Selected Topics from Recent NMR Studies of Organolithium Compounds

Após uma breve introdução à espectroscopia de RMN de metais alcalinos e alcalino terrosos, esta revisão concentra-se nas investigações de RMN em compostos organo-lítios. O método de impressão digital isotópica, que baseia-se no deslocamento das ressonâncicas de Li induzido por deutério, é apresentado e exemplificado com aplicações sobre o comportamento de agregação de sistemas de ciclopropil-lítio e formação de agregados mistos entre metil-lítio e sais de lítio. No capítulo seguinte discutem-se experimentos unie bidimensionais, tanto para sistemas de spin homonucleares quanto heteronucleares. Finalmente, descrevem-se os aspectos estruturais associados ao benzil-lítio e a formação de sistemas poli-lítio pela redução de bifenilas por lítio.


Introduction
The alkaline and alkaline earth metals, a group of elements which comprises the four biologically most important cations (Na + , K + , Ca 2+ , Mg 2+ ), provides us with an appreciable number of magnetic nuclei (Table 1 1,2 ).No wonder then, that NMR spectroscopy finds widespread applications, including such diverse topics like ion solvation in solution, investigations of ion binding to biological macromolecules and enzymes, solid state NMR of minerals and metal-doped fullerenes, as well as sodium NMR imaging.
With respect to investigations of structure and dynamics in organometallic chemistry, however, high-resolution NMR spectroscopy of most of these nuclides suffers from large quadrupole moments which lead to severe line broadening.Notable exceptions are beryllium, 9 Be, cesium, 133 Cs, and in particular the lithium isotopes 6 Li and 7 Li which can be successfully employed in various one-and two-dimensional NMR experiments.Especially 6 Li, which has the smallest quadrupole moment of all stable nuclides and which has been classified ludicrously as an 'honorary spin-1/2 nucleus' 3 , is an important tool for the elucidation of structure and dynamics in lithiated carbon, nitrogen, and phosphorus compounds.
A concise and informative review on NMR of alkali and alkaline earth metals was lately given by Akitt 2 , who also lists the earlier progress reports for this field.Laszlo 3,4 and Lutz 5 provided additional articles, as did Drakenberg 6 and just recently again Laszlo 7 .Several extensive progress reports dealing with 6,7 Li-NMR have appeared [8][9][10][11][12][13] , a fact which underlines the continuous activity in this area.On the other hand, the biological importance of certain group I and II metals like sodium, magnesium, and calcium has initiated numerous NMR investigations of the respective nuclides in biological systems and results from this field, including accounts on sodium NMR imaging, have been summarized by several authors [14][15][16][17][18][19][20][21][22] .In addition, completely new areas for NMR investigations became accessable with the discovery of alkali anions 23 , the synthesis of alkali and alkaline earth intercalation compounds of fullerenes [24][25][26][27] , and studies on clay minerals used as catalysts in organic synthesis 28 .Two Specialists Periodical Reports 29,30 summarize regularily the literature on NMR investigations involving alkali and alkaline earth metals.
For high-resolution NMR in organometallic chemistry, especially 6,7 Li, but to some extent also 9 Be and 133 Cs are the nuclides of choice, while NMR of the remaining nuclei in Table 1 is less common for a number of reasons.As already mentioned, line broadening as a result of fast quadrupole relaxation renders the measurement of chemical shifts difficult if not impossible.For the same reason, scalar spin-spin coupling, which forms the basis of many modern NMR experiments, is not resolved or is even absent due to purely ionic bonding or the existence of solvent separated ion pairs.The majority of NMR investigations is thus confined to chemical shift and relaxation studies.In addition, because of effective quadrupolar relaxation, most of the heavier nuclei are not expected to show nuclear Overhauser effects which have proved so important in the structural elucidation of organolithium compounds.Aside from 1 H, 6,7 Li NOE effects, only for 133 Cs NOE spectra have been reported 31,32 .Finally, from all organometallic systems of main group metals, the lithium compounds are by far the most important for synthetic applications, only rivaled in the field of carbon compounds by the Grignard reagents.Initial attempts to use 25 Mg NMR in this area met with success [33][34][35] , but have not initiated further efforts in this direction, despite reported improvements in the experimental technique 36 .
It is thus quite understandable, that from the viewpoint of structural research on organometallic systems 6,7 Li-NMR is much more attractive.In addition to 1 H, 6 Li and 1 H, 7 Li nuclear Overhauser effects, ample spin-spin coupling between 6,7 Li and other nuclei like 1 H, 13 C, 15 N, 29 Si, 31 P etc. exists and opens the doors to Alices wonderland of modern one-and two-dimensional NMR.The following account, therefore, deals exclusively with selected topics from recent NMR investigations of lithiated systems, where small linewidths and scalar spin-spin coupling paves the way for experiments which lead to a deeper understanding of structure and bonding.

Structure Determinations Via 2 H-induced 6 Li-NMR Isotope Shifts
small is beautiful NMR isotope effects are long known 37 , but it was only after the introduction of high-field instrumentation that these parameters, which are often in the ppb region, became generally accessible.They soon were recognized as interesting data in connection with research on structure and bonding [38][39][40][41] .If an atom n X is replaced by its heavier isotope m X (m > n), a NMR shift, ∆(Y)( m/n X) is observed for the nucleus Y which may be directly attached to m X or several bonds away.For one-bond effects the shift is exclusively to high field (low frequency), while isotope shifts induced over several bonds may have the opposite direction.Two illustrative examples for one-bond effects from the literature are shown in Fig. 1.
The reason for the isotope shift lies in the bond lengths changes associated with the isotopic replacement, which lead to a slightly shorter bond for the compounds with the heavier isotope (Fig. 2).This is due to the anharmonicity of the X-Y bond potential and the lower zero-point vibrational energy of the m X-Y as compared to the n X-Y bond.This results in a shielding effect for Y but also for nuclei several bonds away.However, in the case of isotope shifts over more than one bond, the opposite sign (low-field or highfrequency shift) is often observed 42 .
In organic compounds, deuterium-induced shifts of 13 C resonances have been studied extensively and correlations with carbon hybridization and substitution 43 , hyperconjugation 44 , dihedral angles 45 , and spin-spin coupling constants 46 were found.Apart from these aspects which are related to physical organic chemistry, isotope shifts have also been used in a straightforward way as assignment aids in 13 C-NMR [47][48][49] . 2 H/ 1 H isotope shifts decrease with the number of bonds between deuterium and the 13 C nucleus which is observed and are usually too small to be detected if more than four bonds are involved.However, in unsaturated compounds effects over as much as twelve bonds have been reported 50,51 .
The isotopic fingerprint method which we introduced as a tool to study aggregation of organolithium compounds 52 uses for the first time 2 H-induced isotope shifts of 6 Li-NMR signals.The idea was, that, for example in the case of a tetramer like methyllithium in diethylether, a 1:1 mixture of deuteriated and non-deuteriated material, CD 3   6   Li and CH 3 6 Li, should yield different environments for the 6 Li nuclei.As shown in diagrams 1a -1d, the direct surrounding of a particular 6 Li nucleus might consist of three, two, one, or no CH 3 group, leading to the environments hhh, hhd, hdd, and ddd.Considering the statistical distribution of the deuteriated ligand, a quadruplet with an intensity ratio of 1:3:3:1 was expected and indeed observed (Fig. 3).Here, the isotope shift amounts to roughly 16 ppb  per CD 3 group and is of positive sign on the δ-scale (lowfield or high-frequency shift).
By a straightforward extension of this reasoning, a doublet is expected for a monomer and a triplet for a dimer (Fig. 4).Thus, clusters of different size are characterized by isotopic fingerprints, where the intensity ratio within the multiplets follows Pascal's triangle.In general, the number of observed lines is n + 1 and the intensity distribution is given by the expression (a + b) n , where n is the number of organic ligands around each lithium cation and a and b are the mole fractions of 2 H-labeled and non-labeled material, respectively.
The argument developed above takes into account only next neighbors and corresponds to the local environment approximation introduced by Brown. 53Indeed, 2 H-induced isotope shifts from deuterons residing in organic ligands not directly attached to the 6 Li nucleus under study are mostly too small to be detected and have sofar been observed in simple alkyllithium compounds only in a few cases (see below).The remote neighbor thus normally does not effect the lithium resonance as long as we deal with aggregates which are static on the NMR time scale.Considering the magnitude of the shift effect (16 ppb or 0.9 Hz at 58.88 MHz for 6 Li on a 400 MHz 1 H instrument), the lifetime of the particular cluster should be in the order of 2 s or more.If the lifetime falls short of this limit, intra-aggregate exchange brings also the remote neighbors into play and for a tetramer, again with equal numbers of deuteriated and non-deuteriated ligands, five different environments exist: hhhh, hhhd, hhdd, hddd, and dddd.Now a quintuplet results, as observed for the fluxional phenyllithium tetramer (Fig. 5a).
Finally, with the inset of inter-aggregate exchange, line broadening starts and a singlet is found in the fast exchange limit (Fig. 5).
An advantage of the isotopic fingerprint method as compared to other NMR techniques which are used to study aggregation phenomena and which rely on the measurement of 13 C spectra (chemical shift studies, observation of 13 C, 6 Li scalar spin-spin coupling) is its high sensitivity due to double isotopic enrichment, which is easily achieved. 6Li is readily incorporated directly or via lithiation with [ 6 Li]butyllithium, while numerous procedures for the deuteriation of organic ligands are available.Thus, even aggre-  gates which coexist in low concentration may be detected and characterized 54 .
In order to illustrate the application of the isotopic fingerprint method further, we discuss below recent findings for lithiated cyclopropyl compounds and results of a study on the structure of mixed aggregates between methyllithium and lithium salts.

Aggregation behavior of 1-Lithio-trans-2,3-dimethyl-cyclopropane
For a study of cyclopropyllithium compounds we chose the trans-2,3-dimethyl system 2 which was synthesized from the corresponding bromide 3, obtained by tributyltinhydride reduction of the 1,1-dibromide 4, which in turn resulted from the addition of dibromocarbene to trans-2butene.A salt-free sample was prepared via the mercury compound 5. Deuterium at C-1 was introduced by reduction of the dibromide with tributyltindeuteride.
For the 6 Li-NMR investigation of the aggregation behavior, a sample of 2 and [D]2 (1:1) in diethylether/THF (1:1) and one mole equivalent LiBr was prepared, which showed a 6 Li doublet (∆δ = 4 ppb) indicating the formation of a mixed dimer [C 5 H 9 Li,LiBr] (Fig. 6a).The observed multiplicity is also compatible with the presence of the monomeric lithium species 2, but in this case a separate 6 Li signal for LiBr should have been observed.The sole resonance at 0.8 ppm (rel.to 0.1 M ext.LiBr in THF) is thus due to the mixed dimer.This finding contrasts with the observation made for the unsubstituted parent compound cyclopropyllithium, where a mixed tetramer, [(C 3 H 5 Li) 2 ,(LiBr) 2 ], has been found in the crystal 55 and in diethylether/THF solution 56 .
The two-dimensional 1 H, 6 Li HOESY spectrum 57 (Fig. 6b) established nuclear Overhauser effects between 6 Li and H(1) as well as H( 2), but cross peaks between 6 Li and 3-CH 3 were not observed.This may be due to steric repulsion between the methyl group and the lithium double bridge which increases the Li-CH 3 distance.
For a salt-free sample of 2 and [D]2 (1:1), prepared via the mercury compound 5 in the same solvent mixture, a 6 Li triplet, which characterizes a dimer, (2) 2 , is observed at 187 K as the dominating signal (Fig. 7a).Interesting lineshape changes are, however, found at lowering the temperature to 161 K.The structure of the 6 Li signal resembles a quadruplet between 170 and 163 K, which is associated with a tetramer.Tetramer formation is, however, rather unlikely considering the relatively modest and steady change in chemical shift which is much better explained by a normal temperature gradient rather than by a change of aggregation state.A 6 Li-NMR spectrum run at 73.5 MHz (500 MHz 1 H instrument) revealed that two overlapping triplets are present at 161 K which deceived a quadruplet at lower field strength (Fig. 7b).Thus, two dimers are present in a ratio of 1.0 : 0.7, a consequence of the chirality of the monomer 2 which forms diastereomeric dimers of the (R,S); (S,R) and (R,R); (S,S) type, respectively.
From the intensity ratio of the signals one calculates K = 0.48 and ∆G o = 1.1 kJ/mol at 163 K, but it is not known which of the two diastereomers is the more stable one.It is interesting, however, that NOE effects are found between 6 Li and H(2) as well as 3-CH 3 in these dimers (Fig. 7c) which indicates that their structure, as far as the orientation of the lithium double bridge with respect to the three-mem- Hg bered rings is concerned, differs from that of the mixed dimer containing LiBr.In the 1 H spectrum the signals for the diastereomers are not separated and it is not clear if the NOE effects result from the d,l or the meso compounds or if both are responsible.
Quite a different picture emerged from measurements of the salt-free sample of 2 in diethylether as the sole solvent.The 6 Li spectrum now shows three signals at 2.02, 2.08, and 2.22 ppm of comparable intensity (1.15 : 1.23 : 1.00).The isotopic fingerprint method yielded a doublet, a triplet, and a quintuplet which characterizes these signals as belonging to the monomer, the dimer, and a fluxional tetramer (Fig. 8).The coexistence of these three different aggregates is unique and apparently a consequence of comparable energies for solvation of the lithium cation with the solvent and the organic ligand.

Mixed aggregate formation between Methyllithium and Lithium salts
NMR studies of mixed aggregate formation between alkyllithium compounds and lithium salts often suffer from low sensitivity of 13 C measurements if the concentration of certain clusters falls below 0.1 M. Here, the isotopic fingerprint method with its high isotopic enrichment can be used to advantage.We investigated methyllithium in the presence of LiI and LiBr, systems studied earlier by Brown 58 and Waak 59 by 7 Li chemical shift measurements.
In the case of the CH 3 Li/LiI system 52 , five 6 Li resonances were observed in the slow exchange limit at 178 K, four of which give rise to typical fingerprints which characterize the 6 Li environment in the different aggregates; the signal at highest field is due to LiI (Fig. 9).The assigments based on signal multiplicity were confirmed by NOE measurements for a non-deuteriated sample, where a constant intensity increase per CH 3 neighbor was found.This result also agrees with the observation of four signals in the 1 H-NMR spectrum.
From an analysis of the measured intensity distribution and the observed 1 H, 6 Li NOE effects, the presence of aggregates Li 4 (CH 3 ) 4 (6), Li 4 (CH 3 ) 3 I (7), Li 4 (CH 3 ) 2 I 2 (8), and Li 4 (CH 3 )I 3 (9) was derived.Due to facile crystallisation of cluster 8 and LiI, instead of a statistical distribution only a non-equilibrium distribution of the aggregates was observed which did not allow to calculate energy differences on the basis of signal integration.

Li
A similar study of the system CH 3 Li/LiBr in diethylether yielded the 6 Li-NMR spectra shown in Fig. 10a, where the NOE difference experiment (Fig. 10b 10d).Thus, an isotope effect of 4.1 ppb from the remote CD 3 group is present.The analysis of the signal There is no clear indication of the presence of a significant concentration of cluster 12 which should yield a dou-blet as its isotopic fingerprint.A number of smaller lines around 0.3 ppm, which indeed yield doublets in spectrum c), are unidentified and may come from this source.The 6 Li resonance of the Li[BrBrBr] environment could coincide with the LiBr signal at 0 ppm.
If THF is used as the sole solvent, dramatic changes in the number of lines and their intensities as well as multiplicities are observed (Fig. 11).Cluster 6 (signal 5) is now the dominating species with a small contribution of 10 (signals 3 and 4).Again a long range isotope effect is observed for environment [LiCH 3 CH 3 ,Br]CH 3 (Fig. 11c).A doublet at 0.73 ppm in spectrum b) (signal 2) indicates the presence of a next neighbor environment [CH 3 BrBr].This cannot, however, originate from cluster 11, because this would require another signal of the same intensity at  ].An interesting information as to the origin of this signal comes from the dynamic behavior of the 6 Li spectrum, which shows coalescence between this doublet with the singlet of LiBr while the remaining resonances are virtually unaffected (Fig. 12).The doublet thus arises from a mixed dimer 13.This is nicely born out by the 13 C-NMR spectrum, which shows in addition the the septuplet of the tetramer 6 (J = 5.7 Hz) a quintuplet with J = 9.8 Hz, compatible with a dimer (Fig. 12b).
Compared to the results of the earlier investigations 58,59 , which were based on the temperature and concentration dependence of the 7 Li chemical shifts, the isotopic fingerprint method thus established the additional existence of aggregates 8, 9 and 13.

Two-D or not Two-D
Scalar spin-spin coupling is one of the fundamental NMR phenomena for chemical structure determinations and lends color to the otherwise rather dull singlet spectra of uncoupled spins.Even more important, scalar interactions form the basis for numerous one-and two-dimensional experiments which yield information on atomic connectivities in a given molecular structure.
In the case of organolithium compounds, the magnitude of spin-spin coupling involving lithium strongly depends on the coupling partner, with fairly large values (> 2 Hz) for 13 C, 15 N, and 31 P and small values (< 1 Hz) for 1 H and homonuclear 6,7 Li, 6,7 Li coupling.The sensitivity of various new NMR techniques for small coupling constants is thus  of considerable interest if 6,7 Li, 1 H or 6,7 Li, 6,7 Li coupling is to be detected.
It is important to remember that information about the structure of the various aggregates of RLi systems which are formed in solution in the presence or absence of stabilizing diamines and other ligands comes primarily from spin-spin coupling or nuclear Overhauser effects which involve lithium and to a lesser extent from chemical shift data of the ligands.X, 1 H coupling (X = 1 H, 13 C, 15 N, 31 P) within the ligands R does not yield information about aggregate size or structure and coupling between protons or X nuclei of different ligands R is normally not observed.Thus, in this context 6,7 Li,X and homonuclear 6,7 Li, 6,7 Li couplings are of fundamental importance.

Homonuclear experiments
From the various homonuclear 2D NMR experiments which can be applied to detect and measure scalar spin-spin coupling, the COSY, COSY-DQF, TOCSY and INADE-QUATE experiment 60 were used in this context successfully for 6 Li, 6 Li spin systems.Experiments whith 6 Li generally profit from the smaller linewidth of 6 Li as compared to 7 Li signals, but the larger 7 Li, 7 Li coupling (factor 2.64 2 ~ 7 due to the ratio γ( 7 Li)/γ( 6 Li) = 2.64) is an attractive feature of 7 Li, 7 Li experiments, since small splitting might lead to an elimination of cross peaks in the 2D spectra if antiphase components result.The identification of homonuclear 6,7 Li, 6,7 Li coupling, which sofar has never been resolved in a normal 1D Li-NMR spectrum, is important in cases were several non-isochronous 6,7 Li-NMR signals are observed. 61Those belonging to the same cluster can then be recognized if homonuclear coupling exists, which requires short lithium distances typical for Li-C-Li arrangements.It is not clear if coupling between the two Li nuclei is transmitted directly or as a geminal interaction via the carbon.
From the 2D techniques cited above, the INADE-QUATE 62 and the COSY-DQF 63 experiment have the additional advantage of a built-in double quantum filter which eliminates any true singlet from the observed spectrum.For the detection of 6 Li, 6 Li coupling, the INADEQUATE experiment is most easily applied with appreciable time saving in its 1D version, 64 recently performed also for 7 Li (Fig. 13).But it is also an attractive choice for other applications and was used to measure for the first time a homonuclear 15 N, 15 N coupling in a mixed aggregate of lithiated amides.As is well known from investigations by Collum et al., 12 lithium diisopropylamide (LDA) forms dimers in THF 65 and cyclic trimers and higher cyclic oligomers in hydrocarbon solvents 66 .For a 1:1 mixture of 15 N and 6 Li labeled LDA and lithium di(3-pentyl)amide (LDPA) in THF we observed the expected four 15 N signals -two of them nearly degenerate -stemming from the symmetric aggregates 14 and 16 and the mixed aggregate 15 (Fig. 14).All signals   [62][63][64] with ∆ = 1/2J (c. 500ms); the observed splitting amounts to 2.4 Hz, but because of the I = 3 /2 spin of 7 Li it does not correspond in a simple way to the homonuclear 7 Li, 7 Li coupling.
show quintuplet splittings due to coupling to two 6 Li with a coupling constant of 5.0 Hz (Fig. 14a).
The 1D 15 N, 15 N INADEQUATE experiment (Fig. 14b), which selects coupled AX systems identifies the two signals belonging to 15 N A and 15 N B of the mixed aggregate which now show an additional antiphase splitting of 1.6 Hz due to the homonuclear geminal 15 N A, 15 N B coupling.A further observation of interest is the different intensity of the two 15 N signals which results from different nuclear Overhauser effects in the two amide residues, where the larger number of protons in the LDPA part of the mixed cluster enhances the intensity of the 15 N B signal.The 15 N assignment which follows from this effect is in agreement with the assignment derived from substituent increments where a β-methyl group leads to a downfield shift 67 .
In changing the solvent to hexane the number of 15 N signals increases which indicates also an increase of coexisting structures (Fig. 15a).The INADEQUATE experiment (Fig. 15b) selects two 15 N AX systems which we assign to cyclic aggregates (RLi) n with n = 3 or 4 (17,  18), because the homonuclear 15 N, 15 N coupling now drops to 1.0 Hz.This is a strong indication of a structural change to a cyclic trimer or a higher cyclic aggregate where only one coupling path is available between the two nitrogens.

Analysis of ligand 1 H spectra
For the analysis of ligand structures, 1 H-NMR plays an important part in many cases and the possibility to start magnetization transfer selectively is an attractive feature of several 1D versions of well-known 2D NMR experiments.For example, the selective homonuclear 1 H TOCSY experiment 60,[68][69][70] , improved by trim pulses (TP) 71 and a z-filter 69 (pulse sequence (1)) can be employed to unravel the strongly coupled 1 H spectrum of cyclohexyllithium.As shown in Fig. 16, starting the magnetization transfer at the tertiary proton adjacent to the metal, which has a resonance well separated from the remaining signals by its low-field shift, axial and equatorial protons at subsequent ring positions are differentiated by the variable mixing time.90° − − Another application of selective excitation is indicated if deuteriated isotopomers of certain solvents are not easily available and 1 H signals of interest might overlap with large solvent peaks.Selective excitation of the particular spin system then allows elimination of the solvent signals and the inspection of spectral regions which were before masked by the solvent lines.An example is shown in Fig. 17 with the application of a 1D COSY experiment 70 to the 1 H spectrum of isopropyllithium, a compound that forms tetramers and hexamers in hydrocarbon solvents. 72,73At around 200 K in pentane the tetramer/hexamer ratio is ca.10:1.Here we start with a selective 90° pulse, thereby defining the origin of the magnetization transfer which follows (pulse sequence (2)), The detection of the methyl resonances of both aggregates, which are hidden under the huge solvent lines, allows the chemical shifts of the methyl protons and the vicinal 1 H, 1 H coupling constants to be measured.An advantage is the antiphase character of both doublets, which facilitates the extraction of the NMR parameters by discriminating artefacts.

Heteronuclear shift correlations
Heteronuclear shift correlations have been used quite frequently with success to correlate 1 H, 13 C, 15 N, and 31 P signals with the relevant 6 Li resonances of the aggregates of interest and in many cases the appropriate experiments with 2 H as a spin-1 nucleus have paved the way [74][75][76][77][78][79] .Over the years, these experimental techniques have been considerably improved and especially the so-called inverse tech-Figure 16.One-dimensional 1 H-TOCSY spectra of cyclohexyllithium with variation of the mixing time provided by the MLEV method (pulse sequence (1)); 1-H2 at -0.9 ppm not shown.niques based on multiple quantum coherences 80 (the HMQC experiment, pulse sequence (3)), where the experimental success relies on the suppression of uncoupled I magnetization, have profited from hardware developments, the application of additional pulses 81 like the BIRD sequence 82 , and more recently from the introduction of linear field gradients 60,83 .
The inverse 13 C, 6 Li experiment with 6 Li detection (pulse sequence (3), I = 6 Li, S = 13 C), which was used for the first successful realization of a two-dimensional 13 C, 6 Li shift correlation, 76 not only yields correlation information, but also allows 13 C, 6 Li coupling constants to be determined since usually the S nucleus is not decoupled during I signal acquisition (Fig. 18a).This experiment can also be performed most effectively and time saving by the corresponding 1D version (pulse sequence ( 4)), as demonstrated in Fig. 18c.

Heteronuclear Overhauser spectroscopy
Finally, turning to 1 H, 6 Li nuclear Overhauser spectroscopy, the 2D 1 H, 6 Li HOESY experiment 85 is one of the important tools in structure elucidation of organolithium compounds 57 .Recent developments in this field have led to the proposal of the inverse experiment with 1 H detection which has the advantage of higher spectral dispersion in the 1 H domain.The idea was originally put forward already in 1990 by Bauer and Schleyer 86a , but only the introduction of linear Bo field gradient techniques paved the way for a practical solution of the experimental difficulty to eliminate the dominating proton magnetization which is not due to a heteronuclear 6 Li → 1 H NOE 86b .It was found that the experiment is best performed with the 7 Li, 1 H spin pair, apparently due to the stronger dipolar interactions and the faster relaxation rate of 7 Li as compared to 6 Li.
In an attempt to transfer these ideas to the one-dimensional version of the NOE measurement, we based our experiments on results reported by Keeler et al. 87 for gradient enhanced 1 H, 1 H nuclear Overhauser (GOESY) spectroscopy and introduced two frequency channels along the lines of the 2D 1 H, 6 Li HOESY experiment.This leads to a pulse sequence shown in Fig. 20, which takes advantage of a later version of the GOESY experiment 88 .Here, the first part up to the gradient pulse G 4 serves for the selection of the desired 7 Li magnetization, I( 7 Li) sel , of a particular lithium resonance, 7 Li k , which is to be transferred to the protons.Therefore, the conditions G 1 = G 2 and G 3 = G 4 refocus I( 7 Li) sel because the two selective 180° pulses change the sign of the coherences.The 90° 1 H pulse produces transverse proton magnetization which is destroyed by the gradient pulse G 5 , leaving for detection only the Overhauser enhancement which builds up during the mixing time through transfer from the selected nucleus 7 Li k .
Noteworthy is the enormous time advantage of the 1D sequence: these spectra were recorded within 35 min, while for the HOESY experiment 13 h had to be invested!

The Benzyllithium Story
Ach wie gut daß niemand weiß, daß ich Rumpelstilzchen heiß Despite the power of modern NMR experiments, even in the case of simple organolithium systems all attempts to determine their solution structure may fail due to a variety of reasons, among which are low solubility and fast exchange dynamics.One of these small molecules, which preserved until recently the secret of its detailed structure in solution, is benzyllithium.Even today, all facets of this structural problem may not have been uncovered.
Early X-ray crystallographic studies for solids consisting of benzyllithium and donors like triethylamine 90 or diethylether 91 as ligands revealed chain structures with Li-C α distances of 217 and 221 pm, respectively, and different orientations of the Li cation with respect to the benzyl residue.With respect to the solution structure, the results of calculations by various semi-empirical and abinitio methods 92 are of interest, which suggested that in principle three alternative structures (19 -21) may be discussed for solvated benzyllithium and its α-substituted derivatives (L = solvent or complexing ligand).Following MNDO results for the heat of formation 93 , the energy difference between the η 1 and η 3 structure is rather small (4 kcal / mole, see next page).Indeed, experimental evidence for a η 1 η 3 equilibrium was presented in the case of α-(dimethylamino)benzyllithium in THF solution 94 .For solids, Boche et al. focused again attention to this structural problem by reporting the results of an X-ray investigation for the [benzyllithium,THF,TMEDA] complex 93 .These workers found a monomeric η 1 structure with pyramidal C α and a Li-C α distance of 221 pm.Among the various α-substituted benzyl systems which have been studied by X-ray diffraction 95 , the trimethylsilyl substituted system [C 6 H 5 CHSi(CH 3 ) 3 Li] .TMEDA is of particular interest.Here, a η 2 structure with pyramidal C α and a Li-C α distance of 213 pm was found in the crystal 96 and according to 1 H, 6 Li and 13 C, 6 Li HOESY measurements 97 , the same or a closely related structure prevails in solution.
The earliest solution studies 98 had already indicated that benzyllithium is monomeric, but in the NMR spectrum of 6 Li labeled material no 13 C, 6 Li coupling constant was found. 99This is also true for α-substituted derivatives 100 , with the single exception of a phenylsubstituted cyclopropyl system 101 .Consequently, for solute samples one could expect solvent separated ion pairs or fast equilibria between contact ion pairs or dynamic processes between both structural alternatives.The existence of rapid dynamic processes was also indicated by the low configurational stability of α-substituted derivatives 102 .
Findings reported recently carry our understanding of these structural aspects a step further.By chaining up the lithium cation to C α via a crown ether 'necklace', Hoffmann and Boche et al. 103 were able to observe for the first time a scalar 13 C α , 6,7 Li coupling constant in compounds 22 and 23 in THF at 203 K (22: J( 13 C α , 7 Li) = 7.0 Hz, 23: J( 13 C α , 6 Li) = 3.1 Hz which corresponds to J( 13 C α , 7 Li) = 9.0 Hz). 1 H, 6 Li HOESY experiments suggest an arrangement such as that shown in 24 for these monomeric systems.
At the same time, using a similar strategy, Fraenkel and Martin 104 found 13 C α , 6 Li couplings of 2.8 and 3.4 Hz in THF at 250 K for the two compounds 25a and 25b and we observed 13 C, 6 Li couplings (2.7 Hz) for the lithium cation trapped in the organic ligand of the Schlenk dimer 26 where the second lithium exists as a solvent separated ion 105 .Even more interesting, Fraenkel and Martin 104 were able to meas-ure a 13 C α , 6 Li coupling of 3.8 Hz for the parent compound itself in the presence of TMEDA, using 13 C and 6 Li labeling, low concentration (0.005 M in THF), and low temperature (180 K).Thus, finally the conversation of the C α and 6,7 Li spin was tapped, but the low value of the coupling constants is unexpected in view of the findings that monomers usually show 13 C, 6 Li coupling close to 17 Hz 99 .Fraenkel assumes that this suggests the existence of a continuum of covalency between 'classical' monomers with large coupling and solvent separated ion pairs with no coupling at all.But, as mentioned above, the benzyllithium system is probably still good for a number of surprises.

Compounds with π
π π πand σ σ σ σ-Bound Lithium some like it hot The strong shielding and deshielding effects exerted by cyclic π-systems on surrounding protons has long fascinated annulene chemists who coined the terms diatropic and paratropic to describe the diamagnetic and paramagnetic shielding properties of (4n+2) and (4n)π-systems, respectively. 106In particular the oxidation or reduction of neutral hydrocarbons to the corresponding dications or dianions, respectively, has generated interesting systems where the difference in the number of π-electrons results in spectacular shielding and deshielding effects in proton NMR spectra 107 .An example from our laboratory is the generation of methano [10]annulene dianion (28) from methano [10] The transformation 27 → 28 was achieved after earlier unsuccessful attempts by using ultrasonic radiation or by simply attaching the sealed NMR tube with the parent hydrocarbon and lithium sand in THF to the rod of a vibrational mixer.This technique was also successful in the case of biphenylene, were we had found 109 that the dianion 29, formed initially via reduction by potassium in THF, reacts with protic solvents to yield benzocyclo-octatetraene (31) via the Woodward-Hoffmann allowed ring opening reaction of the primarily formed 4a,8b-dihydrobiphenylene (30).In the absence of proton donors, 29 has a half-life of 1.7 h and opens the four-membered ring to yield o,o'dilithiodiphenyl (32) 110 , a compound with a lithium double bridge 111 .

The reduction of benzoannelated Biphenylenes
In an attempt to study this reaction in the case of benzoannulated biphenylenes, we treated benzo[b]biphenylene (33) with lithium sand in diethylether.Instead of the dianion we found immediate formation of 2-o-lithiophenyl-3-lithionaphthalene (34), which yields a purple solution and is characterized by two ABCD systems and two singlets in the 1 H-NMR spectrum.Two carbon resonances at 174.2 and 176.0 ppm and a 6 Li singlet at 2.30 ppm (rel.to ext.0.1 M LiBr in THF) complete the information which is significant for the structure.
In contrast, the oxidation of the hydrocarbon 33 with the 'Olah mixture' SbF 5 /SO 2 ClF at -30 °C yielded the 14π electron system 35 which is, at that temperature, perfectly stable.Its Q-value 112 of 1.43 as determined from the bond orders derived on the basis of the vicinal H,H coupling constants 3 J(6,7) and 3 J(7,8) via analysis of the 1 H-NMR spectrum, is typical for a benzoannelated diatropic system, in the present case the 10π electron system of biphenylene dication.Completely different NMR spectra were observed when the reduction of 33 was carried out in THF.In particular the 1 H-spectrum showed spectacular high-field shifts for some of the protons, which resonate at 2.25 and 2.60 ppm.Similar spectacular high-field shifts for 'aromatic' protons were found before in the case of dilithionaphthalenediide 113 .Most conclusive evidence for the structure of the new product came from the deuteron NMR spectrum of the deuterolysis product, which showed four signals, two in the allylic, one in the olefinic, and one in the aromatic region.All spectroscopic data, including the 13 C and 6 Li spectra, where in accord with the tetralithiated structure 36 which has πand σ-bound lithium as a unique feature 114 .Additional proof for the proposed structure came from an experiment where 34 was prepared in diethylether and further reduction was carried out after replacing this solvent by THF.
The interesting structural properties of 36 with πand σ-bound lithium initiated related studies for dibenzo[b,h]biphenylene (37) and naphtho[b]biphenylene (38) 115 .In both cases reduction with lithium sand in diethylether yielded the dianions, 39 and 40, respectively, which could be fully characterized by their NMR spectra.Surprisingly, however, both are paratropic systems with high-field shifted 1 H resonances (2.81, 4.49, and 4.98 ppm for 39, and 2.40, 3.43 and 3.96 ppm for 40), despite the total number of 22 π-electrons.The Q-values are 0.963 for 39 and 0.982 for 40 and point in the same direction.The NMR data of 39 closely resemble those of dilithionaphthalenediide which suggests a mesomeric structure 39a ↔ 39b, while 40 resembles a phenylene-annelated anthracene dianion.In contrast to the dianions of the linear annelated systems, the dianion of the angular annelated benzo[a]biphenylene (41) is perfectly stable.If 37 and 38 are reduced in THF, again four-membered ring opening and a second reduction to the new tetralithio compounds 42 and 43 is observed.

Conclusion
The topics discussed show how a variety of high-resolution NMR techniques can be used in structural research in the field of organolithium compounds.Isotope shifts as well as homo-and heteronuclear shift correlations and nuclear Overhauser spectroscopy provide detailed informations about the aggregation behavior of lithiated carbon compounds which are important synthetic aids.In particu-

Figure 2 .
Figure 2. Schematic representation of an X-Y bond potential for two isotopes of X; n X = light isotope; m X = heavy isotope.

Figure 3 .
Figure3.a) 58.9 MHz 6 Li-NMR spectrum of an equimolar mixture of CH3Li/CD3Li in [D10]diethylether at 161 K with inverse-gated 1 H-decoupling in order to remove line broadening due to scalar 1 H,6 Li coupling and intensity changes caused by 1 H,6 Li nuclear Overhauser effects; b) resolution enhanced isotopic fingerprint of the6 Li resonance.
) identifies those lithium sites which are adjacent to at least one CH 3 group.This leaves a total of five signals, centred at three different chemical shift values (0.44, 1.04/1.08,1.72/1.80ppm rel. to LiBr).The measured NOE effects suggested next neighbor environments [CH 3 BrBr], [CH 3 CH 3 Br], and [CH 3 CH 3 CH 3 ] for these 6 Li resonances and this is borne out by the isotopic fingerprints observed for a sample of composition CH 3 Li/CD 3 Li/LiBr (1:1:2) (Fig. 10c): there is a doublet for signal 2, two triplets for signals 3 and 4, and two quadruplets for signals 5 and 6.As in the case of the iodine containing clusters, we can distinguish the 6 Li resonances with the environments [LiCH 3 CH 3 CH 3 ]CH 3 (signal 5) and [LiCH 3 CH 3 CH 3 ]X (signal 6) with X = Br in the present case, but compared to the iodine case the chemical shift order for these two aggregates is reversed.Furthermore, we have here different signals for [LiCH 3 CH 3 Br]CH 3 and [LiCH 3 CH 3 Br]Br.As shown by the highly resolved spectrum of the two triplets around 1.06 ppm, there is a small doublet splitting of 0.24 Hz for each line of the triplet corresponding to [LiCH 3, CH 3 Br]CH 3 (Fig.

Figure 9 .
Figure 9. a) 58.9 MHz 6 Li-NMR spectrum of a mixture of CH3Li and LiI(1:1) in [D10]diethylether at 178 K; b) isotopic fingerprints observed for the signals shown in a) using an equimolar mixture of CH3Li/CD3Li and two equivalents of LiI.

Figure 10 .
Figure 10.a) 58.9 MHz 6 Li-NMR spectrum of CH3Li in the presence of LiBr (1:1) in [D10]diethylether at 183 K; b) nuclear Overhauser difference spectrum of a); c) isotopic fingerprints for an equimolar mixture of CH3Li/CD3.Li and two moles of LiBr under the same conditions as in a); d) highly resolved signals at 1.0-1.1 ppm showing doublet splitting due to an additional isotope shift for the low-field triplet.

Figure 11 .
Figure 11.a) 58.9 MHz 6 Li-NMR spectrum of CH3Li in the presence of LiBr (1:1) in [D8]THF at 183 K; b) isotopic fingerprints for an equimolar mixture of CH3Li/CD3.Li and two moles of LiBr under the same conditions as in a); c) highly resolved signals at 0.7-0.9ppm showing an additional isotope shift for the low-field triplet.

Figure 12 .
Figure 12. a) Temperature dependence of the 6 Li-NMR spectrum of an equimolar mixture of CH3Li/CD3.Li and two moles of LiBr in [D8]THF; b) 13 C-NMR signals observed for an equimolar mixture of CH3Li/LiBr in [D8]THF at 170 K.

Table 1 .
Nuclear properties of stable alkali and alkaline earth metal isotopes a .
a Adapted from Refs. 1 and 2.
7echniques which utilize the nuclides6Li and7Li yield valuable insights into the course of lithiation reactions, aggregate formation and dynamics. lar