6Li NMR Study of the Equilibrium between Methyllithium and n

Jun 25, 2008 - Influence of a Third Partner, a Chiral Lithium Amide. Franck Paté, Hassan Oulyadi*, Anne .... Hans J. Reich. Chemical Reviews 2013 113...
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Organometallics 2008, 27, 3564–3569 6

Li NMR Study of the Equilibrium between Methyllithium and n-Butyllithium in THF. Influence of a Third Partner, a Chiral Lithium Amide

Franck Pate´,† Hassan Oulyadi,*,† Anne Harrison-Marchand,‡ and Jacques Maddaluno*,‡ Laboratoire de Chimie Organique et Biologique Structurale and Laboratoire des Fonctions Azote´es & Oxyge´ne´es Complexes de l’IRCOF, UMR CNRS 6014 and FR CNRS 3038, UniVersite´ de Rouen et INSA de Rouen, 76821 Mont St Aignan Cedex, France ReceiVed March 20, 2008

A 6Li NMR structural study of mixtures of labeled methyllithium, n-butyllithium, and 3-aminopyrrolidine lithium amide has been achieved in THF at -78 °C. In the first part, the study was focused on the mixed aggregates formed between methyllithium and n-butyllithium. The spectral data suggest that the two reactants form a series of tetramers (MeLi)4(n-BuLi)4-n, of which abundance depends on the proportion of the two alkyllithiums following a purely statistical distribution. The labeled chiral lithium amide was next introduced in the sample, and the competitive formation of the amide-methyllithium and amide-butyllithium mixed dimers was monitored in situ. The NMR spectra show a juxtaposition of signals typical of the entities characterized separately, suggesting that there is no preferential formation of one aggregate over the others. Introduction Alkyllithium derivatives are probably the most popular organometallic reagents employed in organic synthesis.1 Their strongly basic and nucleophilic character explains why they can be employed with comparable successes for deprotonations and condensation on most types of electrophiles. They also find a large range of applications in the halogen-lithium exchange reactions, where their usage is commonplace.2 The structure in solution of RLi’s in the ether solvents, which are the typical reaction media in which these reagents are employed, has undergone many investigations, and excellent reviews gather the most important data concerning the “usual” alkyllithiums.3 The case of methyllithium and n-butyllithium has been the object of particular attention since both are commercially available in different solvents. In contrast, little work has been dedicated to the mixtures of these entities, while the well-known dynamic character of their aggregates suggests that rapid rearrangements are likely to occur. Mixing alkyllithiums sometimes leads to dramatic improvements of the chemical properties of the resulting cocktail.4 In general, the competitive formation of mixed aggregates when more than two partners are involved is seldom investigated, mainly because of the analytical difficulties associated with the * Corresponding authors. E-mail: [email protected]; [email protected]. † Laboratoire de Chimie Organique et Biologique Structurale. ‡ Laboratoire des Fonctions Azote´es & Oxyge´ne´es Complexes. (1) Clayden, J. Organolithium: SelectiVity for Synthesis; Pergamon: Amsterdam, 2002. (2) For an in-depth experimental study see: (a) Bailey, W. F.; Luderer, M. R.; Jordan; K. P, J. Org. Chem. 2006, 71, 2825–2828. For theoretical analyses see: (b) Nakamura, E.; Miyachi, Y.; Koga; N.; Morokuma, K. J. Am. Chem. Soc. 1992, 114, 6686–6692. (c) Boche, G.; Schimeczek, M.; Cioslowski, J.; Piskorz; P, Eur. J. Org. Chem. 1998, 1851–1860. (d) Wilberg, K. B.; Sklenac, S.; Bailey, W. F. J. Org. Chem. 2000, 65, 2014– 2021. (e) Ando, K. J. Org. Chem. 2006, 71, 1837–1850. (3) Bauer, W.; Schleyer, P. v. R. AdV. Carbanion Chem. 1992, 1, 89, and references therein. (4) For instance, the stability of s-BuLi is increased by EtLi addition: http://www.freepatentsonline.com/4460515.html.

characterization of the interacting entities.5 We have recently described the detrimental effect played in asymmetric synthesis by lithium chloride and bromide when preformed methyllithium-3-aminopyrrolidine lithium amide complexes were employed.6 This observation was justified by the high affinity of the lithium halides for the lithium amide. In this paper, we wish to examine the behavior of two alkyllithiums competing for the same lithium amide. This approach tries to get rid of the chemical difference between RLi and LiX to focus on the influence of “pure” steric alterations between two alkyl groups on the affinity for a 3-aminopyrrolidine lithium amide.

Results and Discussion Mixtures of Methyllithium and n-Butyllithium. The simple case of methyllithium and n-butyllithium was first clarified. No structural investigation has been devoted yet to this mixture to our knowledge. A pioneering NMR study, undertaken by Seitz and Brown, is described in a paper dedicated to the similar methyllithium-ethyllithium couple.7 This work mainly relied on a remarkable set of 7Li spectra, but the resolution of the 23 MHz instrument available in 1966 was insufficient to allow the authors to decide unambiguously if the equilibrium they were observing was taking place between trimers or tetramers. We thought such a problem could be efficiently tackled resorting (5) (a) Novak, D. P.; Brown, T. L. J. Am. Chem. Soc. 1972, 94, 3793– 3798. (b) Eppers, O.; Gu¨nther, H. HelV. Chim. Acta 1990, 73, 2071–2082. (c) Desjardins, S.; Flinois, K.; Oulyadi, H.; Davoust, D.; Giessner-Prettre, C.; Parisel, O.; Maddaluno, J. Organometallics 2003, 22, 4090–4097. (d) Fox, T.; Hausmann, H.; Gu¨nther, H. Magn. Reson. Chem. 2004, 42, 788– 794. (6) Pate´, F.; Duguet, N.; Oulyadi, H.; Harrison-Marchand, A.; Fressigne´, C.; Valnot, J.-Y.; Lasne, M.-C.; Maddaluno, J. J. Org. Chem. 2007, 72, 6982–6991. (7) (a) Seitz, L. M.; Brown, T. L. J. Am. Chem. Soc. 1966, 88, 2174– 2178. A few years before, the ethyllithium/tert-butyllithium system was also explored extensively: (b) Weiner, M. A.; West, R. J. Am. Chem. Soc. 1962, 85, 485–486.

10.1021/om800260c CCC: $40.75  2008 American Chemical Society Publication on Web 06/25/2008

Mixed Aggregation between MeLi, n-BuLi, and a Chiral R2NLi

to a 6Li labeling of the partners. This nucleus is characterized by a weak quadrupolar relaxation8 associated with sharp signals, which is extremely useful for the analysis of organolithium compounds in solution.9 Thus, 6Li-labeled methyllithium and n-butyllithium were prepared according to well-known procedures.10 The success of these syntheses was checked by recording the 1H and 6Li spectra of MeLi and n-BuLi in carefully distilled THF-d8 at 195 K (-78 °C). This low temperature is required to ensure a sufficient resolution of the spectra. Then, controlled aliquots of n-BuLi were added to the solution of pure MeLi (c ) 0.33 M) until a 1:1 ratio was reached. Similarly, aliquots of MeLi were added to the pure solution of n-BuLi (c ) 0.27 M) up to the same equimolar ratio. Only the 6Li spectra for these two experiments are reproduced in Figure 1. The corresponding 1H spectra are provided in the Supporting Information (S1). Methyllithium is known to adopt a tetrameric structure in THF, associated with one singlet at 2.68 ppm (spectrum 1a). The 13C spectrum (not shown) exhibits the expected heptet11 at -15.1 ppm with 1J13C-6Li ) 5.8 Hz, characteristic of a cubic aggregate according to the Bauer-Winchester--Schleyer3 empirical rule (1J13C-6Li ) 17 ( 2/n, n being the number of 6Li surrounding the observed 13C). Comparably, the 6Li spectrum of n-butyllithium gives two singlets at 1.95 (major) and 2.35 (minor) ppm (spectrum 1h). Those are assigned to the (n-BuLi)4 and (n-BuLi)2 oligomers, respectively.12 The intermediate 6Li spectra of Figure 1 are extremely similar to those obtained when adding LiBr5c or LiI13 to MeLi, suggesting a comparable and progressive formation of mixed tetramers of general formula (MeLi)4-n(n-BuLi)n, as depicted in Figure 2. This representation clearly shows that the signals associated with the homogeneous symmetrical tetramers A and E should be combined in one singlet (Li1 and Li8, respectively). Following the same logic, B should be associated with two peaks with integrations ratio of 1:3 (Li2/Li3), C to two peaks in a 1:1 ratio (Li4/Li5), and D to two peaks in a 3:1 ratio (Li6/Li7). All these pairs of signals appear (and disappear) in the expected order on the spectra of Figure 1, all the peaks coexisting only on spectra 1c and 1d. The progressive chemical shielding and the relative integration of the two singlets belonging to a same pair are in perfect agreement with the anticipated tendency for these systems. Two bidimensional experiments were run to further support the hypothesis presented above. First, a 6Li,1H HOESY experiment was conducted on a sample presenting a MeLi/n-BuLi ) 2:1 ratio. The spectrum (Figure 3, left) shows that Li1 and Li2 correlate only to the methyl signal, while Li3-Li6 give cross(8) Wehrli, F. W. J. Magn. Reson. 1978, 30, 193–209. (9) (a) Fraenkel, G.; Fraenkel, A. M.; Geckle, M. J.; Frank, S. J. Am. Chem. Soc. 1979, 101, 4745–4747. (b) Seebach, D.; Siegel, H.; Gabriel, J.; Ha¨ssig, R. HelV. Chim. Acta 1980, 63, 2046–2053. (c) Gu¨nther, H. J. Braz. Chem. Soc. 1999, 10, 241–262. For very recent bidimensional developments of these techniques, see: (d) Li, D.; Hopson, R.; Li, W.; Liu, J.; Williard, P. G. Org. Lett. 2008, 10, 909–911. (e) Li, D.; Sun, C.; Liu, J.; Hopson, R.; Li, W.; Williard, P. G. J. Org. Chem. 2008, 73, 2373–2381. (10) (a) Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Prigent, Y.; Davoust, D.; Duhamel, P. J. Am. Chem. Soc. 1997, 119, 10042–10048. (b) Corruble, A.; Davoust, D.; Desjardins, S.; Fressigne´, C.; Giessner-Prettre, C.; HarrisonMarchand, A.; Houte, H.; Lasne, M.-C.; Maddaluno, J.; Oulyadi, H.; Valnot, J.-Y. J. Am. Chem. Soc. 2002, 124, 15267–15279. (11) The 1J13C-7Li spin-spin coupling in MeLi was measured 40 years ago: (a) McKeever, L. D.; Waack, R.; Doran, M. A.; Baker, E. B. J. Am. Chem. Soc. 1968, 90, 3244–3244. (b) McKeever, L. D.; Waack, R.; Doran, M. A.; Baker, E. B. J. Am. Chem. Soc. 1969, 91, 1057–1061. (12) (a) Seebach, D.; Ha¨ssig, R.; Gabriel, J. HelV. Chim. Acta 1983, 66, 308–337. (b) McGarrity, J. F.; Ogle, C. A. J. Am. Chem. Soc. 1985, 107, 1805–1810. (c) Heinzer, J.; Oth, J. F. M.; Seebach, D. HelV. Chim. Acta 1985, 68, 1848–1862. (d) Bauer, W.; Clark, T.; Schleyer, P. v. R. J. Am. Chem. Soc. 1987, 109, 970–977. (e) Keresztes, I.; Williard, P. G. J. Am. Chem. Soc. 2000, 122, 10228–10229.

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Figure 1. 6Li spectra of mixtures between Me6Li and n-Bu6Li.

peaks with both the methyl group and the CH2(R) of the butyl residues. On the other hand, two Li-Li scalar coupling crosspeaks could be evidenced through a 6Li-6Li COSY experiment run on a sample with a MeLi/n-BuLi ) 1:1 ratio (Figure 3, right), which highlights the Li4-Li5 and Li6-Li7 couplings, the constant of which is too low to show up on the 1D spectra. Note that the absence of Li2-Li3 cross correlation is probably a consequence of the low concentration of aggregate B. The variation of the relative abundance, calculated on the basis of the integration of the signals, of the various aggregates along the addition of n-BuLi on MeLi is featured in Table 1 and plotted in Figure 4. According to Novak and Brown, the fractional quantities of each complex, computed supposing that the freeenergy differences between tetramers is zero except for the statistical factors involved in forming the mixed tetramers, is given by5a

F(Li4Me4-nBun) ) f(MeLi)4-n × f(BuLi)n ×

[ (n ! (44!- n) ! ) ]

(1)

where n is the number of butyl(s) in the complex considered, and f(MeLi) and f(BuLi) are the fractional concentrations of MeLi and n-BuLi in the initial mixture, i.e., f(MeLi) + f(BuLi) ) 1. (13) Eppers, O.; Gu¨nther, H. HelV. Chim. Acta 1990, 73, 2071–2082.

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Figure 2. All possible tetrameric aggregates formed between MeLi and n-BuLi in THF.

Figure 3. 6Li,1H HOESY NMR spectrum of a MeLi/n-BuLi ) 2:1 sample (left) and 6Li-6Li COSY NMR spectrum of a MeLi/n-BuLi ) 1:1 sample (right). Both are recorded in THF-d8 at 195 K. Table 1. Theoretical5a and Experimental Abundance of the A-E Aggregates as a Function of the MeLi/n-BuLi Ratio A/B/C/D/E ratio MeLi/n-BuLi ratio

theoretical

experimental

1/0 4/1 4/2 4/3 4/4 3/4 2/4 1/4 1/∞

100/0/0/0/0 41/41/15/3/0 20/40/29/10/1 11/32/36/18/3 6/25/38/25/6 3/18/36/32/11 1/10/29/40/20 0/3/15/41/41 0/0/0/0/100

100/0/0/0/0 25/50/22/3/0 8/32/39/19/2 3/25/38/39/5 1/13/37/40/9 0/6/28/46/20 0/1/21/50/27 0/0/15/44/41 0/0/0/0/100

Considering that a partial hydrolysis of the samples is always possible, the data in the table and in Figure 4 show a relatively good agreement between the purely statistical distribution featured (left) and the one built from the NMR data (right). This accord suggests that the five tetramers are in rapid equilibrium on the laboratory time scale, but slow with respect to the NMR time scale, and that their energy of aggregation is similar, no thermodynamical preference in favor of one or several species being observed. In conclusion to the first part of this work, the data we present suggest that mixing methyllithium and n-butyllithium in THF at low temperature leads rapidly to a statistical distribution of all cubic mixed aggregates, no preferred structure being observed in the solutions we have examined. This contrasts sharply with previous observations on MeLi/LiBr mixtures.5c

Mixtures of a 3-Aminopyrrolidine Lithium Amide with Methyllithium and n-Butyllithium. In relation with our previous works on the mixed aggregates formed between 3-aminopyrrolidine (3AP) lithium amides and alkyl-, vinyl-, or aryllithium,14 we decided to examine the competitive aggregation of methyllithium and n-butyllithium to the same lithium amide. Because it had been used previously in experiments of enantioselective hydroxyalkylation, the lithium amide 1 was retained as a prototype for this study.10b It was 6Li labeled by direct deprotonation of the corresponding amine by exactly 1 equiv of Me6Li in perdeuterated dry THF. The two amidealkyllithium binary complexes were first characterized. The known 1/MeLi was prepared following the protocol described before10b and checked by NMR (0.11 M). The complex 1/nBuLi, never characterized before, was prepared in a similar fashion. Its one- (1H, 6Li, 13C) and two- (1H-1H COSY, 1H-1H NOESY, 6Li-1H HOESY) dimensional spectra were recorded and assigned (Supporting Information S2-S6). The data suggest that 1/n-BuLi adopts the expected endo topology, fully similar to that observed with MeLi. The overall arrangement of these noncovalent complexes seems thus to be controlled by the lithium amide, as observed before.15 (14) Harrison-Marchand, A.; Valnot, J.-Y.; Corruble, A.; Duguet, N.; Oulyadi, H.; Desjardins, S.; Fressigne´, C.; Maddaluno, J. Pure Appl. Chem. 2006, 78, 321–331. (15) Yuan, Y.; Desjardins, S.; Harrison-Marchand, A.; Oulyadi, H.; Fressigne´, C.; Giessner-Prettre, C.; Maddaluno, J. Tetrahedron 2005, 31, 3325–3334.

Mixed Aggregation between MeLi, n-BuLi, and a Chiral R2NLi

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Figure 4. Statistical (left) and experimental (right) distribution of mixed aggregates A-E as a function of the MeLi/n-BuLi ratio.

Next, the mixture of the three partners was investigated: 1.2 equiv of a MeLi solution was added atop the 1/n-BuLi sample. Figure 5d shows that the 6Li spectrum recorded for this mixture results from the superposition of the spectra of 1/n-BuLi, 1/MeLi, and a MeLi/n-BuLi combination (Figure 5a-c). This suggests that, in solution, the different possible complexes undergo a rapid dynamic equilibration, even at -78 °C. Thus, here again all the aggregation energies seem more or less in the same range (Scheme 1). To check the possible influence of the order of introduction of the partners, we did the reverse experiment by adding 1.1 equiv of a solution of n-BuLi (c ) 0.28 M) to a 1/MeLi sample. Here again, the spectrum shows a complete and uncontrolled mixing between the three partners (Figure 5e). Thus, the second part of this study indicates that mixing two alkyllithiums and one 3AP lithium amide proceeds to an uncontrolled aggregation, leading to all possible combinations between the different partners. In particular, no preference for a given lithium amide-alkyllithium mixed aggregate could be observed.

Experimental Part General Considerations. Commercial tetrahydrofuran-d8 was distilled over sodium and benzophenone. 6Li (95%) was purchased from Aldrich and washed in freshly distilled pentane. Pentane and heptane were distilled over lithium aluminum hydride. n-Bromobutane was distilled over CaH2. Argon was dried and deoxygenated by bubbling through a commercial solution of butyllithium in hexane. 6 Li Methyllithium Salt-Free Solution in Ether.16 Finely cut 6-lithium metal ribbon (0.5 g, 83 mmol), 0.5% (weight) of sodium (ca. 2.5 mg, 0.11 mmol), and three small pieces of broken glass were introduced in a two-necked pear-shaped flask (50 mL) equipped with a glass stopper and a condenser fitted with a balloon of dry argon. The metallic cuttings were covered with octadecane (10 mL), and the solution was heated (reflux of octadecane: 317 °C) with a hot air gun while vigorously stirring. When a maximum amount of the lithium was melted, the flask was placed in a cold bath (-40 °C), allowing the lithium to precipitate as a fine shiny shot. The octadecane was extracted with freshly distilled heptane (16) Kamiensky, C. W.; Esmay, D. L. J. Org. Chem. 1960, 25, 1807– 1808. (17) Duhamel, L.; Plaquevent, J.-C. J. Organomet. Chem. 1993, 448, 1–3.

(10 mL) using a syringe. After intensive stirring, the heptane was removed and the metal washed twice with this same solvent. Diethyl ether was syringed, and the condenser was quickly replaced by a CO2 condenser fitted with a balloon of dry argon. Chloromethane (2.3 mL, 41.5 mmol) was condensed directly from the sealed cylinder to a graduated trap at -40 °C and then added very slowly (2.3 mL was added over a period of 45 min), connecting the trap to the top of the CO2 condenser. The formation of a gray salt corresponding to LiCl was observed, and the disappearance of the 6 Li metal was noticed. After replacing the CO2 condenser with a septum, the resulting reaction mixture was stirred for 20 h at room temperature under dry argon. The stirring was stopped, allowing LiCl to settle. The etheral solution was then pumped off the flask with a syringe and directly inserted into centrifugation tubes placed under dry argon. The residual traces of salt were centrifuged and the clear final solution was collected in a dry flask flushed under dry argon, then titrated17 (1.4 M, 55% yield) and kept until further use. [6Li] Methyllithium Salt-Free Solution in Tetrahydrofuran-d8. A solution of [6Li]-methyllithium in ether prepared above (2.5 mL) was syringed in a tube fitted with a septum and flushed under dry argon. The tube was then placed under vacuum (20 mmHg) for 1 h to evaporate the ether. The resulting white solid was then dissolved in freshly distilled tetrahydrofuran-d8 and concentrated under vacuum for 1 h to evaporate the last traces of ether. THF-d8 (3 to 3.5 mL) was finally added, and the resulting solution was titrated17 (0.5 to 0.7 M). [6Li] n-Butyllithium Salt-Free Solution in Pentane.18 Finely cut 6-lithium metal ribbon (0.3 g, 50 mmol) was introduced in a two-necked pear-shaped flask (50 mL) equipped with a balloon of dry argon. The metallic cuttings were covered with freshly distilled pentane (10 mL). After intensive stirring, the pentane was removed and the metal washed twice with this same solvent. A new amount of 10 mL of pentane was introduced, and a solution of freshly distilled n-bromobutane (2.14 mL, 20 mmol) in pentane (6 mL) was syringed at room temperature over a period of 30 min. The resulting reaction mixture was stirred for 20 h at room temperature under dry argon. The hydrocarbon solution was then pumped off the flask with a syringe and directly inserted into centrifugation tubes placed under dry argon. The residual traces of salt were centrifuged, and the clear final solution was collected in a dry flask flushed under dry argon, then titrated17 and kept until further use. (18) Fraenkel, G.; Henrichs, M.; Hewitt, J. M.; Su, B. M.; Geckle, M. J. J. Am. Chem. Soc. 1980, 102, 3345–3350.

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Pate´ et al. Scheme 1

13

C chemical shifts were referenced to the solvent THF-d8 signals at δ 1.73 and 25.37 respectively. Lithium spectra were referenced to external 0.3 M 6LiCl in MeOH-d4 (δ 0.0).

Figure 5. 6Li spectra in THF at 195 K of (a) 1/n-BuLi; (b) 1/MeLi; (c) (MeLi)2(n-BuLi)2; (d) a mixture resulting from the addition of MeLi on 1/n-BuLi; (e) a mixture resulting from the addition of n-BuLi on 1/MeLi. [6Li] n-Butyllithium Salt-Free Solution in Tetrahydrofuran-d8. A solution of [6Li]-n-butyllithium in pentane prepared above (2.5 mL) was syringed in a tube fitted with a septum and flushed under dry argon. The tube was then placed under vacuum (20 mmHg) for 1 h to evaporate the pentane. The resulting white solid was then dissolved in freshly distilled tetrahydrofuran-d8 and concentrated under vacuum for 1 h to evaporate the last traces of hydrocarbon. THF-d8 (3 to 3.5 mL) was finally added, and the resulting solution was titrated.17 [6Li]-Lithium Amides 1. A solution of amine 1 (0.137 mmol) in freshly distilled tetrahydrofuran-d8 (0.2 mL) was transferred into a dry 5 mm NMR tube fitted with a septum and flushed under argon. A solution of [6Li]-methyllithium (1 equiv) or n-butyllithium freshly prepared in tetrahydrofuran-d8 was added dropwise at -78 °C with a syringe to the above solution. The tube was vigorously shaken and quickly dropped in the precooled (-78 °C) NMR probe. Instrumental Considerations. All NMR experiments were performed on a Bruker Avance DMX 500 spectrometer, equipped with a z-gradient unit and a 5 mm {1H, 6Li, 13C, and 15N} quadruple-resonance probe. Measuring frequencies were 500 MHz (1H), 125 MHz (13C), 73 MHz (6Li), and 50 MHz (15N). 1H and

1D NMR Measurements. The proton and lithium onedimensional experiments were recorded with standard parameters. In order to remove 13C -1H coupling, the one-dimensional 13C spectra were recorded with broadband proton decoupling. 2D NMR Measurements. 6Li/6Li COSY.19 The following parameters were used for acquiring and processing the spectrum in absolute values: 128 experiments with 1024 data points and 8 scans each were recorded; no proton decoupling was used; one time zero filling in f1; pure sine bell window function was applied before Fourier transformation. 6 Li/1H HOESY.20 The following parameters were used for acquiring and processing the spectrum in phase-sensitive mode: 128 experiments with 1024 data points and 16 scans each were recorded; pure phase line shapes were obtained by using time proportional phase incrementation (TPPI) phase cycling; variable mixing times, depending on the sample, were used; one time zero filling in f1; π/2 and π/3 shifted since square window functions were applied to f2 and f1 dimensions, respectively, before Fourier transformation. 1 H/1H COSY.21 The following parameters were used for acquiring and processing the spectra in absolute values: 256 experiments with 2048 data points and 8 scans each were recorded; one time zero filling in f1; pure sine bell window function was applied before Fourier transformation. 1 H/13C HMQC.22 The following parameters were used for acquiring and processing the spectra in phase-sensitive mode: 512 experiments with 2048 data points and 8 scans each were recorded; pure phase line shapes were obtained by using time proportional phase incrementation (TPPI) phase cycling, one time zero filling in f1; π/2 shifted sine square window functions were applied to f2 and f1 dimensions before Fourier transformation. 1 H/1H NOESY.23 The following parameters were used for acquiring and processing the spectra in phase-sensitive mode: 256 experiments with 2048 data points and 16 scans each were recorded; pure phase line shapes were obtained by using time proportional phase incrementation (TPPI) phase cycling, variable mixing times, depending on the sample, were used; one time zero filling in f1; π/2 shifted sine square window functions were applied to f2 and f1 dimensions before Fourier Transformation (19) Bax, A.; Freeman, R. J. Magn. Reson. 1981, 44, 542–561. (20) Yu, A. C.; Levy, G. J. Am. Chem. Soc. 1984, 106, 6533–6537. (21) Aue, W. P.; Bartholdi, E.; Ernst, R. R. J. Chem. Phys. 1976, 64, 2229–2246. (22) Bax, A.; Griffey, R. H.; Hawkins, B. L. J. Magn. Reson. 1983, 55, 301–315. (23) Wagner, R.; Berger, S. J. Magn. Reson. 1996, 123A, 119–121.

Mixed Aggregation between MeLi, n-BuLi, and a Chiral R2NLi Processing of NMR data was performed on a SGI O2 computer, using the manufacturer’s program Xwinnmr2.1 (Bruker).

Conclusion This work describes the evolution of the composition of solutions of binary or ternary lithiated systems in equilibrium in THF at low temperature. The first part of the study clearly shows that mixing methyl- and n-butyllithium leads to a statistical distribution of the tetramers of general formula (MeLi)4(n-BuLi)4-n. No preference for a given composition could be evidenced, in contrast to what was observed with the (MeLi)4(LiBr)4-n system.4 Therefore, it seems that the differences between MeLi and n-BuLi, including steric effects, are small enough not to influence the relative stability of the mixed tetramers. This result is relatively surprising when considering the large aggregation energy computed for methyllithium tetramers with respect to higher alkyllithium compounds.24 Our data bring full support to the hypotheses proposed by Seitz and Brown more than 40 years ago: the current NMR equipment, and in particular the 6Li spectra, does away with the ambiguities left by the data of 1966. In addition, the rapid and efficient equilibration between such species can probably explain why mixtures of secondary and primary alkyllithiums (such as s-BuLi and EtLi)4 are more stable and easier to handle than the pure branched reagents. The second part of the study deals with ternary species involving the two alkyllithiums plus a 3-aminopyrrolidine (24) See for instance: (a) Kwon, O.; Sevin, F.; McKee, M. L. J. Phys. Chem. A 2001, 105, 913–922. (b) Gohaud, N.; Begue, D.; Pouchan, C. Chem. Phys. 2005, 310, 85–96. (c) Pratt, L. M.; Truhlar, D. G.; Cramer, C. J.; Kass, S. R.; Thompson, J. D. J. Org. Chem. 2007, 72, 2962–2966.

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lithium amide 1. Preforming a 1:1 mixed aggregate between one alkyllithium and the amide, then adding the second alkyllithium, affords a mixture in which the various species (1:1 mixed aggregates and alkyllithium tetramers) evolve independently and reach a rapid equilibrium. It thus seems that a 3-aminopyrrolidine lithium amide is unable to discriminate between primary alkyllithiums in solution, to form selectively a favored aggregate that could be further exploited. In particular, such a dynamic screening between competing entities could have been of interest in asymmetric synthesis. Because it is likely to be more selective, a competition involving a primary and a secondary alkyllithium could constitute a better choice in this prospect. Finally, these results will help to discuss data obtained in the enantioselective hydroxyalkylation of aldehydes by two competitive alkyllithiums. Such intriguing results will be reported in due time.

Acknowledgment. This work was conducted on equipment bought and maintained thanks to the continuous and generous support of the Conseil Re´gional de Haute-Normandie. Part of the funding came through the inter-regional network PUNCHorga, which is acknowledged for its commitment. Part of this work was funded by the Agence Nationale pour la Recherche through grant ANR-07-BLAN0294-01. Supporting Information Available: This material is available free of charge via the Internet at http://pubs.acs.org. OM800260C