variables need only be considered in detailed measurements. Use of the temperature-shift relationship is reported either in just improving or in substituting the concentration-shift studies.g2 Sensitivity of instruments may be enhanced by increasing the radiofrequency field, as the limit of saturation could be increased by the presence of the paramagnetic ions even though these LSRs have fairly inefficient spin relaxation properties. The author wishes to thank Dr. A. P. Johnson for many useful discussions. lpoA. Johnson and G. W. Everett, jun., J. Amer. Chern. SOC.,1970,92,6704.