Max R. Peterson, Jr.
and Georae - H. Wahl. JI. North Carolina State University Raleigh, 27607
I
I
Lanthanide NMR Shift Reagents A powerful new stereochemical tool
T h e effects of paramagnetism on nuclear magnetic resonances have been studied since the very beginning of nuclear magnetic resonance (nmr) spectroscopy (I). It has been only within the last few years, however, that paramagnetic effects have been systematically applied to structure determination and peak assignments for organic molecules. Most of the work to date has been done with various lanthanide complexes (2-8) which produce spectral simplifications in the nmr spectra of aldehydes, ketones, alcohols, amines, and other molecules having a relatively basic lone pair of electrons (9a). The addition of certain lanthanide complexes ("Shift Reagents") to an nmr solution of a compound which possesses an appropriate lone pair of electrons causes the proton resonances to bccomc spread out with the effect being greatest on the resonances of hydrogens nearest the ~ i t eof coordination. Coupling constant,^ appear to be virtually unaffected (9b). In many instances, with a sufficiently high concentration of the shift reagent, spectra become firstorder. These "lanthanide induced shifts" (LIS, or AvJ are thought to be due primarily to pseudocontact interactions (10) and for any particular molecule a t a given t,emperature are inversely proportional to the cube of the internuclear distance ( r 4 between the lanthanide metaland the proton under consideration (eqn. (1)) (11) Avi = K/rjg
(1)
Equation (1) is a highly simplified version of the equation derived for pseudocontact interactions by McConnell and Robertson (12) and fails to include an angle factor which appears to be important in some instances (15, 14). According to eqn. (I), then, the principal factor influencing the shift of a particular nmr peak is the distance separating the metal ion from the proton which is responsible for that peak. Thus, the closer the proton to the metal t,he greater the shift observed. The direction of the shift, i.e., upfield or downfield, depends primarily upon the lanthanide complex used. Complexes of europium, erbium, thulium, and ytterbium shift nmr resonances to lower field while complexes of cerium, praseodymium, deodymium, samarium, terbium, and holmium tend to shift resonances to higher field (2,S). Most of the lanthanide complexes also give considerable line broadening at higher concentrations (2). This effect is undesirable due to loss of resolution. Complexes of europium and praseodymium are by far the best shift reagents in this respect giving shift broadening~of only 0.003 and 0.005 Hz/Hz of shift, respectively ( 2 ) . The most commonly used complexes are tris - (2,2,6,6- tetramethyl - heptane- 3,5 - dionato)euro-
pium(III), commonly abbreviated Eu(DPAQ3 (I), and tris - (2,2,6,6 - tetramethylheptane - 3,5 - dionato) praseodymium(III), usually abbreviated Pr(DPM)3. The two are complementary in that E U ( D P M ) shifts ~ proton resonances to lower field while Pr(DPM)pshifts resonances to higher field (2,s).
Hinckley (9) was the first to report use of the europium shift reagent as its bispyridine adduct. Sanders and Williams (15) shortly thereafter reported that the pyridine-free complex, E U ( D P M ) ~(If?), increased the shifts observed by a factor of 4 at comparable concentrations. Sanders and Williams (9) have also estimated the relative order of complexation of various functional groups with Eu(DPM); as judged from relative shifts in comparable molecules (amines > alcohols > ketones > aldehydes > ethers > esters > nitriles). Applications of E U ( D P M )to ~ structural and conformational studies are many and varied (9-11, 13, 16, 17-50). Classic examples are the first order spectra of mhexanol and benzyl alcohol obtained by Sanders and Williams (15) using this shift reagent (see figure).
100 M H z 1H nmr spectra of CCI, rolutionr of; (A1 n-hexand plus 0.26 mole equivolenb of EdDPMh; (81 benryl ofcoho1 plus 0.39 mole oquivalentr of Eu(DPMla. (Reproduced by permission from reference (151.1
Hinckley (17) has used the bispyridine adduct, Eu(DPM)3.2Py, to assign the methyl ahsorptions in the 'H spectrum of D-camphor (11).
estimated (33) to he in the ranges 60-75' and 80-95", respectively, and thus give negative (upfield) shifts. Siddall (34) has reported an upfield shift of onc of the @-methyl doublets of 2,6-di-2-propylacetanilide (V) 0 II
The approximate metal-methyl distances of I1 in a pseudocomplex with Eu(DPM)3.2Py decrease in the order Me(l0) > Me(8) > Me(9). Hinckley recorded the spectrum of I1 alone in solution and then added dropwise a solution of Eu(DPM)3.2Py recording the nmr spectrum after each of several successive additions. The change in chemical shift for each methyl peak was then plotted against E u ( D P M ) ~ . ~concentration. P~ All threc gave curves of diffcrcnt positive slope as expected from eqn. (1). This then allowed confident assignment of the methyl peaks in the original spectrum of pure D-camphor. By use of EU(DPRI)~ the 'H nmr bands of all of the "different" protons in 2-adamantanol (19, 29) (111) have been assigned. The spectra obtained for I11 are not as complicated as might be expected due to the very small vicinal coupling constants (2-3 Hz) exhibited by compounds of adamantane (31). The spectrum of I11 alone is extremely uninformative (32).
Several authors (33, 34) have reported upfield shifts using EU(DPM)~.Shapiro and co-workers (53) have explained observed upfield shifts for H-3' and H-4' in cis3-(1-naphthyl)-1,3,5,5-tetramethylcyclohexan-l-ol (IV) :%MeMe-.
Me
IV in terms of eqn. (2) (a more complete form of eqn. (1)) K(3 cos' x - 1) Av* = pi3
(2)
in which Avt is the pseudocontact shift for the ith proton, x is the angle describing the position of the proton relative to the assumed symmetry axis of the europium complex, r t is the Eu-H internuclear distance, and K is a constant. The angle term (3 cos2x - 1) is positive for x values from 0 to 54' and from 126 to 180' and a positive Aut (shift to lower field) is observed, however when x has a value from 55 to 125" the angle term and Avt become negative (i.e., shifts to higher field are observed). I n the case of IV, H-3' and H-4' fall into the latter category with 0-Eu-H angles
v
and has also attributed the upfield shift to the anale fact,or mentioned above. E U ( D P M )and ~ Yb(DPILl)aeffects on 14Nresonances have been studied for a varietv of com~ounds(35). As mieht be ex~ectedthe maenkude of t i e 14N shif/s ohserved appears to be relatei to the basicity of the nitrogen lone pair and t,o steric effects (56). Eu(DPIVI)~has also been used in peak assignments and stereochemical studies involving steroids (10, 11, 15, 20) sulfoxides (18, 27), and oximes (36). Whitesides and Lewis (37) have reported use of the dissymmetric shift reagent tris[3-(tert-bntylhydroxymethy1ene)-D-camphorate]-europium (VI)
as a method for determining enantiomeric purity. These authors report that all of the protons of (R)-aphenylethylamine are shifted farther downfield than their counterparts in the (s) enantiomer when a mixture of the two are placed in a CC14solution containing VI. Differences in concentrations of the two enantiomers must also be considered. The enantiomer present in lower concentration is shifted more, presumably due to the larger VI: enantiomer mole ratio. The shift reagent (VI) works very well for certain amines but fails to give sufficiently large differences in induced shifts for less basic enantiomeric pairs. The importance of Pr(DPM)8 is equally as well documented as the europium analog though not as extensively applied (2, 3, 5, 14, 58). The first order spectrum of 1-pentanol reported by Hart, et al. (3), using the praseodymium reagent is similar to that reported for n-hexanol with Eu(DPAf), (15) (see figure) except that the resonances are all shifted to high field (up to approximately 8 ppm upfield from TAIS). Belanger, et al. (5), have used Pr(DPM)a to simplify the nmr spectra of 4-tert-butylcyclohexanone (VII) and 2,2-dimethyl-4-te~tbutylcyclohexanone (VIII). The spectra obtained for the two compounds in the presence of the shift reagent were first order.
Volume 49, Number 12, December 1972
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791
Moss and co-workers (14, 58) have made use of Pr(DPM)3to make both 'H and IaCnmr peak assignments for borne01 (IX).
be readily integrated. Shift reagents have thus become a powerful stereochemical tool, complementary to other techniques such as the NOE and spin-deconpling. Note Added in Proof
M A E Ix These authors were able to calculate a set of relative pseudocontact shifts for the various hydrogens for the 'H spectrum and the various carbons for the IaC spectrum by including the angle factor mentioned above (eqn. (2)). Sunko, et al. (59) studied the temperature and concentration dependence of Pr(DPM)%induced shifts in alcohols. Induced shifts were found to be directly related to the absolute concentrations of the alcohol and the shift reagent and inversely proportional to the temperature at which they were measured. Several comparisons of Eu(DPM)3 and Pr(DPM)a as shift reagents have been reported (2, 5, 5, 58). While the praseodymium reagent induces larger shifts than does the europium complex in similar concentrations, the former suffers a greater loss of resolution. With Pr(DPM)%there is also a "bunching" effect on the nmr bands a t lower concentrations. This is due to the fact that generally those protons nearest the coordination site absorb furthest downfield in the normal spectrum and are shifted furthest upfield in the presence of the shift reagent. Rondeau and Sicvers (6) have reported that europium and praseodymium complexes of 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl4,&octanedione (fod) are superior shift reagents for weak Lewis bases such as ethers and esters. E ~ ( f o dand ) ~ P r ( f ~ dare ) ~ also superior in terms of solubility (which can be a problem with the DPM analogs (5,6)) hut require greater care in handling since they are extremely moisture sensitive. Use of Yb(DPAI)3 as a shift reagent has met with reasonable success despite excessive (five times that for for Eu(DPM)$(40)) line broadening (55, 40,41). This reagent is reported to induce downfield shifts approximately twice as large as those induced by EU(DPM)~ at similar concentrations (40). Shift reagents not involving a lanthanide metal have also been reported. Wicholas (42)has reported use of [Fe2L40]Cia. nHzO (where L is a derivative of phenanthroline) as a shift reagent. Szarek and Baird (45) have used C o ( a c a ~and ) ~ Zaev and co-workers (44) have used NiBr2.3Hz0. Maskasky and Kenney (45) 'have made use of the ring-current effect of some germaniumporphyrin systems to induced resonance shifts in certain types of compounds. The shift reagents discussed here are becoming increasingly important in stereochemical assignments in complex molecules. The information gained through their application to stmctnres bearing the required lone pair of electrons, in general, greatly exceeds that which may be obtained by a study of Nuclear Overhauser Effects (NOE) alone (46). The NOE, also a thronghspace effect, gives information only for those protons of a molecule that are in very close spatial proximity to each other and whose resonances are sufficiently isolated from each other and from the rest of the spectrum as to 792
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lournol of Chemicol Education
Since acceptance of this paper two good reviews have appeared (47, 48). X-ray investigations of HO(DPM)~ ( 4 - p i ~ (49) ) ~ and of E U ( D P M ) ~ ((50) ~ ~ have ) ~ recently appeared. Since the highest order symmetry axis found in the structure of each is C2, quantitative calcnlations of the LIS which employ eqn. (2) are now suspect. The first observation of nmr signals for both "frec" and "complexed" substrate involved a deuterated E u ( f ~ d reagent )~ and excess dimethylsulfoxide in CD2C12at -80" (51). Each mol of shift reagent is found to coordinate with 2.0 + 0.2 mol of dimethyl sulfoxide corresponding to a coordination number of S for the europium ion. Several good practical papers have also appeared. Hary and Love (52) discuss the use of shift reagents in polyfnnctional molecnlcs. Several groups have presented discussions of the errors involved in LIS calculations (52-6). Two methods for the determination of complexation equilibrium constants have recently appealed (67,68). Literoture Cited (1) B r . o ~ ~ ~ ~ n N., o e nPURCELL, , E. M., AND POYND, R. V.. P h y ~ Rev., . 73, 679 (1948). (2) CRVMF,D. R., SANDERB. J. K. M., AND WILLIAMB, D. H., Tatrohadron Lett., 4419 (1970). (3) BRIGGB, d.. FROBT. G. H., HART.F. A,, M088,G.P..A N D STANIFORTR. M. L., Chem. Commun.. 749 (1970). K. G.. NIEBOEB, E.. R0860TTI. F. J. C.. WILLIAM$, R. I. P. (4) MORI~.LBB, XAVIEB, A. V.. A N D DWEK, R. A,, C h ~ mCornnun., . I132 (1970). P.. C., TISANE, D.. A N D RICBER.J. C., Chcm. (5) B E L ~ G E R . FAEPPEL. Commz~n..266 (1971). (6) RONDBAU, R. E., A N D L ~ v ~ nR. r , E., J . Amer. Cham. Soe., 93, 1522
,."?,, ,.m,A,.
(7) A m m o , N., BHACCA, N. 6.. SELBIN.J., A N D WANDER.J. D.. J. Arnw. Cham. Soc., 93,2564 (1971). (8) HART.F. A,. N B W B E ~ Y J.. E., A N D S n ~ w D., . Chcm. Commun., 45,
(13) (14) (15) (16) (17) (18) (191 (20) (21) (22)
93,2417 (1971). MCCONNELL, H. M.. AND ROBERTBON, R. E.. J. Cham. Phya.. 29. 1361 (1958). DEMAnco. P.V., EIZEY, T. K., LEWIS,R. B.. AND WZNPERT,E..J., Amcr. Chcm. Soe., 92, 5734: 5737 (1970). BRlacs, J., H*RT. F. A..*ND MOB%G . P.. Chem. Commun.. 1506 (1970). Smoens, J. K. M., A N D WILLIAMB. D. H., Chem. Commun., 422 (1970). Prepazed by the method of E I ~ E N H RK. A J., ~ , A N D SIEYERB, R. E., J. Amar. Cham. Soc.. 87, 5254 (1965). HINCKLEI. C. C.. J. Ow. Chcm.. 35,2834 (1970). ANDERBEN. K. I(., AND U.B.G. J. J.. Telrohrdron Ldl.. 5253 (1970). A. F., m n R ~ c a x * ~D., M . , Tatrohcdron Lett., 5149; COCXEBI~L, 5152 \.". nom, -.*-,. CBUMP,D. R., S m o ~ a sJ. . K. M., A N D W I L L ~ MD.~ H.. . Tetrahedron Lelt.. 4949 (1970). C ~ n n o mF. I., A N D BLACKWBLL, J. T,. Tetmhed~onLat., 4173 (19701. Lrsx*. K. J., FENTIM*N,A. F., JR., *ND FOGTZ, R. L., Tstrahcdron L d l . ,
-"". \&".",. A&
