Entropies of Organolithium Aggregation Based on Measured Microsolvation Numbers

The recent measurement (<i>J. Am. Chem. Soc.</i> <b>2008</b>, <i>130</i>, 14179–14188) of the microsolvation numbers of monodentate, nonchelating ethereal donor ligands coordinating to the monomers and dimers of two sterically shielded C­(aryl)–Li compounds permits the determination of well-founded dimerization enthalpies (Δ<i>H</i>⁰) and entropies (Δ<i>S</i>⁰) from properly formulated equilibrium constants, which must include the concentrations of the free donor ligands. The monomers are found to dimerize <i>endo</i>thermically (Δ<i>H</i>⁰ > 0) in [D₈]­toluene solution in the presence of the donor <i>t</i>BuOMe or THF, but only slightly exothermically (Δ<i>H</i>⁰ = −0.5 kcal per mol of dimer) with the donor Et₂O. The dimerization entropies Δ<i>S</i>⁰ (in cal mol^–1 K^–1) with the respective equivalents of released donor ligands are 7.2 and 11.0 (with 2 equiv of <i>t</i>BuOMe in the two cases), 6.1 (with 2 Et₂O), and 34.1 (with 4 THF). It is shown that the improper omission of microsolvation from the equilibrium constant (a usual practice when the ligand numbers are not known) can lead to “contaminated” aggregation entropies Δ<i>S</i>_ψ, which may deviate considerably from the “true” entropies Δ<i>S</i>⁰. A method is provided for estimating the required microsolvation numbers from ¹³C/Li NMR coupling constants ¹<i>J</i>_C,Li for less congested organolithium types whose coordinated and free donor ligands cannot be distinguished by NMR integration

Microsolvation and ¹³C−Li NMR Coupling

The empirical expression 1JCLi = L[n(a + d)]−1 is proposed; it claims a reciprocal dependence of the NMR coupling constant 1J(13C, Li) in a C−Li compound on two factors: (i) the number n of lithium nuclei in bonding contact with the observed carbanion center and (ii) the sum (a + d) of the numbers a of anions and d of donor ligands coordinated at the Li nucleus that generates the observed 1JCLi value. The expression was derived from integrations of separate NMR resonances of coordinated and free monodentate donor ligands (t-BuOMe, Et2O, or THF) in toluene solutions of dimeric and monomeric 2-(α-aryl-α-lithiomethylidene)-1,1,3,3-tetramethylindan at moderately low temperatures. This unusually slow ligand interchange is ascribed to steric congestion in these compounds, which is further characterized by measurements of nuclear Overhauser correlations and by solid-state structures of the dimers bearing only one donor per lithium atom (d = 1). Increasing microsolvation numbers d are also accompanied by typical changes of the NMR chemical shifts δ (positive for the carbanionic 13Cα, negative for Cpara and p-H). The aforementioned empirical expression for 1JCLi appears to be applicable to other cases of solvated monomeric, dimeric, or tetrameric C−Li compounds (alkyl, alkenyl, alkynyl, and aryl) and even to unsolvated (d ≈ 0) trimeric, tetrameric, or hexameric organolithium aggregates, indicating that 1JCLi might serve as a tool for assessing unknown microsolvation numbers. The importance of obtaining evidence about the 13C NMR C−Li multiplet splitting of both the nonfluxional and fluxional aggregates is emphasized

Microsolvation and ¹³C−Li NMR Coupling

The empirical expression 1JCLi = L[n(a + d)]−1 is proposed; it claims a reciprocal dependence of the NMR coupling constant 1J(13C, Li) in a C−Li compound on two factors: (i) the number n of lithium nuclei in bonding contact with the observed carbanion center and (ii) the sum (a + d) of the numbers a of anions and d of donor ligands coordinated at the Li nucleus that generates the observed 1JCLi value. The expression was derived from integrations of separate NMR resonances of coordinated and free monodentate donor ligands (t-BuOMe, Et2O, or THF) in toluene solutions of dimeric and monomeric 2-(α-aryl-α-lithiomethylidene)-1,1,3,3-tetramethylindan at moderately low temperatures. This unusually slow ligand interchange is ascribed to steric congestion in these compounds, which is further characterized by measurements of nuclear Overhauser correlations and by solid-state structures of the dimers bearing only one donor per lithium atom (d = 1). Increasing microsolvation numbers d are also accompanied by typical changes of the NMR chemical shifts δ (positive for the carbanionic 13Cα, negative for Cpara and p-H). The aforementioned empirical expression for 1JCLi appears to be applicable to other cases of solvated monomeric, dimeric, or tetrameric C−Li compounds (alkyl, alkenyl, alkynyl, and aryl) and even to unsolvated (d ≈ 0) trimeric, tetrameric, or hexameric organolithium aggregates, indicating that 1JCLi might serve as a tool for assessing unknown microsolvation numbers. The importance of obtaining evidence about the 13C NMR C−Li multiplet splitting of both the nonfluxional and fluxional aggregates is emphasized

Microsolvation and ¹³C−Li NMR Coupling

The empirical expression 1JCLi = L[n(a + d)]−1 is proposed; it claims a reciprocal dependence of the NMR coupling constant 1J(13C, Li) in a C−Li compound on two factors: (i) the number n of lithium nuclei in bonding contact with the observed carbanion center and (ii) the sum (a + d) of the numbers a of anions and d of donor ligands coordinated at the Li nucleus that generates the observed 1JCLi value. The expression was derived from integrations of separate NMR resonances of coordinated and free monodentate donor ligands (t-BuOMe, Et2O, or THF) in toluene solutions of dimeric and monomeric 2-(α-aryl-α-lithiomethylidene)-1,1,3,3-tetramethylindan at moderately low temperatures. This unusually slow ligand interchange is ascribed to steric congestion in these compounds, which is further characterized by measurements of nuclear Overhauser correlations and by solid-state structures of the dimers bearing only one donor per lithium atom (d = 1). Increasing microsolvation numbers d are also accompanied by typical changes of the NMR chemical shifts δ (positive for the carbanionic 13Cα, negative for Cpara and p-H). The aforementioned empirical expression for 1JCLi appears to be applicable to other cases of solvated monomeric, dimeric, or tetrameric C−Li compounds (alkyl, alkenyl, alkynyl, and aryl) and even to unsolvated (d ≈ 0) trimeric, tetrameric, or hexameric organolithium aggregates, indicating that 1JCLi might serve as a tool for assessing unknown microsolvation numbers. The importance of obtaining evidence about the 13C NMR C−Li multiplet splitting of both the nonfluxional and fluxional aggregates is emphasized

Microsolvation and ¹³C−Li NMR Coupling

The empirical expression 1JCLi = L[n(a + d)]−1 is proposed; it claims a reciprocal dependence of the NMR coupling constant 1J(13C, Li) in a C−Li compound on two factors: (i) the number n of lithium nuclei in bonding contact with the observed carbanion center and (ii) the sum (a + d) of the numbers a of anions and d of donor ligands coordinated at the Li nucleus that generates the observed 1JCLi value. The expression was derived from integrations of separate NMR resonances of coordinated and free monodentate donor ligands (t-BuOMe, Et2O, or THF) in toluene solutions of dimeric and monomeric 2-(α-aryl-α-lithiomethylidene)-1,1,3,3-tetramethylindan at moderately low temperatures. This unusually slow ligand interchange is ascribed to steric congestion in these compounds, which is further characterized by measurements of nuclear Overhauser correlations and by solid-state structures of the dimers bearing only one donor per lithium atom (d = 1). Increasing microsolvation numbers d are also accompanied by typical changes of the NMR chemical shifts δ (positive for the carbanionic 13Cα, negative for Cpara and p-H). The aforementioned empirical expression for 1JCLi appears to be applicable to other cases of solvated monomeric, dimeric, or tetrameric C−Li compounds (alkyl, alkenyl, alkynyl, and aryl) and even to unsolvated (d ≈ 0) trimeric, tetrameric, or hexameric organolithium aggregates, indicating that 1JCLi might serve as a tool for assessing unknown microsolvation numbers. The importance of obtaining evidence about the 13C NMR C−Li multiplet splitting of both the nonfluxional and fluxional aggregates is emphasized

Analysis of covariance (ANCOVA) between hand grip, CoQ₁₀/cholesterol ratio, age and BMI in A) the basic study population (n = 334) and B) the validation population (n = 967), including 658 overweight/obese subjects.

Analysis of covariance (ANCOVA) between hand grip, CoQ10/cholesterol ratio, age and BMI in A) the basic study population (n = 334) and B) the validation population (n = 967), including 658 overweight/obese subjects.</p

Pseudomonomolecular, Ionic sp²‑Stereoinversion Mechanism of 1‑Aryl-1-alkenyllithiums

The trans/cis stereoinversion of the trigonal carbanion centers C-α in a series of monomeric 2-(α-aryl-α-lithiomethylidene)-1,1,3,3-tetramethylindanes (known to be trisolvated at Li) is rapid on the NMR time scales (400 and 100.6 MHz) in THF solution. The far-reaching redistribution of electric charge in the ground-state molecules caused by lithiation (formal replacement of α-H by α-Li) is illustrated through NMR shifts, Δδ. The transition states for stereoinversion are significantly more polar and charge-delocalized than the ground states (Hammett ρ = +5.2), pointing to a mechanism that involves heterolysis of the C–Li bond via a solvent-separated ion pair (SSIP). This requires immobilization of only one additional (the fourth) THF molecule at Li⁺, which accounts for part of the apparent activation entropies of ca. −23 cal mol^–1 K^–1 and constitutes a kinetic privilege of THF depending on microsolvation at Li. Thus, the sp²-stereoinversion process is “catalyzed” by the solvent THF; its mechanism is monomolecular with respect to the ground-state species because the pseudo-first-order rate constants, measured through NMR line shape analyses, are independent of the concentrations (inclusive of decomposition) of the dissolved species (hence no associations and no dissociation to give free carbanion intermediates). In the deduced pseudomonomolecular mechanism (bimolecular through solvent participation), the angular C-α of the SSIP undergoes rehybridization (approximately in-plane inversion) through a close-to-linear transition state; this motion occurs with a concomitant “conducted tour” migration of Li⁺(THF)₄ and is unimpaired by additional <i>ortho</i>-methylations at α-aryl. The synthetic route started with preparations of three α-chloro congeners through the carbenoid chain reaction, followed by vinylic substitution of α-Cl by α-SnMe₃ (most efficient in THF despite steric congestion). The final Sn/Li interchange reaction afforded the new 1-aryl-1-alkenyllithium samples, initially uncontaminated by free Li⁺

Characterization of the basic study population (<i>n</i> = 334).

<p>Characterization of the basic study population (<i>n</i> = 334).</p

Carbenoid Chain Reactions: Substitutions by Organolithium Compounds at Unactivated 1-Chloro-1-alkenes^†

The deceptively simple “cross-coupling” reactions Alk2CCA−Cl + RLi → Alk2CCA−R + LiCl (A = H, D, or Cl) occur via an alkylidenecarbenoid chain mechanism in three steps without a transition metal catalyst. In the initiating step 1, the sterically shielded 2-(chloromethylidene)-1,1,3,3-tetramethylindans 2a−c (Alk2CCA−Cl) generate a Cl,Li-alkylidenecarbenoid (Alk2CCLi−Cl, 6) through the transfer of atom A to RLi (methyllithium, n-butyllithium, or aryllithium). The chain cycle consists of the following two steps:  (i) A fast vinylic substitution reaction of these RLi at carbenoid 6 (step 2) with formation of the chain carrier Alk2CCLi−R (8), and (ii) a rate-limiting transfer of atom A (step 3) from reagent 2 to the chain carrier 8 with formation of the product Alk2CCA−R (4) and with regeneration of carbenoid 6. This chain propagation step 3 was sufficiently slow to allow steady-state concentrations of Alk2CCLi−Aryl to be observed (by NMR) with RLi = C6H5Li (in Et2O) and with 4-(Me3Si)C6H4Li (in t-BuOMe), whereas these chain processes were much faster in THF solution. PhC⋮CLi cannot perform step 1, but its carbenoid chain processes with reagents 2a and 2c may be started with MeLi, whereafter LiC⋮CPh reacts faster than MeLi in the product-determining step 2 to generate the chain carrier Alk2CCLi−C⋮CPh (8g), which completes its chain cycle through the slower step 3. The sterically congested products were formed with surprising ease even with RLi as bulky as 2,6-dimethylphenyllithium and 2,4,6-tri-tert-butylphenyllithium

Coenzyme Q₁₀ Status as a Determinant of Muscular Strength in Two Independent Cohorts

<div><p>Aging is associated with sarcopenia, which is a loss of skeletal muscle mass and function. Coenzyme Q₁₀ (CoQ₁₀) is involved in several important functions that are related to bioenergetics and protection against oxidative damage; however, the role of CoQ₁₀ as a determinant of muscular strength is not well documented. The aim of the present study was to evaluate the determinants of muscular strength by examining hand grip force in relation to CoQ₁₀ status, gender, age and body mass index (BMI) in two independent cohorts (n = 334, n = 967). Furthermore, peak flow as a function of respiratory muscle force was assessed. Spearman’s correlation revealed a significant positive association between CoQ₁₀/cholesterol level and hand grip in the basic study population (p<0.01) as well as in the validation population (p<0.001). In the latter, we also found a negative correlation with the CoQ₁₀ redox state (p<0.01), which represents a lower percentage of the reduced form of CoQ₁₀ (ubiquinol) in subjects who exhibit a lower muscular strength. Furthermore, the age of the subjects showed a negative correlation with hand grip (p<0.001), whereas BMI was positively correlated with hand grip (p<0.01), although only in the normal weight subgroup (BMI <25 kg/m²). Analysis of the covariance (ANCOVA) with hand grip as the dependent variable revealed CoQ₁₀/cholesterol as a determinant of muscular strength and gender as the strongest effector of hand grip. In conclusion, our data suggest that both a low CoQ₁₀/cholesterol level and a low percentage of the reduced form of CoQ₁₀ could be an indicator of an increased risk of sarcopenia in humans due to their negative associations to upper body muscle strength, peak flow and muscle mass.</p></div