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Shift Reagents in NMR Spectroscopy
By Reinhard von Ammon and R. Dieter Fischer‘*’
The number of possible applications of N M R spectroscopy has
rapidly increased during the past few years. New fields of
applications have been opened by the development of supraconducting
solenoids and various spin-decoupling techniques and by the method
of ‘‘pulsed Fourier transform NMR-spectroscopy”. These methods
originate mainly from progress in instrumentation. Recently,
another “technique” has been introduced into N M R spectroscopy,
which-principally on the basis of chemical and spectroscopic
experience- is much less expensive but nevertheless useful. The
basic principles, background, and most important applications of
this method, known as the “NMR-shift-reagent technique”, form the
subject of this paper.
1. Introduction
An NMR-spectrum can be analyzed the more easily the more
pronounced the chemical shifts of the nuclei of a sample are in
comparison to the spin-spin coupling effects. The ideal case is a
first order spectrum where the shift difference of the multiplet
centers are large compared to the components of the multiplets.
Possible means of simplifying spectra are spin decoupling“] or- in
certain cases-the introduction of suitable isotopes into the
molecule under investigation. Another way is the variation of the
magnetic field acting on the various nuclear magnets. If we discern
between in- creasing the homogeneous, external magnetic field
of
the spectrometer and superimposing the “primary field” by
additional internal “secondary fields”, two alter- native
possibilities are evident.
A consequence of choosing the first possibility is the aim of
commercial suppliers to produce N M R spec- trometers with higher
field strengths and improved resolution. The present status has-by
means of supra- conducting solenoids-reached field strengths corre-
sponding t o proton resonance frequencies of approx- imately 300
MHz.
The development of the other alternative is based upon
experience of the chemist with materials whose magnetic properties
are strongly anisotropic“]. An example is the ring current effect
causing chemically not very different
5 L 3 2 1 4 t- 6Cppml position increasing.fieid
of strength - I TMS
, ‘ 4 1 2 3 L 5 6 7 8 9
posltlon 6 [ppml- increasing field of
TMS strength- -
n-C8H1’7 I
Fig. I . (a) ‘H-NMR spectrum of n-octanol (90 MHz); the
&scale (ppm) referred to TMS, solvent CCl,; (b) ‘H-NMR spectrum
(100 MHz) of the n-octyl part of dioctvlgermanium-porphin I21:
&scale referred to TMS, solvent CDCI,.
[*I Dr. R. v. Ammon protons t o exhibit a large separation of
their resonance lines. Thus, in the diamagnetic porphin ring of the
compound shown in Fig. 1, the primary field induces
1*1 A secondary field is anisotropic if its magnitude and
direction change with the direction of the primary field.
Institut fur Heisse Chemie des Kemforschungszentrums 7 5
Karlsruhe, Postfach 3640 (Germany) Prof. Dr. R. D. Fischer Institut
fur Anorganische Chemie der Universitat Erlangen- Niirnberg 852
Erlangen. Egerlandstrasse (Germany)
_ _ ~
Angew. Chem. internat. Edit. Vol. I 1 (1972) 1 No. 8 675
-
an additionalanisotropicfield which acts very differently upon
the methylene proton pairs of the two axially coordinated n-octyl
chains‘”. Similar signal spreadings are caused by the magnetic
anisotropy of the phthalo- cyanine ( = Pc) system in adducts of the
type Fe(II)Pc. 2s (S = amines etc.)[1261 or by the weakly
paramagnetic uranyl ion[)’.
Any perceptible change of the structure of the substrate during
the adduct formation is, however, to be avoided.
The molar ratio [SI : [R] does not necessarily have to be 1 : 1;
it is important, however, that the mean lifetime of the adduct S-R
is sufficiently small on the N M R time scale that only one
averaged spectrum is observed for S and S-R.
6
1.3 h i “ I
I I
4 3 2 1 0 200 120 11.0 6 0 50 L.0
Fig. 2. ‘H-NMR spectra (60 MHz) of 2-adamantanol (a) before and
(b) after addition of Eu(dpm), as shift reagent: molar ratio shift
reagent: substrate =0.67, solvent CDCI, [4].
- 6 t ppml t- S [pprnl rzzczl Much stronger secondary fields and
therefore a still more pronounced expansion of the spectra can be
induced, however, in paramagnetic systems with at least one
unpaired electron. Fig. 2 illustrates the changes in the ‘H-NMR
spectrum of adamantanol caused by the interaction of this substrate
with the paramagnetic “shift reagent”
tris(dipivalomethanato)europium(m), Eu(dpm), (cf. Fig. 7), a system
with six unpaired 4f e Iec t ron~[~’ .
A further illustration is the H-NMR spectrum of ( - 1- nicotine
recorded at 6OC5] and 220 MHzI6] in the absence (Fig. 3 a and 3b)
and at 90 MHz (Fig. 3c) in the presence of the organometallic shift
reagent tricyclo- pentadienylpraseodymium(II1) I7].
Whereas the enhancement of the external primary field causes a
linear expansion of the spectra leaving the rel- ative chemical
shifts (in ppm) unchanged, the internal secondary field may also
change the sequence of the signals. Since the strength of this
field decreases with increasing distance from the origin of the
magnetic field lines, “geometric shifts” (see below) become the
ordering principle of the spectrum instead of the familiar chemical
shifts in all cases where the influence of the secondary field is
strong.
One may speak of an N M R shift reagent (R) if the N M R
spectrum of a substance S is simplified (with respect to spectral
analysis) through interaction with the reagent. The interaction
between S and R should be prompted by addition of the reagent to
the sample in the sense of a t least one of the three equilibria (1
a)-(l c). S(11 + Rlf) + SIIIRII) (1 a)[‘) Sli)Rll + Sl2) + Sl2)RllJ
+ Sll) (1b)l’l S(i1RltJ + R(21 + S(tIRl21 + Rll) (lc)l*1
1’1 For simplicity only 1 : 1 adducts are considered at the
monent (cf. Section 3.2.1.2).
90 80 70 / I
I ,
8 0 70 40 30 20
li --- 6 [ p p m l
9 8 7 J j 3 2 - 6 [ ppml C I
3.4
I < , i
5 10 1s ZO”50 55 6 [pprn] -+ incre?sing 1ie.d
cxEiiz s1:eyth 4 Fig. 3. ‘H-NMR spectra of (-)-nicotine,
recorded under various conditions: (a) 60 MHz in CCI, [S]; (b) 220
MHz in CDC1, referred to TMS [61; (c) 90 MHz in D,-toluene after
adduct formation with an esuimolar amount of Pr(C,H,),: F-scale
referred to C,H, 171.
676 Angew. Chem. internat. Edit. 1 Vol. I 1 (1972) / N o . 8
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2. Theory
Although the principle of the shift reagent technique has been
known for some time and, in several cases, has been applied
before[8-l’.’551, it was not until 1969 that Hinckley“” initiated
the systematic development of this branch of N M R spectroscopy [’
3. 14.127, 128,1 58. 1601. The following survey of the theoretical
background, which has been treated elsewhere in several detailed
article^"^ - 2 1 1 , concentrates on the most important as- pects
necessary for an understanding of the quantitative correlations
between the properties of a shift reagent, the substrate, and the
observed spectra.
2.1. The “Isotropic” Shift
The contribution Atso of an internal secondary field to the
resonance frequencies 6, of a substance S within the adduct S-R in
solution is experimentally obtained as the difference of the
resonance frequencies under the influence of and without the
secondary field:
Although the internal secondary field is practically al- ways
anisotropic, A:,, is generally called the “isotropic” shift,
because it is the averaged result over all orienta- tions of a
molecule moving freely in solution. In the case of a paramagnetic
shift reagent the term “para- magnetic shift” is also used.
If the shift reagent does not contain unpaired electrons, A? is
identical with the dipolar or “pseudocontact” term .PIR, which
takes into account all magnetic dipolar interactions of the
magnetic moment of the ith nucleus with theanisotropicmagneticfield
ofthevalenceelectron shell of the shift reagent. If unpaired
electrons are present, A? is composed of the dipolar contribution
and a (Fermi-)contact term A? taking into account the influence of
a possible spin delocalization within the adduct S-R:
2.1.1. Magnetic Dipolar Interactions
It often seems justified to relate the internal secondary field
of a molecule in solution for any orientation rela-
Fig. 4. Coordinates r , , 9, and o, of a nucleus i in the
coordinate system x, Y, z with the three principal components x , ,
x y , and x, of the magnetic susceptibility.
tive to the direction of the external primary field to a
magnetic “point dipole” of well defined position within the
molecule. (The center of this point dipole is gen- erally at the
nucleus of a paramagnetic transition metal ion, but not necessarily
a t the center of a cyclic n-electron system.) A!’. can then be
expressed as a function of the internal molecular coordinates r , ,
9, and w, (see Fig. 4) and the three principal components xx, x y
and xr of the measurable magnetic suscepti-
( N , = Loschmidt’s constant).
The equations (Sa)-(6b) are valid for certain types of
relaxation conditions which are particularly frequently encountered
L221.
Particularly important for the shift reagent technique is the
special case of an axially symmetric secondary field. defined by:
xZ-x ; X ~ = X , , - X ~ . This case applies, for instance, to
metal complexes with axially symmetric ligand fields, but also to
the example in Fig. 1 b. Since D”=O, equation (4) reduces to
(7) Ap‘“(ax) = - D G ,
Contrary to the non-axially symmetric case the A:’Yax)- values
of a system are directly proportional to the corresponding
“geometric factors” G,:
A?? A F : A F etc. = G , : G,: G, etc. (8)
Unfortunately, the rigorously axially symmetric case is rarely
met in practice[’61.’621. However, in a number of S-R systems with
lower symmetry the second term in equation (4) should average to
zero because of the rotations of S relative to R which are often
very fast on the NMR time scale. It is, nevertheless, most
essential that-in accordance with equations (4) and (7)---A.PtR is
proportional to r;3 in all cases (cf. Section 4.1).
For the case of a non-axially symmetric complex where the
substrate rotates freely around an axis running through the metal
ion, the following esuation has been proposed11621 :
A“’” = ---I- 1 D‘(3cos‘a- 1 ) - D“sinLacos2~1(3cos2y- I ) (9) 2
r’
The angle y is included by the radius vector r, (Fig. 4) and the
rotation axis of the substrate; a and refer to the position of the
rotation axis in analogy to 9 and a.
The spectral shifting potential of a shift reagent is deter-
mined by its anisotropy parameters D‘ and D”, which are usually
temperature d e ~ e n d e n t ” ~ ~ ’ . In the series of axially
symmetric, organometallic shift reagents of the type
(C5H5)3Ln(~~~)127,1441 with Ln = La through Lu, the parameter
D’(ax) is proportional to the para-
Angew. Chem. internal. Edil. / Vol. I 1 (1972) / No. 8 677
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magnetic shift A F of a specified proton of the sub- strate s.
If S = cyclohex~lisonitrile, the variation of D’(ax) = - A Y / G ,
is quite pronounced (Fig. 5 ) .
A similar periodicity has been found for a series of homologous
chelate adducts L n ( d ~ m ) , S ~ [ ’ ~ ’ . The same very
characteristic dependence of AdiP on the number of f electrons of
Ln was confirmed with the mag- netic anisotropy parameters very
recently determined for the crystalline adducts[1621. It is
remarkable that, according to available data for homologous series
of lanthanoid complexes, the ions of each of the three “triads”
[Ce, Pr, Ndl, ITb, DY, Hol, and [Er, Tm, Yb] induce dipolar shifts
of the same signf2”. Bleaney et al.”631 have just recently given a
theoretical explanation for this periodicity.
1 2 -
11
10
1 - 5 7 - Y
> 6 - 5- r , -
3 -
2 -
1 -
-20 I601 I l l 1 l l l l l i 1 1 ‘ l
la Ce Pr Nd Pm SmEu Gd Tb Dy Ho Er TmYb l u l7zzEJ
+01 +O 075 -0 05 -
01 -
+o 2
-0 2 -03 -0 4 -0 5
-1 0
Fig. 5. Isotropic shifts (in ppm) of the C,H,,-protons in
&position of the adducts between cyclohexylisonitrile and the
lanthanoid- (iii)-tricuclopentadienides, Ln(C,H,), 171. Solvent
D,-toluene: T = 302’K. 90 MHz. The linewidths at half-height (Hz)
are given in parentheses.
The sign of A?’. can often be predicted more easily than its
absolute magnitude: thus, in the example of Fig. 1 b we have x,,,xI
< 0 (diamagnetism) and in the case of the UO;’ ion xI > 0
(temperature-independent paramagnetism). Further, G, > Oand G,
< 0, respectivel~, forthetwoexamples. IfX,i
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The calculation of A, is even more difficult than the
calculation of D’ and D”*261. Since there is n o means of
correlating the contact shift with geometric coordi- nates, as was
shown for the pseudocontact shift, and since a reliable
factorization of the experimental shift into the dipolar and
contact contributions is not pos- sible in many cases, noticeable
contact contributions in the shift reagent technique usually
prevent quantitative structural evaluations.
Paramagnetic lanthanoid complexes fulfil the require- ment of
negligible contact interactions particularly
because the radial extension of the 4 f orbitals is exceedingly
small. According t o experience, however, it is safe to neglect
contact contributions even in 4f- systems only if a t least three
atoms (i. e. four bonds) are situated between the nucleus under
investigation and the paramagnetic center. From extensive ”0- and ‘
H - N M R studies of lanthanoid a q u o - c o m ~ l e x e s [ ~ ~ ’
it was concluded that AEn%AgD holds for the 0-a toms in the first
coordination sphere, whereas the overall shift At;O of the
neighboring H-atoms still contains a contact contribution of a t
most 60%.
2.2. Dynamic Effects
The equations given in Section 2.1 allow quantitative
predictions as to magnitude and sign of the isotropic shifts; they
d o not, however, contain a term including the linewidth allowing
predictions referring to the chances of a signal to be observed.
Unfortunately, drastic signal broadenings have t o be expected fre-
quently in paramagnetic samples containing unpaired electrons.
These may be caused not only by intra- molecular spin
delocalization, but also by time-depend- ent intermolecular in te
rac t i~ns[*~l .
These undesirable line broadenings may be partially compensated
for if the mean lifetime of the electronic spin states (electron
spin-lattice relaxation time Tie) is drastically reduced with
respect to the correlation time for the thermal motion of the
molecules. Besides extremely low T,, values, rapid changes of the
ligand field at the paramagnetic metal ion can also give rise to
narrow linewidths.
The term T,’ clearly corresponds to the rate of trans- forming
the excitation energy of a discrete spin level into thermal energy
of the surrounding “lattice” (i. e. coordination + solvation
sphere). T,’ increases with increasing temperature and with the
strength of the external magnetic field, and, a t the same time,
with increasing magnitude of the spin-orbit coupling con- stant,
but with decreasing energetic difference between the electronic
ground state and the next excited ( = ligand field) states. The
last two requirements are again fulfilled particularly well by
systems containing unpaired 4 f o r 5 f electrons.
Apart from the spin-only system G d 3 + (f’), lanthanold and
actinoid complexes actually exhibit N M R linewidths between a few
Hz and several hundred H2“4,30,’651 According to systematic study
of the linewidths in the
spectra of the adducts Ln(dpm),S,by H o r r ~ c k s “ ~ ’ and
according to general experience complexes of Eu and Pr exhibit the
sharpest signals. On the other hand, the signals of most
d”-transition metal complexes are sufficiently narrow only in
exceptional cases (Coz+ and Ni2+). The detection of the N M R
signals of para- magnetic organic radicals is usually prevented by
their excessive linewidths.
Chemically, the lifetime of the relevant electronic states can
also be reduced by rapid reactions of type (1 a)-(1 c). Signal
narrowing is also t o be expected if the adduct S-R is able to
alternate between several conformations (S-R)’, (S-R)”. . .
etc.
3. Systematic Approach t o Shift Reagents
3.1. General Requirements
An effective and versatile shift reagent should fulfil at least
four requirements:
1 . Optimal shifting potential combined with minimal signal
broadening effect;
2. ability to interact with a great number of substrates, i. e.
marked acidic or basic properties;
3 . sufficient solubility;
4. absence of interfering absorptions in the usual range of
substrate spectra.
Ideal, universally applicable shift reagents cannot be realized:
Lewis-acid shift reagents are effective only with basic substrates
(and vice versa). High reactivity (for instance towards extremely
weak bases) is not compatible with the chemical stability required
at the same time. A high reactivity even excludes the use of polar
solvents, since their functional groups would compete with the
substrate.
Requirements 1 to 4 d o not yet take into consideration that
quantitative information about the molecular struc- ture o r the
conformational behavior of a substrate is sometimes desirable. With
regard to such studies the following requirements should also be
fulfilled:
5 . Pseudocontact should dominate over Fermi-contact
interactions;
6 . the secondary fields should have axial symmetry, and the
point-dipole approximation should be valid;
7. theadduct S-R should be conformationally uniform (whereas the
substrate itself may have several confor- mations);
8. a straightforward temperature dependence of the isotropic
shifts ( e . g . temperature-independence o r linear variation of
Also with l/n.
Whereas postulates 5 to 7 are the prerequisites for the
applicability of equations (4) to (8). postulate 8 is particularly
advantageous for conformational studies within wide temperature
ranges1271. This last point, however, has rarely been found to be
truec9’, 123, I z 4 . 1521.
Angew. Chem. internat. Edit. 1 Vol. I 1 (1972) 1 No. 8 679
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3.2. Types of Shift Reagents Applied
3.2.1. Coordination Compounds Containing Unpaired d o f f
Electrons
Although numerous examples of the application of dn- complexes
as shift reagents have become
, coordination compounds of the rare earth elements have more
favorable properties.
The special features of the 4f radial function^"^] of these
elements result in an optimal fulfilment of require- ments I and 5
. In addition, the characteristic flexibility of the rare earth
ions with regard to their preferential coordination number"461
ensures the spontaneous for- mation of sufficiently stable
adducts.
With respect to their various applications and their chemical
nature we classify shift reagents containing unpaired d or f
electrons as typical salts, chelates, and organometallics.
known [8 - 11.34 - 38.129- 131,1551
3.2.1.1. Salts
Most representatives of this class are simple salts of
transition element or lanthanoid ions forming solvated ions-mainly
in aqueous solution-which are capable of additionally coordinating
a polar substrate (cf. Table
Table 1. Some examples for the application of shift reagents of
the salt type to studies on substrates in aqueous solution.
Shift reagent Substrate Ref.
COCI, n-oropanol [81 CUCI, carnosine [401 (FeNH,),(SO,), amino
acids I411 Eu(NO,);6D2O organophosphorus compounds I421 Ln(CIO,),.6
H,O amino acids, carboxylic acids [431
EuCI,. 6 H ,O carboxylic acids [441 EuCI, ribose 5-phosphate
I1151 EuCl, mononucleotides 11 561
(Ln : Pr. Eu)
1 ) . Shift reagents of this type are suited only in rare cases
to quantitative spectral analyses because of inad- equate
fulfilment of postulations 1, 6, and 7"15.1561. Such reagents had
already been employed for more than a decadeL8' before Hinckley's
first paper[IZ1.
3.2.1.2. Chelates
This category comprises the systems best known and most widely
used, including also Hinckley's original reagent Eu(dpm), . 2 p ~ r
" ' ~ . All representatives of this class (Fig. 7) constitute
b-diketonato complexes of the general formula L,,MX, (L=chelate h a
n d ) . In the case of transition metal complexes L2 M at best two
co- ordination sites are available for the substrate. Lan- thanoid
complexes L3MX, with n = O provide several free, acidic
coordination sites. Because of the varia- bility of the
coordination number of rare earth e l e r n e n t ~ " ~ ~ ~ ' ~ ' ~
, complexes with n = 1 or 2 may still exhibit at least one free
coordination site, even in the case of Hinckley's reagent (M = Eu,
X = pyridine, n = 2, formal coordination number: 8).
Voluminous substituents of simple structure are prefer- ably
chosen as substituents R (Fig. 71, e. g . CH,, C6HS, n-C3F7 or
C(CH3),. Thus postulations 3, 4, and 7 are accounted for.
dpm or tmhd: K'= R = -C(CH3), fod: 12'= -C(CH3)3, R =
-CF2-CF2-CF3
Fig. 7. General structure of shift reagents of the chelate
type.
The accumulation of voluminous substituents R should limit the
number of possible conformations of the shift reagent, especially
if m = 3[451. It also diminishes the affinity of the reagent toward
water, which, if absorbed, decreases its shifting a b i l i t ~ ' ~
~ - ~ ~ ' . Fiuorinated substi-
enhance the solubility and -presumably through inductive
effects-the acceptor strength of the reagent.
For the chelate ligand with R' = R" = C(CH,)3f501 the notation
"dpm" (from: "dipivalo-methanato-") or "tmhd" (from:
"tetramethylheptanedionato-") has come into current use in the
literature. The ligand with R' = C(CH,), and R" = n-C3F7[49.1541 is
written "fod" (from: "heptafluoro-dinieth4 Ir,ctanetlionato-").
"Fod" complexes are also in use in their perdeuterated forms
(postulate 4). A good account of the practical problems connected
with the application of lanthanoid shift reagents is given in
Ref.[1271.
The composition of the adducts formed in solution between a
shift reagent and a monofunctional substrate is by no means
uniform. Obviously it also depends on the nature of the substrate.
Thus, the existence of 1 : 1 a d d u c t ~ [ ~ ' ~ . ' ~ ~ ] and 2
: 1 a d d u ~ t s [ l ~ ~ ~ has definitely been proven. So far
little is known about the conformations of the adduct in solution.
According to recent observa- tions it cannot be excluded that the
preferential confor- mation of an adduct is influenced by the
nature of the coordinated s~bs t ra te l"~ .
In the crystalline state evidence exists for well-defined
adducts between tris(P-diketonat0)lanthanoid com- plexes and 1 to 4
additional ligands, especially ~ a t e r ~ ' ~ ~ . ' ~ ~ ] . X-ray
structure analyses of the 1 :2 adducts Ho(dpm),- 2 (4-p i~ol ine)
'~~I and Eu(dpm),-2 pyr1871 pro- vided evidence that the two
substrate molecules d o not have coaxial positions in the adduct.
The symmetry of the complexes is only C2"621. Analogous results are
provided by the known structures of several crystalline 1 : 1 ad
duct^"^^'. If these results would hold also in solution, axially
symmetric ligand fields at the central ion could be expected only
in rare cases.
Most chelate reagents are more o r less hygroscopic and
chemically unstable towards weak acids such as carbonic acids and
phenols, and sometimes even alcohols[1641. They are, nevertheless,
the shift reagents most widely used today and are certainly the
ones best suited for standard applications.
tuents149. 1571
680 Angew. Chem. internal. Edit. 1 Vol. I I (1972) I No. 8
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3.2.1.3. Organometallics diamagnetism ( e . g . in cyclic
n-electron systems, Fig. 1 b) or through temperature-independent
paramagnetism
The tricyclopentadienyl complexes of several lanthan- ( e . g .
UO;'). Another shift reagent of this class is oids ( C , H , ) , L
~ ( I I I ) * ~ ~ ~ belong to this category. These
iron(Ir)phthalocyanine, FePc, which is paramagnetic. compounds can
coordinate only a single unidentate On axial coordination of two
bases like amines, how- ligand S: ever, the resulting
quasi-octahedral, low-spin complex
FePcS, is diamagnetic"26'.
(C,H,),Ln + S =$ (C,H,),LnS
The acceptor strength of these compounds generally exceeds the
acidity of the chelate Thus it is often possible to isolate
well-defined 1 : 1-adducts free of the components. On the other
hand, the sensi-- tivity of the organometallic shift reagents
towards acids, water, and oxygen exceeds the sensitivity of the
chelate complexes considerably. Therefore they have to be
manipulated in an inert gas atmosphere and in carefully purified
solvents.
Apart from the fact that the shifting potential of the
tricyclopentadienyl complexes sometimes exceeds the corresponding
chelate complexes, a particular advan- tage of many adducts
(C5Hs)3LnS is the C3, point symmetry of the effective ligand field
a t the central ion"'. Such systems fulfil postulates 6 and 7 and
thus often allow quantitative evaluations of the observed spectra
with respect to refined structural and conforma- t ionaI analyses
[7.27. 1441.
Although the solubility of the free complexes (C,H,),Ln in inert
media like benzene o r toluene is often rather limited, the
solubilities of the adducts often turn out to be quite high,
depending on the substrate 1e.g. (C,H,),Nd: ca. 1 mg/ml; (C,H,),Nd
.nicotine: ca. 100 mgiml].
3.2.2. Shift Reagents without Unpaired d or f Electrons
3.2.2.1. Metal-free Radical Systems
Organic nitroxide radicals often exhibit electron spin- lattice
relaxation times which-in contrast to other stable organic
radicals-allow relatively sharp N M R signals to be observed.
Therefore utilization of systems like (CH,),NO or [(CH3),CI2NO as
shift reagents was a t t e m ~ t e d [ ' ~ . ~ ~ ] . Incontrast to
theacidic metal complexes these compounds tend to interact with
acidic substrates. This fact has been made use of in the
investigation of hydrogen bonds.
Moreover, nitroxide radicals can weakly interact with other
organic radicals thus reducing drastically the originally very
large T,, values of these compounds. By this means the N M R
spectra of several organic radicals could be o b s e r ~ e d [ ~ ~
. ~ ~ ~ .
3.2.2.2. Non-radical Shift Reagents
This category comprises those systems which develop a noticeable
anisotropy either through a strong induced
[*I The assumption of this relatively high symmetry IS justified
for the N M R experiment inview of the proven free rotation of the
C,H,-rings.
The advantages of shift reagents of this category are sharp
signals and temperature-independent isotropic shifts. Their
resolving power, however, is only excep- tionally equivalent to
shift reagents with unpaired elec- trons.
Recently, the use of some anionic n-electron systems as shift
reagents ( e . g . [B(C6H,),l- o r IP(Cl2H8),1-) has been
reported'571. These compounds are especially suited to reaction
with cationic substrates in strongly polar solvents. The results
published so far deal mainly with short-lived ion pairs of these
anions with various- in some cases chiral-quaternary phosphonium
ions.
4. Analysis of Shifted Spectra
4.1. Concentration Dependence of the Isotropic Shifts
The concentration dependence of the isotropic shift of a
substrate signal averaged over all possible species present in
solution can be expressed most clearly by the equilibrium
concentrations of the free and complexed substrate :
In this equation, I I ~ - ~ and nS are the molar fractions of
the adduct and the substrate, respectively.
Practically, however, only the initial concentrations [Rlo and
[Slo of the shift reagent and substrate are usually known. One is
forced, therefore, to express 6,,, as a function of L = [Rlo/[Slo
instead of the molar fractions. In diagrams of both 6,,, = f(nR-s)
and 6,,, =f(L) curves of the type shown in Fig. 8 a are
obtained.
In the first case, the extrapolated ordinate intercept and the
slope of the linear part are always equal to 6s ( =chemical shift
of the free substrate) and 6R--S - 6s, the "molar isotropic shift"
of the 1:l-adduct. The analogous correlation in the second case can
be approx- imated only with the restriction that [Rlo< [Sl0 and
the formation constant KL3" of the adduct is sufficiently large.
The main reason is that, as was observed exper- i r n e n t a I I ~
[ ~ ~ . ' ~ " . the stone of the lineal- scclions in dia- grams
IS,,, = f(L) depend noticeably on the absolute substrate
concentration.
Several authors have derived equations allowing the evaluation
of ~ R - - s and K with satisfactory accu- racy[14' - 1 4 ' . I h 9
] . According to Armitage et a1.[141.'591 . a diagram ISlo =
fCS&i) in the concentration range IS10 9 [Rlo at constant [Rlo
yields straight lines:
Angew. Chem. internal. Edit. 1 Vol. I 1 (1972) I No. 8 681
-
From the slope and the y-intercept of such a straight line the
chemical shift hRPs and the formation constant K of the adduct can
easily be obtained. These two parameters are occasionally termed
''intrinsic LIS para- meters" (lanthanoid induced shift)"431. Fig.
8 b is a diagram of [Slo = f(S,A) showing the straight lines ob-
tained for the three different protons of n-propylamine in the
presence of E ~ ( d p m ) , " ~ ~ ~ . It is remarkable that for the
three protons the intercepts are identical (thus resulting in an
identical K value), although the slopes (and thus the values 6R-s)
vary markedly.
0 2 OL 06 08 10 12 [ R I ~ I [ S l ~
-ooL 6& x 102[s] - Fig. 8. (a) Idealized dependence of the
observed shift 6,,, on the molar ratio of the initial
concentrations of shift reagent [RJo and substrate IS]". 65
=Chemical shift of the free substrate, 6, = shift of the 1 :
1-adduct. (b) Plot of 6.~~; = f([Slo) for the three different
protons of n-propylamine at constant Eu(dpm), concentration (en. 0
. 0 0 6 ~ in CDCI,) [1591.
Equation (13) is valid only for 1 : 1 adducts. Suitable
modifications can be obtained, however, taking into account
different stoichiometries. Unknown adduct compositions may thus be
determined"51.1591.
Deviations of the idealized curve shown In Fig. 8 a at higher
values of L may be caused by the finite mag- nitude of K o r by the
self-association of P r ( d ~ m ) ~ and Eu(dpm), which has been
proved independently also in
OccasionaIIv curvatures at low L values are also observed (Fig.
9)1331. However, a determination of the chemical shifts 6s by
extrapolation appears to be justified in most cases110.341. If
either substrate or shift reagent are polyfunctional, the plots
Sex, = f(L) may be completely curved or may exhibit several linear
parts (cf. Section 5.2).
4.2. Graphical Signal Assignment
Frequently the problem of signal assignment can rapidly be
solved by making use of the fact that the isotropic shifts decrease
with increasing distance of the respective nuclei from the bonding
site between shift reagent and substrate. An example is the
distinction between the cis- and the trans form[58.59.78.145.1531
of geometric isomers, as in the case of a phosphetane (Fig.
trans cis
A'""(H-3) = 160 H z Aiso(H-3) = 224 Hz
Fig. 10. Isotropic shift of the 3-proton in cis- and
rruns-2.2.3.4.4- pentamethyl-1-phenylphosphetan-1-one after
addition of 0 48 equivalents of Eu(dpm), in CDC1, 1611.
Because of the direct proportionality between and rL-, Icf.
equations (4) and (7)l it is usually practical to plot these
quantities on a logarithmic In the case of axial symmetry one gets
on taking the logarithms of equation (7):
0 1 0 2 0 3 0 4 0 5 06 07 0 8 0 9 Gzg [Eu ldpmI3]/[Substrate~+
Fig 9 'H-NMR shifts of the naohthyl protons of crs-1,3,5,5-tetra-
methyl-S-(l-naphthyl)cyclohexan-l 01 as a function of the Eu(dpm),
concentration [331
As long as the term in the brackets is constant, equation (14)
is the function of a straight line with slope -3 . The essential
requirement for this term to be constant is:
If this condition holds, 9 may take all values between 0 and ca.
50". and between 60 and ca. 90". Since with 9 = 54.7"
log(3cos'9,- 1) = - ffi
large deviations from linearity are to be expected in the
critical angular range SO" < 9 < 60".
682 Angew. Chem. infernat. Edit. 1 Val. I 1 (1972) 1 No. 8
-
Fig. 11 shows the diagram logA, = f(logt-,f for the two
conformers present at -70°C of the compound (C5W5),PrCNC6H,, with
the cyclohexane ring equato- rially or axially substituted[271. The
deviation from the best straight line with slope - 3 of the points
with 9-values close to the critical range is obvious.
5 6 7 8 9 1 0 20 30 40 50 jb892.111 lliSo IpprnI - Fig. 11 . The
isotropic shifts A'- of the C,H,,-signals in the 'H-NMR spectrum of
(C,H,),PrCNC,H,, at - 70°C as a function of the geometric
parameters r(A) and 9; slope of the best straight line: - 3.2
[271.
1 = 6-H (Ee), 9 = 9' 8 = P-H (Aa), 9 = 14' - 2 = 6-H (Ae), 9 =
2' 9 = P-H (Ea), 9 = 24' 3 = y-H (Ee), 9 = 20' 10 =. P-H (Ee), 9 =
24' 4 = 6-H (Ea), 9 = 20 I 1 =P-H(Ae). 9 = 2 6 " 5 = 6-H (Aa) , 9 =
24 - 12=y-H(Aa) . 9 = g ' - 6 = y-H (Ae), 9 = 3' 1 3 = a - H ( E )
, 9 = 1 3 ' 7 = y-H (Ea), 9 = 12 1 4 = a - H ( A ) . 9 = 1 3 '
A = axially substituted conformation E = equatoriallv
substituted conformation a = axial proton e =equatorial proton
Underlined numbers = points with greatest deviation from the best
straight line.
In the case of protons separated from the metal ion by only
three bonds (e.g. the a-protons in alcohols or e p ~ x i d e s [ ~
~ - ~ ~ ] ) , the large deviations frequently encoun- tered from
the best straight line have been tentatively interpreted with the
assumption of Fermi-contact inter- actions (see Section 2.1.2).
Farid et a/.'661, however, could prove for two such cases[62.671
that these devia- tions were due t o the neglect of the angular
dependence.
From equation (14) it can be deduced that a better fit of all
points to the straight line should be achieved by appreciably
increasing the anisotropy factor D (i. e. by replacing the Pr ion
buTb(rrr) o r DY(III), cf. Fig. 5).
Occasionally, in the diagram log A, = f(logr,) straight lines
with slopes smaller than - 3 have been foundL67-75.1371. In spite
of the approximations used which are responsible for this
effect[761, reliable assign- ments were achieved in these cases
also.
4.3. Position of the Metal Atom
The distances r, can be determined from molecular models (e . g.
Dreiding). The metal-ligand distances should be known for this
procedure; if they are not, they must be approximated. In some
cases sufficiently linear plots of IogA, = f(1ogt-J were obtained
even when r, was put equal to the distance between the atom i of
the substrate and the periphery of the lone pair a t the donor
atom[67-691. Using this method, E r n ~ t [ ~ ~ ] found, e. g . ,
that the preferential conformation of 2,6-dimethyl-
cyclohexylamine is that shown in Fig. 12. It appears to be
somewhat more realistic to express the distance metal-donor atom as
the sum of the two covalent radii[641.
Fig. 12. Preferential conformation of 2.6-dimethrlcrclohexrl-
amine [751.
Sanders and found the distance between Eu ion and 0 atom in the
adduct of 4-tert-butyl- cyclohexanone and Eu(dpm), shown in Fig.
13a by it- erative adjustment of the distances r with the
isotropic
1- a\
k
Fig. 13. (a) Probable position of the Eu(id ion in the adduct
between Eu(dpm), and 4-rert-butvlcyclohexanone 1771; (b) Most
probable position ofthe Eu(i~i) ion in the adduct between Eu(dpm),
and endo-norbornenol 11391. The 0 atom is at the origin of the
internal coordinate system, the 0-C-2 bond is placed along the
negative z axis, atom C-1 is placed io the x-z plane with the
Dositive x coordinate.
shifts. Such iterations can conveniently be carried out by ~ ~ m
p ~ t e r ' ~ ~ ~ ~ ~ ~ ~ ' ~ ~ ~ ~ ~ ~ ~ , especially if the
angular term and internal rotations are also taken into
consideration. The adduct of Eu(dpm), with endo-norbornen01"~~~'~~~
is an example (Fig. 13b). The distances Eu-0 or Yb-0 thus obtained
in adducts with shift reagents of the chelate type are generally
between 3.0 and 3.5 A,L78-801. In the case of fluorenone and
1-indanone, however, a satisfactory correlation was obtained with a
distance Yb-0 of 1.5 k 0.2 (Fig. 14). The results of two
structuredeterminations by X-ray methods in the solid state are,
for comparison: Ho-N in Ho(dpm),(4-pi~oIine)~ 2.53 A[451 and Eu-N
in Eu(dpm),(pyr)r 2.65 A[871.
Angew. Chem. internal. Edit. 1 Vol. I1 (1972) No. 8 683
-
- E, t 15! 10
5 7 I
3 L 5 6 7 8 9 - r CAI- Fig. 14. The isotropic shifts as a
function of the distance r in the adducts between Yb(dpm), and
fluorenone and I-indanone, respectively [81].
4.4. Influence of the Angular Term
Iftheangular dependenceof GI [equation (6)1 is taken into
account, the correlation between the A,-values and the geometric
factors is generally improved [ 2 7 . 4 8 . 6 6 . 8 2 . 8 3 . 1 3 8
1 .
Thus, in the case of the axially symmetric adduct
(C,H,),PrCNC,H, 1[271 the standard deviation of the best straight
line logAl=f(logr,) is 25.6% (Fig. l l ) , whereas it decreases to
2 .8% in the plot A,=f(G,) (Fig. 15). A similar improvement by
nearly an order of magnitude could be achieved with an adduct of a
shift reagent of the chelate This example shows that it is
obviously advantageous not to neglect the
A-Form
aA a E&
2 L 6 8 10 12 li, 16 18 lo3 G [8?1 -
Fig. 15. Correlation between the isotropic shifts measured at -
70°C of the C,H,,-protons and their G-values in the two chair
conformers ofthe adduct (C,H,),PrCNC,H,, (solvent: D,toluene) 1271.
The nomenclature used to label the protons belonging to the points
of the plot is given in the caption to Fig. 11.
term 3cos2s- 1 also in cases of lower than axial symmetry.
The change of sign of this term at 9 = 54.7" is respon- sible
for the occasional observation of shifts to high field using Eu
complexes, which generally cause shifts to lower
field[33.44.85.86~8s.891. For instance, in the alcohol shown in
Fig. 9 the signals of the naphthyl protons 3' and 4' are shifted,
contrary t o the signals of all other protons, to high field[331.
These results are explained in a straightforward manner by the
coordination of the Eu ion at the axial OH-group.
4.5. Internal Rotations
In substrate molecules with internal rotational degrees of
freedom which cannot be frozen-in in the tempera- ture range used
for the measurements, the Ai-values have to be correlated with mean
G, values taking into account all possible rotamers. The mean Gi
value is influenced most strongly by internal rotations whose
rotational axes d o not coincide with the principal axis of
symmetry of the complex. Equation (9) has been proposed for the
case that the metal ion lies within the rotation axis"621.
From the good correlation in the diagram A, = f(G,) of
(C,H,),PrCNC,H, 12'] (Fig. 15) a linear Pr-CN=N arrangement along
the threefold principal rotation axis of the complex can be
deduced. For the analogous alkoxy-complex (C,H,),UC,H however, a
quan- titative correlation between A, and G , was not achieved,
since the rotation axis 0-C in the bent U-0-C group does not
coincide with the principal molecular axis U-0. In most cases of
this kind an exact deter- mination of the mean Gi values is quite
tedious and requires the use of a computer. In unfavorable cases,
therefore, only qualitative signal assignments are pos- sible, even
if a powerful shift reagent is used.
5. Special Applications
5.1. Determination of Spin Coupling Constants
Shift reagents lowering the order of the spectrum of a substrate
without broadening the signals excessively, simplify the
determination of coupling constant^'^^-^^].
Table 2 . Coupling constants of
rmns-5-rert-butyl-2-methyl-1,3,2- dioxa~hosahoran-2-one (Fig. 16).
Upper line: Numbers obtained with computer program LAOCN3. Lower
line: Numbers directly taken from the expanded spectrum.
[Eu (dam ,)I [substrate] JAB J A X J B , JAP JBP
0 -11.1 10.5 4.47 4.14 20.2 0.5 11 11 4 3 20
Table 2 shows the coupling constants. of a heterocyclic AA'
BB'XY-system (Fig. 16)L941. The data obtained from an iterative
computer analysis of the spectrum of
684 Angew. Chem. internat. Edit. 1 Vol. 11 (1972) 1 No. 8
-
the free substrate are listed in the upper line, and in anilines
and the shift of the phenyl protons in the the lower line the
constants directly read off from the 0- and rn-position obtained at
constant Eu(dpm), con- spectrum recorded in the presence of a shift
reagent. centration (Fig. 17a).
I
H, H, I I t-Bu
As important as the basic strength of the substrate are the
steric conditions in the vicinity of the basic center[791. Thus, in
the series aniline, N-methylaniline. and N,N- dimethylaniline the
shifts decrease in spite of increas- ing pK,-values (Fig. 17
b)[991.
I 7
b l
-5OHz----i
Fig. 16. 'H-NMR spectrum of rru~s-5-rer/-butyl-2-methyl-l.3,2-
dioxophosphoran-2-one [941. (a) 0.2 M in CCL: (b) With 0.5
equivalents of Eufdpm),. The coupling constants directly taken from
the spectrum are indicated.
The influence of adduct formation on the magnitude of the
coupling constants of a substrate is comparable to a substituent
effect in all cases where a change of the substrate conformation is
negligible""'. A linear increase of up to 1 0 % in several geminal
coupling constants in camphor and 3,5,5-trimethyl-3-Cp-chloro-
pheny1)cyclohexane has been noted upon increasing the concentration
of the reagents Eu(dpm)3 o r Eu(fodI3 up to a molar ratio L:
0.7"57'. In the case of noticeable contact interactions additional
changes of the coupling constants may possibly O C C U ~ [ ~ ~ . ~
~ ' . A closer examina- tion of this effect is generally prevented
by line broadening.
5.2. Influence of the Basicity of the Substrate; Polyfunctional
Substrates
The formation constant of a n adduct between a substrate and a
shift reagent (cf. Section 4.1) and thus the iso- tropic shifts of
the substrate depend markedly on the basicity of the substrate.
Thus, the "molar shift" induc- ed in substrate RX by Eu(dpm)3
decreases in the order X = NH, > O H > C=O > -0- > COzR
> CNr771. This series could be extended by some very weakly
basic molecules, such as M-SO,CH,, o r the organometallics
(C,H,),Sn o r [(C,H,)Fe(C0),l,[981.
Ernst and M a n n ~ c h r e c k [ ~ ~ ] found a linear
correlation between the pKa-values of a series of p-substituted
2.46
pK. = 5.06 pK, ,= 4.85 ib892.171 (b)
Fig. 17. (a) Correlation between the pK,-values of p-substituted
anilines and the isotropic shifts (in ppm) of the 0- and m-protons
(molar ratio Eu(dpm),/substrate = 0.2; solvent CDCI,). (b) Influ-
ence of the substitution at the nitrogen of aniline on the
isotropic shifts (in ppm) of the phenyl protons 1991.
If a substrate molecule contains two donor functions whose
equilibrium constants of complex formation with the shift reagent
differ greatly (like -OH and -CO,R['ooJ o r P=O and C=O"o'l), in
the diagram 6 = f(L), where 6 is the additive isotropic shift"371,
pronounced changes of the slope at the equimolar ratio ( L = 1.0)
for nuclei close t o one of the two basic centers a re observed.
Evidently the weaker basic group does not coordinate before most o
r all of the stronger function has reacted. Figure 18 shows the
results obtained with a substrate carrying a n alcohol and an ester
function""'.
According to H i n c k Z e ~ [ ~ ~ ' the contributions of the
two donor centers of a bifunctional substrate t o the overall shift
can be separated graphically in the following man- ner (Fig. 19):
in the diagram logAA = f(logrA) of testosterone the AA value of
proton i very likely originates from Eu(dpm), coordinated at the
OH-group. It seems justified to draw a straight line of slope - 3
through point i, since such a line was experimentally found for the
protons of the structurally very similar, but monofunctional
cholesterol['21. The vertical differ- ences of the experimental
shifts of protons j and 1 from this line are equal t o the
contribution AB resulting from
Angew. Chem. internal. Edit. 1 Vol. 11 (1972) / No. 8 685
-
OH H-3 I
H-6 I COOMe
, H-1 x
/ / x
, / x
L I I L L 0 0.4 0.8 1.2 1 6 2.0
Eu Idprn131f[Subs t ra te l~
Fig. 18. The chemical shifts (ppm relative to TMS) of the
protons of
methyl-trans-9-hydroxybicyclo(3.3.l)nonane-endo-3-carbox~l- ate as
a function of the molar ratio Eu(dpm),isubstrate 11001.
Eu(dpm), coordinated at the carbonyl group. These shifts again
fall approximately on a straight line log AB = f(logr,) of slope -
3. The shifts- AA and AB
500
Fermi contact 200 . contribution
tog rb- \og rn - Fig. 19. Graphical determination of the
relative coordination strength of the OH and -0 functions in
testosterone: double- logarithmic plot of the isotropic shifts A
(in Hz) of protons i, 1. k, and 1 as a function of the distances rA
and r, (in A) (cf. text) 1631.
corresponding to the same distance r are proportional to the
complex formation constants K,, and KoH. In
Hart and LoveL'021determined the relative basic strength of
functional groups by inter- or intramolecular compe- tition: under
the influence of Eu(dprnI3 an esuirnolar mixture of
acetone-tetrahydrofuran exhibits the molar shifts indicated in Fig.
20a and b. From the changes of the shifts one can deduce that
Eu(dpm), coordinates tetrahydrofuran about 8 times better than
acetone.
this case the ratio AA/AB = KcoiKon =0.47.
0 H , C K C H 3 1.2
(11.1)
(a)
24.9 (28.0) 11.1 (12.7)
I H 170
( C ) (d)
Fig. 20. Extrapolated molar isotropic shifts (in ppm) of the
protons oftwo monofunctional substrates in an equimolar mixture and
of two bifunctional substrates on addition of Eu(dpm), 11021. In
parentheses: values of the pure substances. (a) acetone, (b)
tetrahydrofuran, (c) thioxane. (d) morpholine.
Similar competition experiments were carried out with
bifunctional molecules (Fig. 20c and d). From a large number of
data a series of basicity was deduced which was practically
identical to the one cited above.
5.3. Polymers
Solutions of polymers such as polyethylene oxide""31 and
poly(methy1 m e t h a c r ~ l a t e ) " ~ ~ * ' ~ ~ ~ also display
in- duced shifts upon the addition of lanthanoid chelates leading
to a substantial improvement of the resolution of their rather
complex NMR spectra. In the case of polypropylene glycol"o51 it was
possible to separate the 'H-NMR bands of the end methyl groups from
the bands of the methyl groups in the polymeric chain, thus
allowing determination of the molecular weight by direct comparison
of signal intensities.
5.4. Dynamic Processes
Dynamic processes whose reaction rates are in a favor- able
range on the N M R time scale (rate constant k : 3 to 300 s-')
cause line broadening, and finally line splitting, if the
temperature is lowered. At the splitting o r coalescence
temperature T'the following approximate correlation holds between
the rate constant k, and the maximum peak separation AV"~~':
Apart from the fact that the rate of such a process can be
changed by complex formation with a shift reagent,
686 Angew. Chem. internat. Edil. 1 Vol. 11 (1972) 1 No. 8
-
the temperature rises if Av is increased by the para- magnetic
effect. Some processes can therefore be ob- served better in the
presence of a shift reagent, because the broadening and splitting
of the signals occurs in a more suitable temperature range.
One has to distinguish between intra- and intermolec-
ulardynamic processes. Intramolecular processes within the
substrate are sometimes obscured in the N M R spectrum by
intermolecular ligand exchange phenom- ena1107. 1081
Ligand exchange in a system lanthanoid chelate-sub- strate was
observed for the first time by Evans and Wyatt11331: in a mixture
of Eu(fod), with an excess of dimethyl sulfoxide in CD2C12 the CH3
signal broadens considerably on cooling the solution to - 45 "C
(Fig. 21 ).
CHDCI,
(50 to 127"C120.1091). On addition of Yb(dprn), Beaute et
a/."09' noticed an appreciable increase in the coa- lescence
temperature, but n o significant change in the
I
0 10 20 30 Av [Hzl-
CHDCI,
free OMS0
L 5 6 7 IA89221/ z -
Fig. 21. 'H-NMR spectra of a 0 . 1 3 1 ~ solution in CHDCI, of
dimethyl sulfoxide (DMSO) after addition of 0 . 0 4 4 ~ Eu(fod), at
(a), 38°C; (b) - 45°C; and (c) - 80°C 11 331.
At - 80°C this signal splits into signals corresponding t o the
free and complexed substrate. A stoichiometric ratio S: R = 2: 1
can be deduced from the relative intensities of these lines.
The determination of solvation numbers of metal ions ( e . g .
UO:+) in solution by the separate observation of the N M R signal
of the free and the shifted signal of the complexed solvent a t low
temperature is a well established
An intramolecular process observable without the inter- ference
of ligand exchange is the rotational isomerism of amides whose
coalescence temperature is rather high
I II
Fig. 22. Coalescence temperatures ( T J and free enthalpies of
activation (AC:) for N,N-dimethrlformamlde (I) and N,N-di-
methylacetamide (11) without and with addition of Yb(dpm),. The
curves represent the temperature dependence of the frequency
difference Av of the methyl signals 11091. Molar ratio
IYb(dpm),l/[Il: (1) = 0 , (2) =0.06; IYb(dpm),l/lIIl: ( 3 ) =0, (4)
=0.05. The numbers at the formulas represent the extra- polated
molar shifts (in ppm) of the respective protons.
a1 30°C
C l -30°C
l l r \
20 30 40 50
Fig. 23. Temperature dependence of the 'H-NMR spectrum
(C,H,,-part) of the adduct between (C,H,),Pr and C N C , H , ,
1271; 6-scale (abscissa) relative to C,H,: solvent: D,-toluene.
Nomenclature of the protons the same as in Fig. 11.
6 [ppml-
Angew. Chem. internat. Edit. / Vol. I1 (1972) / No. 8 687
-
free enthalpy of activation of this rotation (Fig. 22). Sch
warzhans[20', however, found the coalescence tem- perature in the
spectrum of N,N-dirnethylacetamide unchanged upon complex formation
with UBr4"loJ. Thence he deduced that the C O group and not the
nitrogen atom is the center of coordination.
The chair-chair interconversion of a monosubstituted cyclohexane
(cyclohexylisonitrile) upon adduct forma- tion with (C,H,),Pr[271
was studied by observing the temperature dependence of seven
signals of the C6Hl , protons. The coalescence temperatures of
several signal pairs with particularly large Av are raised so much
that large signal broadenings occur already at a little below room
temperature (Fig. 23).
5.5. Reaction Mechanisms
The mechanism of a reaction which is catalyzed by lanthanoid
ions can be studied with the shift reagent technisue if these ions
can act a t the same time as paramagnetic shift reagents on the N M
R spectrum of the substrate. Thus, during the decarboxylation of
oxaloacetic acid either of the complexes I and I1
I IT
JTZ O=C-C'C\CO,Et 66 11
I11 l\i Fig. 24. Possible intermediates ( I and 11) during the
decornposi- tion of oxaloacetic acid catalyzed by Ln(ii3 ions 1441.
111 and IV: Substances of comparable structure.
(Fig. 24) can be formed as an intermediate. For the elucidation
of the mechanism, Reyes-Zamora and Z ~ a i ' ~ ~ ] prepared the
half esters I11 and IV (Fig. 24). Upon addition of EuCI, the CH,
protons of 111 ex- hibited theusuallowfieldshift in the 'H-NMR
spectrum, in contrast t o the signals of IV which were shifted to
high field. As oxaloacetic acid shows a low field shift on addition
of EuCI,, the authors concluded that the intermediate must have
structure I which is the only possible one that the half ester 111
can form with the metal.
The kinetics of the catalytic deuteration of 4-tert-butyl-
hexanone were studied by measuring the intensity de- crease of the
various 'H-NMR signals of that substrate after spectral
simplification with E u ( d ~ m ) , { ' ~ ~ ' .
5.6. Pulsed Fourier-Transform 13C-NMR Spectroscopy
Shift reagents have hitherto been employed almost ex- clusively
in 'H-NMR spectroscopy, not only because the proton is still the
nucleus most widely used, but also because the spectral resolution
efficiency of the shift reagents is greatest here. However, there
are inter- esting applications in the NMR-spectroscopy of other
nuclei, e. g . in pulsed Fourier-transform ( = P.F.T)
~3C-NMR-spectroscopy~1131. The investigation of chol- esterol in
the presence of E ~ ( d p m ) , [ ' ~ ~ ' is an example.
Gansow et ~ l . 1 " ~ ~ assigned the P.F.T. "C-NMR spec- trum of
isoborneol, recorded by the common 'H- broadband decoupling
technique (Fig. 25). British
Fig. 25. Isotropic T - N M R t1141 and 'H-NMR [64, 1141 shifts
(in ppm) of isobomeol ( 0 . 3 4 ~ ) in an eauimolar mixture with
Eu(dpm), in CCL. CH, groups=*; all shifts are to low field; the ' H
data are written in italics.
expanded the relatively complex l3C-NMR spectrum of
ribose-5-phosphate by adding Eu3+ ions in aaueous solution. The
assignment of the signals was achieved by means of
hetero-spin-decoupling: the selective irradiation of definite
'H-decoupling frequen- cies was feasible only in the spectrum
simplified by the Eu ions Fig. 26).
bl l i l
3a :" 1 bl liiil
30 20 10 0 - S [pprnl Fig. 26 (a) IH-NMR spectrum (100 MHz) of
ribose-5-~hos~hate ( 0 . 7 ~ in D,O) in the absence (above) and in
the presence of 0.97 M E u ~ + ions at pH = 1.1. DSS =sodium salt
of 2,2-dimethyl-2- silapentane-5-sulfonic acid; I a to 5 B=nuclei
in position 1 to 5 with respect to the phosphate group of the a-
and B-anomer, respectively. (bf 13C-NMR spectra (25.2 MHz. P. F.T.
techniaue) of ribose-5-phosphate (0.6 M ) with an addition of 0.72
M Eu' ions 11 151; (i) 'H-broad band decoupliny: Cii) selective
irradiation of the 21)-'H frequency; (iii) selective irradiation at
the 3a-'H freauency .
688 Angew. Chem. internat. Edit. 1 Vol. I 1 (1972) No. 8
-
5.7. Chiral Shift Reagents The absence of chiral splitting in
the case ofenantiotop- ic[1501 pairs of nuclei in otherwise
nonchiral substrates ( e . g . the methyl groups in 2-propanol or
dimethyl sulf- oxide)[1201 as well as the dependence of Ach,r on
the con- centration ratio reagent: is consistent with
Pirkle et a1.["6.1321 noticed that the NMR spectra of the
enantiomers of asymmetric compounds (particularly
alcohols,a-hydroxy-acids, amines, amino acids and sulf- oxides)
differ appreciably In optically active solvents, e. g . (R)- ( -
)-2,2,2-trifluorophenylethanol. These differences are presumably
caused by the formation of diastereo- meric adducts between the
substrate and the optically active solvent. The latter is to be
considered as a chiral shift reagent. The splitting of the spectra
results from a different position of the substrate nuclei in the
dia- stereomers with respect t o the magnetic field produced by the
ring current of the x-system of the solvent.
Prior t o the introduction of more efficient chiral shift
reagents of the chelate type numerous N M R studies were conducted
on paramagnetic complexes of the d- transition elements with
asymmetric chelate ligandsf"7."s1. Primary concern in
investigations of this type is directed, however, at the spectra of
the chelate ligands. The first chiral shift reagent of the chelate
type with a lanthanoid central ion was prepared by Whiteside and
Other, similar reagents with praseodymium and europium as central
ions were de- scribed later"20.1211. Fig. 27 illustrates the effect
of the chiral shift reagent ( 1 ) (Table 3) o n the ' H - N M R
Table 3. Chiral shift reagents of the B-diketonato type
( I ) R = -C(CH,), (2) R = -CF, (3) R = R'
( 5 ) R' = R" = R' ( 6 ) R' = R', R" = R'
(7) R ' = l l % R 2 + 2 3 % R ' ; R " = R3 (8) R' = R' ; R" =
11% R2 + 23% R'. ( 4 ) R = l l % R 2
+ 23%R1
spectrum of pure (S)-a-phenylethylamine and on a mixture of both
enantiomers of this substrate. All signals in the spectrum of the
pure (S)-enantiomer appear doubled in the spectrum of the mixture
with the splitting Achlr being largest for nuclei in the vicinity
of the asymmetric center of the substrate. Whereas the
utilizability of ( I ) is limited to rela- tively strong donors
like amines, chiral splitting is also induced in the spectra of
alcohols, ketones, esters, and sulfoxides by the more acidic chiral
shift reagents (2) t o ( 8 ) (Table 3). Table 4 gives a survey of
the chiral shifting potential of such reagents. A particularly
straightforward synthesis of the h a n d of chiral shift reagent (
2 ) (Table 3) is given in Ref."49'.
I
180 170 160 150 1LO 130 120 110 100 9 0 8 0 - 6 [pprnl Fig. 27.
'H-NMR spectra of a-phenvlethylamine in CCI, after addition of
trisf~3-tert-butylhydrox~methylene~-o-cam~horatol- europiurn(1ri)
[I 191. Molar ratio ~Eu-corn~lexl/tsubstratel: 0.5 to 0.6. (a) Pure
(S/-form of the amine; (b) mixture of (9- and (Rbform.
Table 4. Signal shifts 4h,r induced by chirdl shift reagents
(R).
Substrate Proton
2-octanol
1 -phenulethyl acetate
1 -rnethyl-2-nor- bornanone
1 -phenulethuI- amine
2-phenyl-2- butanol
benzyi methyl sulfoxide
2-butyl formate
u-CH, 121 0.11 I I
-C02CCH3 (21 0.18
(21 0.11
' 31 1.13 I ( 8 ) 1.65
-+, (31 0.32 ( 8 , 0.25
-CHzS- i . 0.6
z 0.6
> 0.6
ca 1.3 ca. 0 . 8
ca. 1.3 ca. 0.8 ca. 1.3 ca. 0.8 ca. 1 3 ra. 0.8
[a1 The numbers refer to the compounds in Table 3
the assumption that the formation of conformationally stable
diastereomers is an essential requirement for the spectral
splitting. In particular, if the formation con- stants of the
diastereomers differ measurably, the assumption seems justified
that different geometric factors correspond t o analogous nuclei of
the sub- strate in the diastereomeric pair. A comparison of the
Achir values given in Table 4 with comparable data of
diastereomeric systems without unpaired electrons
Angew. Chem. internal. Edil. / Vol. I1 (1972) / N o . 8 689
-
shows that the anisotropic field of the lanthanoid ion improves
the splitting of the spectrum by approximately an order of
magnitude.
5.8. Isotope Effects
A further interesting application of shift reagents of the
chelate type was found by Hinckley et a1.[‘35.’361 and other
author^"^'^'^^^'^^^: the I H-NMR spectra of alcohols partially
deuterated at the position geminal to the OH-group are doubled
under the influence of Eu complexes. The isotropic shifts of the
doubled signals differ by 1 to 3.5 %. The authors discuss as
possible reasons for this splitting a change in the basicity of the
hydroxyl oxygen by the deuterium substitution or dif- ferences in
the strength of a secondary hydrogen bond- ing between the geminal
H (or D) and the ring oxygens of the metal chelate ligands.
Received: Mar 9. 1972 [A 892 IEI German version: Angew. Chem.
84, 737 (1972)
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2337.
Organic Syntheses uia Free-Radical Displacement Reactions of
Organoboranes[**l
By Herbert C. Brown and M. Mark M i d l a n d [ * ]
In the few short years since the discovery that organoboranes
undergo facile free-radical substitution, application of these
reactions has become a major new area of synthetic utility.
Organoboranes undergo a wide variety of free-radical reactions such
as aut- oxidation to the alcohol or hydroperoxide, 1.4 addition to
a,P-unsaturated deriv- atives, addition to disulfides, and
oxygen-induced radical coupling. It is evident that organoboranes
constitute a versatile new source of free radicals and that these
reactions can be readily controlled t o give very clean syntheses.
The application of these re- actions will be discussed.
1. Organoboranes as Excellent Sources of Free Radicals
Recognition that the organoboranes are excellent sour- ces of
free radicals and can participate in free-radical chain reactions
cameabout through detailed mechanistic studies of the reaction of
organoboranes with OXY- gen"- and with u,B-unsaturated carbonyl
corn- pounds'41.
Originally, it was suggested that the autoxidation of a
trialkylborane proceeds via an intermediate "borine- peroxide" / 1
' ' ' More recently, it was recognized that
e e R,B-0=0 / I )
these peroxides are true alkyl peroxide derivatives, con-
taining the structure ROOB:. Thus, the reaction of oxygen with
tri-sec-butylborane in dilute solution yields the diperoxide (2)
'". However, the formation of these
I*] Prof. H . C. Brown and M. Mark Midland R. B . Wetherill
Laboratory Purdue University Lafayette. Indiana 47907 (USA)
I**] Based in part o n Chapter XIX of a forthcoming book (Baker
Lectures) by H. C . Brown: Boranes tn Organic Chemistry. Cornell
University Press, Ithaca. N. Y . (USA)
peroxides was long considered to involve non-radical processes
because many of the usual radical inhibitors, such as hydroauinone,
had n o apparent effect upon the r e a ~ t i o n ~ ' ~ .
The oxidation of optically active 1 -phenylethylboronic acid
gave a racernic product and this was considered to besuggestiveofa
process involving radicals[". Indeed, i t was observed that a
remarkable induction period occurs in the autoxidation of this
compound in the presence of added inhibitors such as copper(r1) N ,
N - dibutyldithiocarbamate and galvinoxyl 12.6-di-rert-
butyl-a-(3,5-di-rerr-butyl-4-0~0 -2.5 -cyclohexadien - 1 -
ylidene)-ptolyloxyll['l. It was then discovered that gal- vinoxyl
also effectively inhibits the autoxidation of tri- i s o b u t ~ l
b o r a n e [ ~ ~ , the epimeric trinorbornylboranes'*' and other
organoborane~*~] . These findings led to the suggestion that the
autoxidation of trialkylboranes pro- ceeds via a free-radical chain
processr' - 3 1 .
R I B + 0 2 --t R - + R2B0, . R . S O ? 4 RO,. RO?. i BR, -
RO,BR: + R .
Perhaps the most unusual feature about this proposed process is
the assumption that a free alkylperoxy radical is capable of
rapidly attacking boron with displace- ment of an alkyl radical,
the latter then continuing the chain. Evidence for this reaction
course has accumulated rapidly. For example, when
di-rert-butylperoxide is
692 Angew. Chem. inrernat. Edit. / Vol. I1 (1972) 1 No. 8