Selected topics from recent NMR studies of organolithium compounds

Review

Selected Topics from Recent NMR Studies of Organolithium Compounds

Harald Günther

University of Siegen, FB 8, OCII

D-57068 Siegen, Germany

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 ⁶Li 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 uni- e 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.

After a short introduction to NMR spectroscopy of alkali and alkaline earth metals the review concentrates on NMR investigations of organolithium compounds. The isotopic fingerprint method, which rests on deuterium-induced isotope shifts for ⁶Li resonances, is introduced and exemplified with applications from the aggregation behavior of cyclopropyllithium systems and mixed aggregate formation between methyllithium and lithium salts. In the following chapter, one- and two-dimensional pulse experiments, both for homo- and for heteronuclear spin systems are discussed. Finally, the structural aspects associated with benzyllithium are outlined and the formation of polylithium systems by lithium reduction of biphenylenes is described.

Keywords: NMR, ⁶Li-NMR, ¹⁵N-NMR, isotope shifts, isotopic fingerprints, pulse methods, spin-spin coupling, organolithium compounds, aggregation, benzyllithium structure, p-systems, polylithium systems, reduction

Introduction

The alkaline and alkaline earth metals, a group of elements which comprises the four biologically most important cations (Na^+, K⁺, Ca2⁺, Mg2⁺), 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, ⁹Be, cesium, ¹³³Cs, and in particular the lithium isotopes ⁶Li and ⁷Li which can be successfully employed in various one- and two-dimensional NMR experiments. Especially ⁶Li, 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 Lutz⁵ provided additional articles, as did Drakenberg⁶ and just recently again Laszlo⁷. Several extensive progress reports dealing with ^6,7Li-NMR have appeared^8-13, 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^14-22. In addition, completely new areas for NMR investigations became accessable with the discovery of alkali anions²³, the synthesis of alkali and alkaline earth intercalation compounds of fullerenes^24-27, and studies on clay minerals used as catalysts in organic synthesis²⁸. 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 ^6,7Li, but to some extent also ⁹Be and ¹³³Cs 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 ¹H, ^6,7Li NOE effects, only for ¹³³Cs 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 ²⁵Mg NMR in this area met with success^33-35, but have not initiated further efforts in this direction, despite reported improvements in the experimental technique³⁶.

It is thus quite understandable, that from the viewpoint of structural research on organometallic systems ^6,7Li-NMR is much more attractive. In addition to ¹H, ⁶Li and ¹H, ⁷Li nuclear Overhauser effects, ample spin-spin coupling between ^6,7Li and other nuclei like ¹H, ¹³C, ¹⁵N, ²⁹Si, ³¹P 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 ²H-induced ⁶Li-NMR Isotope Shifts

small is beautiful

NMR isotope effects are long known³⁷, 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^38-41. If an atom ⁿX is replaced by its heavier isotope ^mX (m > n), a NMR shift,D(Y)(^m/nX)is observed for the nucleus Y which may be directly attached to ^mX 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 ^mX-Y as compared to the ⁿX-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 high-frequency shift) is often observed⁴².

In organic compounds, deuterium-induced shifts of ¹³C resonances have been studied extensively and correlations with carbon hybridization and substitution⁴³, hyperconjugation⁴⁴, dihedral angles⁴⁵, and spin-spin coupling constants⁴⁶ 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 ¹³C-NMR^47-49. ²H/¹H isotope shifts decrease with the number of bonds between deuterium and the ¹³C 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 compounds⁵² uses for the first time ²H-induced isotope shifts of ⁶Li-NMR signals. The idea was, that, for example in the case of a tetramer likemethyllithium in diethylether, a 1:1 mixture of deuteriated and non-deuteriated material, CD₃⁶Li and CH₃⁶Li, shouldyield different environments for the ⁶Li nuclei.As shown in diagrams 1a - 1d, the direct surrounding of a particular ⁶Linucleus might consist of three, two, one, or no CH₃ group, leading to the environments hhh, hhd, hdd, and ddd. Considering thestatistical distribution of the deuteriated ligand, a quadruplet with an intensity ratio of 1:3:3:1 was expected and indeedobserved (Fig. 3). Here, the isotope shift amounts to roughly 16 ppb per CD₃ group and is of positivesign on the d-scale (low-field 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 ²H-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.⁵³ Indeed, ²H-induced isotope shifts from deuterons residing in organic ligands not directlyattached to the ⁶Li nucleus under study are mostly too small to be detected and have sofar been observed in simplealkyllithium 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 ⁶Li on a 400 MHz ¹H 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 ¹³C spectra (chemical shift studies, observation of ¹³C,⁶Liscalar spin-spin coupling) is its high sensitivity due to double isotopic enrichment, which is easily achieved. ⁶Li is readily incorporateddirectly or via lithiation with [⁶Li]butyllithium, while numerous procedures for the deuteriation of organic ligands are available. Thus, even aggregates 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-2-butene. 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 ⁶Li-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 ⁶Li doublet (Dd = 4 ppb) indicating the formation of a mixed dimer [C₅H₉Li,LiBr] (Fig. 6a). The observed multiplicity is also compatible with the presence of the monomeric lithium species 2, but inthis case a separate⁶Li 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, [(C₃H₅Li)_2,(LiBr)₂], has been found in thecrystal⁵⁵ and in diethylether/THF solution⁵⁶.

The two-dimensional ¹H, ⁶Li HOESY spectrum⁵⁷ (Fig. 6b) established nuclear Overhauser effects between ⁶Li and H(1) aswell as H(2), but cross peaks between ⁶Li and 3-CH₃ were not observed. This may be due to steric repulsion between the methyl group and the lithium double bridge which increases the Li-CH₃ 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 ⁶Li 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 the⁶Li signal resembles a quadrupletbetween 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 ofaggregation state. A ⁶Li-NMR spectrum run at 73.5 MHz (500 MHz ¹H 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 DG^o = 1.1 kJ/mol at 163 K, but it is not known which of thetwo diastereomers is the more stable one. It is interesting, however, that NOE effects are found between ⁶Li andH(2) as well as 3-CH₃ 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-membered rings is concerned, differs from that of the mixed dimer containing LiBr. In the¹H spectrum the signals for the diastereomers are not separated and it is not clear if the NOE effects resultfrom 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 ⁶Li 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 ¹³C 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 Brown⁵⁸ and Waak⁵⁹ by ⁷Li chemical shift measurements.

In the case of the CH₃Li/LiI system⁵², five ⁶Li resonances were observed in the slow exchange limit at 178 K, four of which give rise to typical fingerprints which characterize the 6Li 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 constantintensity increase per CH₃ neighbor was found. This result also agrees with theobservation of four signals in the ¹H-NMR spectrum.

From an analysis of the measured intensity distribution and the observed ¹H, ⁶Li NOE effects, the presence of aggregates Li₄(CH₃)₄ (6), Li₄(CH₃)₃I (7), Li₄(CH₃)₂I₂ (8), and Li₄(CH₃)I₃ (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.

A similar study of the system CH₃Li/LiBr in diethylether yielded the⁶Li-NMR spectra shown in Fig. 10a, where the NOEdifference experiment (Fig. 10b) identifies those lithium sites which are adjacent to at least one CH₃ group. This leaves a total of five signals, centred at three different chemical shift values (0.44, 1.04/1.08, 1.72/1.80 ppm rel. to LiBr).

The measured NOE effects suggested next neighbor environments [CH₃BrBr], [CH₃CH₃Br], and [CH₃CH₃CH₃] forthese⁶Li resonances and this is borne out by the isotopic fingerprints observed for a sample of composition CH₃Li/CD₃Li/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 and6. As in the case of the iodine containing clusters, we can distinguish the ⁶Li resonances with theenvironments [LiCH₃CH₃CH₃]CH₃ (signal 5) and [LiCH₃CH₃CH₃]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[LiCH₃CH₃Br]CH₃ and [LiCH₃CH₃Br]Br. As shown by the highly resolved spectrum of the two tripletsaround 1.06 ppm, there is a small doublet splitting of 0.24 Hz for each line of the triplet corresponding to [LiCH₃,CH₃Br]CH₃ (Fig. 10d). Thus, an isotope effect of 4.1 ppb from the remote CD₃ group is present. The analysis of the signal intensities, the splitting patterns as well as the NOE effects shows that apart from the tetramer6 (signal 5) the mixed aggregates 10 (signals 4 and 6) and 11 (signals 2 and 3) are present.

There is no clear indication of the presence of a significant concentration of cluster 12 which should yield a doublet 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 ⁶Li 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 [LiCH₃CH₃,Br]CH₃ (Fig. 11c). A doublet at 0.73 ppm inspectrum b) (signal 2) indicates the presence of a next neighbor environment [CH₃BrBr]. This cannot, however, originate fromcluster 11, because this would require another signal of the same intensity at ca. 1.1 ppm for the next neighbor combination[CH₃CH₃Br]. An interesting information as to the origin of this signal comes from the dynamic behavior of the⁶Li spectrum, which shows coalescence between this doublet with the singlet of LiBr while the remaining resonances are virtuallyunaffected (Fig. 12). The doublet thus arises from a mixed dimer 13. This is nicely born out by the ¹³C-NMRspectrum, 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 ⁷Li chemical shifts, the isotopic fingerprint method thus established the additional existence of aggregates 8, 9 and 13.

One- and Two-Dimensional NMR Experiments Based on Scalar Spin-Spin Coupling and Nuclear Overhauser Effects

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 ¹³C, ¹⁵N, and ³¹P and small values (< 1 Hz) for ¹H and homonuclear ^6,7Li,^6,7Li coupling. The sensitivity of various new NMR techniques for small coupling constants is thus of considerableinterest if ^6,7Li,¹H or ^6,7Li,^6,7Li 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,¹H coupling (X = ¹H, ¹³C, ¹⁵N, ³¹P) within the ligands R does not yield information about aggregate size or structure andcoupling between protons or X nuclei of different ligands R is normally not observed. Thus, in this context ^6,7Li,X andhomonuclear ^6,7Li,^6,7Li 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 INADEQUATE experiment⁶⁰ were used in this context successfully for ⁶Li,⁶Li spin systems. Experiments whith ⁶Li generally profit from the smaller linewidth of ⁶Li as compared to ⁷Li signals,but the larger ⁷Li,⁷Li coupling (factor2.642 ~ 7due to the ratio g(⁷Li)/g(⁶Li) = 2.64) is an attractive feature of ⁷Li,⁷Li experiments, since small splitting might lead to an elimination of cross peaks in the 2D spectra if antiphase componentsresult. The identification of homonuclear ^6,7Li,^6,7Li coupling, which sofar has never been resolved in a normal 1D Li-NMR spectrum, is important in cases were several non-isochronous ^6,7Li-NMR signals are observed.⁶¹ Thosebelonging 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 the2D techniques cited above, the INADEQUATE⁶² and the COSY-DQF⁶³ experiment have the additional advantageof a built-in double quantum filter which eliminates any true singlet from the observed spectrum. For the detection of ⁶Li,⁶Li coupling, the INADEQUATE experiment is most easily applied with appreciable time saving in its 1Dversion,⁶⁴ recently performed also for ⁷Li (Fig. 13). But it is also an attractive choice for other applications and was used to measurefor the first time a homonuclear ¹⁵N,¹⁵N coupling in a mixed aggregate of lithiated amides. As is well known frominvestigations by Collum et al.,¹² lithium diisopropylamide (LDA) forms dimers in THF⁶⁵ and cyclic trimers and highercyclic oligomers in hydrocarbon solvents⁶⁶. For a 1:1 mixture of ¹⁵N and ⁶Li labeled LDA and lithium di(3-pentyl)amide(LDPA) in THF we observed the expected four ¹⁵N signals - two of them nearly degenerate - stemming fromthe symmetric aggregates 14 and 16 and the mixed aggregate 15 (Fig. 14). All signals show quintuplet splittings due to coupling to two ⁶Li with a coupling constant of 5.0 Hz (Fig. 14a).

The 1D ¹⁵N,¹⁵N INADEQUATE experiment (Fig. 14b), which selects coupled AX systems identifies the two signals belonging to ¹⁵N_A and ¹⁵N_B of the mixed aggregate which now show an additional antiphase splitting of 1.6 Hz due to the¹⁵N_A,¹⁵N_B coupling. A further observation of interest is the different intensity of the two¹⁵N 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 ¹⁵N_B signal. The¹⁵N assignment which follows from this effect is in agreement with the assignment derived from substituent increments where a b-methyl group leads to a downfield shift^67.

In changing the solvent to hexane the number of ¹⁵N signals increases which indicates also an increase of coexisting structures (Fig. 15a). The INADEQUATE experiment (Fig. 15b) selects two ¹⁵N AX systems which we assign to cyclic aggregates (RLi)_n with n = 3 or 4 (17, 18), because the homonuclear¹⁵N,¹⁵N 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 ¹H spectra

For the analysis of ligand structures, ¹H-NMR plays an important part in many cases and the possibility to startmagnetization transfer selectively is an attractive feature of several1D versions of well-known2D NMR experiments. Forexample, the selective homonuclear ¹H TOCSY experiment^60,68-70, improved by trim pulses (TP)⁷¹ and a z-filter⁶⁹ (pulse sequence (1)) can be employed to unravel the strongly coupled ¹H 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.

Another application of selective excitation is indicated if deuteriated isotopomers of certain solvents are not easily available and ¹H 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 experiment⁷⁰ to the ¹H spectrum of isopropyllithium, a compound that forms tetramers and hexamers in hydrocarbon solvents.^72,73 At 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 ¹H,¹H 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 ¹H, ¹³C, ¹⁵N, and ³¹P signalswith the relevant ⁶Li resonances of the aggregates of interest and in many cases the appropriate experiments with ²H as aspin-1 nucleus have paved the way^74-79. Over the years, these experimental techniques have been considerably improved and especially the so-called inverse techniques based on multiple quantum coherences⁸⁰ (the HMQC experiment, pulse sequence (3)), where the experimental success relies on the suppression of uncoupled I magnetization, have profited from hardware developments, theapplication of additional pulses⁸¹ like the BIRD sequence⁸², and more recently from the introduction of linearfield gradients^60,83.

The inverse ¹³C,⁶Li experiment with ⁶Li detection (pulse sequence (3), I = ⁶Li, S = ¹³C), which was used for the firstsuccessful realization of a two-dimensional ¹³C,⁶Li shift correlation,⁷⁶ not only yields correlation information, but also allows ¹³C,⁶Li 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.

A recent addition to the list of X,⁶Li correlations is the ²⁹Si,⁶Li experiment based on sizable scalar ²⁹Si,⁶Li coupling⁸⁴. Anexample is shown in Fig. 19 with the result for the dimer of (E)-1-lithio-2-(o-lithiophenyl)-1-trimethylsilylethene (Fig. 19).

Heteronuclear Overhauser spectroscopy

Finally, turning to ¹H,⁶Li nuclear Overhauser spectroscopy, the 2D ¹H,⁶Li HOESY experiment⁸⁵ is one of the importanttools in structure elucidation of organolithium compounds⁵⁷. Recent developments in this field have led to the proposal of the inverse experiment with ¹H detection which has the advantage of higher spectral dispersion in the ¹H domain. The ideawas originally put forward already in 1990 by Bauer and Schleyer^86a, but only the introduction of linear B_o field gradienttechniques paved the way for a practical solution of the experimental difficulty to eliminate the dominating proton magnetization which isnot due to a heteronuclear⁶Li ®¹H NOE^86b. It was found that the experiment is best performed with the ⁷Li,¹H spin pair, apparently due to the stronger dipolar interactions and the faster relaxation rate of ⁷Li ascompared to ⁶Li.

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 ¹H,¹H nuclear Overhauser (GOESY) spectroscopy and introducedtwo frequency channels along the lines of the 2D ¹H,⁶Li HOESY experiment. This leads to a pulse sequence shown in Fig. 20, which takes advantage of a later version of the GOESY experiment⁸⁸. Here, the first part up to the gradientpulse G₄ serves for the selection of the desired⁷Li magnetization, I(⁷Li)_sel , of a particular lithium resonance, ⁷Li_k, which is to be transferred to the protons. Therefore, the conditions G₁ = G₂ and G₃ = G₄ refocus I(⁷Li)_sel because the twoselective 180° pulses change the sign of the coherences. The 90°¹H pulse produces transverse proton magnetization whichis destroyed by the gradient pulse G₅ , leaving for detection only the Overhauser enhancement which builds up during themixing time through transfer from the selected nucleus ⁷Li_k.

Experimental results for the well characterized dimer of (Z)-2-lithio-1-(o-lithiophenyl)ethen⁸⁹ are shown in Fig. 21. Inspectrum b) we see strong NOE's between Li(2) and both olefinic protons, in spectrum c) between Li(2') and H(3) at the aromatic ring.Weaker responses are coming in spectrum b) for H(3) and in spectrum c) for H(1) and H(2). In contrast, the 2D ¹H,⁶Li HOESY spectrum (Fig. 21d) shows only the relationships Li(2)/H(2) and Li(2')/H(3) which are also the strongest in the 1D experiment.

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 triethylamine⁹⁰ or diethylether⁹¹ ain struas ligands revealed chctures with Li-C_a 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 ab-initio methods⁹² are of interest, which suggested that in principle three alternative structures (19 -21) may be discussed for solvated benzyllithium and itsa-substituted derivatives (L = solvent or complexing ligand). Following MNDO results for the heat of formation⁹³, the energy difference between the h¹ and h³ structure is rather small (~ 4 kcal / mole, see next page).

Indeed, experimental evidence for a h¹h³ equilibrium was presented in the case ofa-(dimethylamino)benzyllithium in THF solution⁹⁴.

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] complex⁹³. These workers found a monomerich¹ structure with pyramidal C_a and aLi-C_a distance of 221 pm. Among the variousa-substituted benzyl systems which have been studied by X-ray diffraction⁹⁵, the trimethylsilyl substituted system [C₆H₅CHSi(CH₃)₃Li]^.TMEDA is of particular interest. Here, ah² structure with pyramidal C_a and a Li-C_a distance of 213 pm was found in the crystal⁹⁶ and according to ¹H,⁶Li and ¹³C,⁶Li HOESY measurements⁹⁷, the same or a closely related structure prevails in solution.

The earliest solution studies⁹⁸ had already indicated that benzyllithium is monomeric, but in the NMR spectrum of ⁶Lilabeled material no ¹³C,⁶Li coupling constant was found.⁹⁹ This is also true fora-substituted derivatives¹⁰⁰, with the singleexception of a phenylsubstituted cyclopropyl system¹⁰¹. Consequently, for solute samples one could expect solventseparated ion pairs or fast equilibria between contact ion pairs or dynamic processes between both structural alternatives. The existenceof rapid dynamic processes was also indicated by the low configurational stability ofa-substituted derivatives¹⁰².

Findings reported recently carry our understanding of these structural aspects a step further. By chaining up the lithium cation to C_a via a crown ether 'necklace', Hoffmann and Boche et al.¹⁰³ were able to observe for the first time a scalar ¹³C_a,^6,7Li coupling constant in compounds 22 and 23 in THF at 203 K (22: J(¹³C_a,⁷Li) = 7.0 Hz, 23: J(¹³C_a,⁶Li) = 3.1Hz which corresponds to J(¹³C_a,⁷Li) = 9.0 Hz). ¹H,⁶Li 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 Martin¹⁰⁴ found ¹³C_a,⁶Li couplings of 2.8 and 3.4 Hz in THF at 250 K for the two compounds 25a and 25b and we observed ¹³C, ⁶Li couplings (2.7 Hz) for the lithium cation trapped in theorganic ligand of the Schlenk dimer 26 where the second lithium exists as a solvent separated ion¹⁰⁵. Even moreinteresting, Fraenkel and Martin¹⁰⁴ were able to measure a ¹³C_a,⁶Li coupling of 3.8 Hz for the parent compound itself in the presence of TMEDA, using ¹³C and ⁶Li labeling, low concentration (0.005 M in THF), and low temperature (180 K). Thus, finallythe conversation of the C_a and ^6,7Li spin was tapped, but the low value of the coupling constants isunexpected in view of the findings that monomers usually show ¹³C, ⁶Li coupling close to 17 Hz⁹⁹. Fraenkel assumes thatthis 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 p- and s-Bound Lithium

some like it hot

The strong shielding and deshielding effects exerted by cyclic p-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)p-systems, respectively.¹⁰⁶ In 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 ofp-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]annulene (27) by reduction with lithium metal.¹⁰⁸

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 found¹⁰⁹ 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 hand 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 ¹H-NMR spectrum. Two carbon resonances at 174.2 and 176.0 ppm and a ⁶Li 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' SbF₅/SO₂ClF at -30 °C yielded the 14p electron system 35 which is, at that temperature, perfectly stable. Its Q-value¹¹² of 1.43 as determined from the bond orders derived on the basis of the vicinal H,H coupling constants ³J(6,7) and ³J(7,8) via analysis of the ¹H-NMR spectrum,is typical for a benzoannelated diatropic system, in the presentcase the 10p electron system of biphenylene dication.

Completely different NMR spectra were observed when the reduction of 33 was carried out in THF. In particular the ¹H- 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 dilithionaphthalenediide¹¹³. Mostconclusive 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 ¹³C and ⁶Li spectra, where in accord with the tetralithiated structure36 which has p- and s-bound lithium as a unique feature¹¹⁴. 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 p- and s-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 ¹H 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 p-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 particular techniques which utilize the nuclides ⁶Li and ⁷Li yield valuable insights into the course of lithiation reactions, aggregate formation and dynamics.

Acknowledgements

As far as our own efforts in the field of organolithium chemistry and its NMR spectroscopy are concerned, I am deeply obliged to my coworkers for their enthusiastic collaboration. In particular I thank Werner Andres, Rainer Benken, Klaus Bergander, Bernd Böhler, Oswald Eppers, Thomas Fox, Maria-Eugenia Günther, Heike Hausmann, Runxi He, Dietmar Hüls, Martin Kreutz, Hans-Egbert Mons, Detlef Moskau, and Cirsten Zaeske for their fine contributions. Many ideas and stimulations came from my colleague, Prof. Dr. Adalbert Maercker, Siegen, and his coworkers, which is gratefully acknowledged. Thanks for financial support is due to the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and the Chemetall Company, Frankfurt.

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Received: March 29, 1999

Publication Dates

• Publication in this collection
  21 June 2001
• Date of issue
  Aug 1999

History

• Received
  29 Mar 1999