A computational study of mixed aggregates of chloromethyllithium with lithium dialkylamides

DFT calculations were performed to examine the possible formation of mixed aggregates between chloromethyllithium carbenoids and lithium dimethylamide (LiDMA). In the gas phase mixed aggregates were readily formed and consisted of mixed dimers, mixed trimers, and mixed tetramers. THF solvation disfavored the formation of mixed tetramers and resulted in less exergonic free energies of mixed dimer and mixed trimer formation.     

A computational study of lithium enolate mixed aggregates

Ab initio calculations were performed to examine the formation of mixed dimer and trimer aggregates between the lithium enolate of acetaldehyde (lithium vinyloxide, LiOV) and lithium chloride, lithium bromide, and lithium amides. Gas-phase calculations showed that in the absence of solvation effects, the mixed trimer 2LiOV.LiX is the most favored species. Solvation in ethereal solvents was modeled by a combination of specific coordination of dimethyl ether ligands on each lithium and "dielectric solvation" (DSE, dielectric solvation energies), immersion of each molecule in a cavity within a continuous dielectric having the dielectric constant of THF at room temperature. DSE is less important for aggregates (reduced dipoles or quadrupoles) than monomers (dipoles) and is also reduced for the coordinatively solvated species. Both solvation terms reduce the exothermicity of aggregation. In many cases, lithium salts that are three- rather than four-coordinate have significant populations at room temperature. The strongly basic lithium amides prefer mixed aggregates with weaker bases than homoaggregates. The computational results are consistent with the limited experimental data available.     

Ketone enolization with lithium dialkylamides: the effects of structure,solvation, and mixed aggregates with excess butyllithium

The effects of lithium dialkylamide structure, mixed aggregate formation, and solvation on the stereoselectivity of ketone enolization were examined. Of the lithium dialkylamides examined, lithium tetramethylpiperidide (LiTMP) in THF resulted in the best enolization selectivity. The stereoselectivity was further improved in the presence of a LiTMP-butyllithium mixed aggregate. The use of less polar solvents reduced the enolization stereoselectivity. Ab initio calculations predict LDA and LiTMP to form mixed cyclic dimers in ethereal solvents. The calculations also predict LiTMP-alkyllithium mixed aggregates to competitively inhibit the formation of less stereoselective LiTMP-lithium enolate mixed aggregates.     

Reaction of magnesium alkylidene carbenoids with lithium acetylides and lithium thiolates: a novel synthesis of conjugated enynes and vinyl sulfides

Magnesium alkylidene carbenoids were generated from 1-chlorovinyl p-tolyl sulfoxides with i-PrMgCl at −78 °C in THF or toluene via the sulfoxide-magnesium exchange reaction. Reaction of the generated magnesium alkylidene carbenoids with lithium acetylides or lithium thiolates gave conjugated enynes or vinyl sulfides, respectively, in moderate to good yields. The intermediate of this reaction was found to be the alkenyl anion and it could be trapped with some electrophiles to give tetra-substituted conjugated enynes and vinyl sulfides.     

Equilibrium constants and alkylation kinetics of two lithium enolates/LiHMDS mixed aggregates in THF

[reaction: see text] Mixed aggregates between lithium enolates and lithium hexamethyldisilazide (LiHMDS) have been studied in THF using UV-vis spectroscopy. The equilibrium constants (K(agg)) between monomeric LiEn and monomeric LiHMDS are 760 and 560 M(-1) when LiEn are LiSIBP and LiBnPAT, respectively. The alkylation kinetics of the reactions with benzyl bromide were studied at 25 degrees C. The rate constants for the mixed aggregates, k(Mixed), are substantially smaller than those of the monomeric enolates.     

Origin of the detrimental effect of lithium halides on an enantioselective nucleophilic alkylation of aldehydes

The effect of lithium halides on the enantioselectivity of the addition of methyllithium on o-tolualdehyde, in the presence of chiral lithium amides derived from chiral 3-aminopyrrolidines (3APLi), has been investigated. The enantiomeric excess of the resulting 1-o-tolylethanol was found to drop upon addition of significant amounts of LiCl, introduced before the aldehyde. The competitive affinity between the lithium amide, the methyllithium, and the lithium halides in THF was examined by multinuclear NMR spectroscopy and DFT calculations. The results showed that the original mixed aggregate of the chiral lithium amide and methyllithium is rapidly, totally, and irreversibly replaced by a similar 1:1 complex involving one lithium chloride or bromide and one lithium amide. While the MeLi/LiX substitution occurs with some degree of epimerization at the nitrogen for the endo-MeLi:3APLi complex, it is mostly stereospecific for the exo-type arrangements of the aggregate. The thermodynamic preference for mixed aggregates between 3APLi and LiX was confirmed by static DFT calculations: the data show that the LiCl and LiBr aggregates are more stable than their MeLi counterparts by more than 10 kcal.mol(-1) provided THF is explicitly taken into account. These results suggest that a sequestration of the source of chirality by the lithium halides is at the origin of the detrimental effect of these additives on the ee of the model reaction.     

Mixed aggregates of dilithiodiamines with alkyllithiums and lithium enolates

The formation of mixed aggregates of N,N′-dilithiodiamines with alkyllithiums and lithium enolates was investigated. Enolization of 3-pentanone with the dilithium salt of N,N′-dimethyl-1,3-propanediamine generated both the E and Z enolates and the E/Z ratio changed in the presence of a lithium enolate or excess butyllithium. The formation of mixed aggregates was modeled with the B3LYP DFT method and it was found that mixed aggregate formation is energetically favorable. The infrared spectra of dilithio-N,N′-dimethyl-1,3-propanediamine in the presence of excess butyllithium or lithium enolate are consistent with the formation of mixed aggregates.     

Recent advances in the chemistry of magnesium carbenoids

This tutorial review deals with recent advances in the chemistry and synthetic use of magnesium carbenoids. The reactivity of traditional carbenoids (alpha-haloalkyllithium species) was successfully reduced by using magnesium as the metal instead of lithium. Properties of these relatively stable carbenoids, magnesium carbenoids, were widely investigated and it was found that the magnesium carbenoids have very interesting reactivity toward several nucleophiles. The magnesium carbenoids, magnesium cyclopropylidenes, magnesium alkylidene carbenoids, and magnesium beta-oxido carbenoids are generated from alpha-chloroalkyl (or alpha-chloroalkenyl) aryl sulfoxides with a Grignard reagent at low temperature by sulfoxide-magnesium exchange reaction. The stability of the generated magnesium carbenoids and several new reactions based on the electrophilicity of the magnesium carbenoids, including 1,3-CH insertion, are reviewed. Magnesium carbenoids open up the new world of the chemistry of carbenoids.     

Mechanistic competition variations due to the substituents in the lithium carbenoid promoted cyclopropanation reactions

The cylcopropanation reactions of the LiCH₂X (X = F, Cl, Br and I) carbenoids with ethylene were investigated at the CCSD(T)/6-311G^∗∗//B3LYP/6-311G^∗∗ level of theory along two reaction pathways: methylene transfer and carbometalation. There exists a competition between these two reaction pathways for the different substituted lithium carbenoids. Interestingly, the substituent has different effect on the methylene transfer and carbometalation pathways. The trend of the activation energies for the methylene transfer pathway is LiCH₂F (9.8 kcal/mol) > LiCH₂Cl (7.6 kcal/mol) ≈ LiCH₂Br (7.4 kcal/mol) ≈ LiCH₂I (7.5 kcal/mol), whereas the activation energies for the carbometalation pathway increases in this order: LiCH₂F (6.1 kcal/mol) < LiCH₂Cl (7.1 kcal/mol) < LiCH₂Br (8.2 kcal/mol) < LiCH₂I (8.5 kcal/mol). The different effect mainly arises from that the substituent of the lithium carbenoid influences the hybridization character of the C¹ atom. The mechanistic competition varies due to the different substituents of the lithium carbenoids during the cyclopropanation reactions. This result is revelatory for us to control mechanistic competition to obtain target product by modifying the substituents of the lithium carbenoids.     

Density functional theory investigation of the remarkable reactivity of geminal dizinc carbenoids (RZn)(2)CHI (R = Et or I) as cyclopropanation reagents with olefins compared to mono zinc carbenoids RZnCHI(2), EtCHIZnR (R = Et or I)

Density functional theory calculations for the cyclopropanation reactions of several mono zinc carbenoids and their corresponding gem-dizinc carbenoids with ethylene are reported. The mono zinc carbenoids react with ethylene via an asynchronous attack on one CH2 group of ethylene with a relatively high barrier to reaction in the 20-25 kcal/mol range similar to other Simmons-Smith type carbenoids previously studied. In contrast, the gem-dizinc carbenoids react with ethylene via a synchronous attack on both CH2 groups of ethylene and substantially lower barriers to reaction (about 15 kcal/mol) compared to their corresponding mono zinc carbenoid. Both mono zinc and gem-dizinc carbenoid reactions can be accelerated by the addition of ZnI2 groups as a Lewis acid, and this lowers the barrier by another 1.0-5.1 kcal/mol and 0.0-5.5 kcal/mol, respectively, for addition of one ZnI2 group. Our results indicate that gem-dizinc carbenoids react with C=C bonds with significantly lower barriers to reaction and in a noticeably different manner than Simmons-Smith type mono zinc carbenoids. The three gem-dizinc carbenoids have a substantially larger positive charge distribution than those in the mono zinc carbenoids and, hence, a stronger electrophilic character for the gem-dizinc carbenoids.     

Effect of solvent on aggregation and reactivity of two lithium enolates(1)

Studies with two lithium enolates show that aggregation varies from comparable to lower in dimethoxyethane (DME) compared to tetrahydrofuran (THF) but that aggregation is much higher in methyl tert-butyl ether (MTBE). Alkylation reactions, which occur dominantly with the enolate monomers, are exceptionally slow in MTBE, but even acylation reactions that can occur with aggregates are orders of magnitude slower in MTBE. These reactions apparently require additional solvation of the lithium cation, and MTBE is ineffective at such solvation.     

Generation of magnesium carbenoids from 1-chloroalkyl phenyl sulfoxides with a Grignard reagent and applications to alkylation and olefin synthesis

Treatment of 1-chloroalkyl phenyl sulfoxides with a Grignard reagent at low temperature gave magnesium carbenoids in quantitative yields. The generated magnesium carbenoids were found to be stable at lower than −60 °C for long periods of time and are reactive with Grignard reagents to give alkylated products. The reaction of the generated magnesium carbenoids with various kinds of lithium α-sulfonyl carbanions gave olefins with carbon-carbon bond-formation in good to high yields. This method offers a good way for the preparation of olefins. The scope and limitations of the above-mentioned reactions are described.     

Computational strategies for evaluating barrier heights for gas-phase reactions of lithium enolates

Gas-phase activation energies were calculated for three lithium enolate reactions by using several different ab initio and density functional theory (DFT) methods to determine which levels of theory generate acceptable results. The reactions included an aldol-type addition of an enolate to an aldehyde, a proton transfer from an alcohol to a lithium enolate, and an S(N)2 reaction of an enolate with chloromethane. For each reaction, the calculations were performed for both the monomeric and dimeric forms of the lithium enolate. It was found that transition state geometry optimization with B3LYP followed by single point MP2 calculations generally provided acceptable results compared to higher level ab initio methods.     

Reaction of magnesium alkylidene carbenoids with lithium alpha-sulfonyl carbanions: a novel synthesis of tri- and tetra-substituted allenes from 1-chlorovinyl p-tolyl sulfoxides and sulfones

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from ketones and chloromethyl p-tolyl sulfoxide, with ethylmagnesium chloride or isopropylmagnesium chloride at below -78 degrees C gave magnesium alkylidene carbenoids in about 90% yields. The reaction of the generated carbenoids with lithium alpha-sulfonyl carbanions was found to afford tri- and tetra-substituted allenes. Both cyclic ketones and acyclic ketones were useful in this procedure. However, the 1-chlorovinyl p-tolyl sulfoxides derived from aldehydes gave only rearranged products, acetylenes, under the reaction conditions. The magnesium alkylidene carbenoid derived from an optically active 1-chlorovinyl p-tolyl sulfoxide was treated with lithium alpha-carbanion of 1-naphthyl phenyl sulfone; however, the obtained allene was found to be racemic. The mechanism of this reaction is also discussed.     

Mechanisms of lithium transport in amorphous polyethylene oxide

We report calculations using a previously reported model of lithium perchlorate in polyethylene oxide in order to understand the mechanism of lithium transport in these systems. Using an algorithm suggested by Voter, we find results for the diffusion rate which are quite close to experimental values. By analysis of the individual events in which large lithium motions occur during short times, we find that no single type of rearrangement of the lithium environment characterizes these events. We estimate the free energies of the lithium ion as a function of position during these events by calculation of potentials of mean force and thus derive an approximate map of the free energy as a function of lithium position during these events. The results are consistent with a Marcus-like picture in which the system slowly climbs a free energy barrier dominated by rearrangement of the polymer around the lithium ions, after which the lithium moves very quickly to a new position. Reducing the torsion forces in the model causes the diffusion rates to increase.     

Controlling factors in chiral bisoxazoline-catalyzed asymmetric lithium ester enolate-imine condensation producing a beta-lactam

A catalytic amount of external chiral bisoxazoline ligand 3a bearing an isopropyl group as a stereocontrolling group catalyzed a reaction of a lithium ester enolate 4b, generated from 3-pentyl 2-methylpropionate, with benzaldehyde anisidine-imine 5 to afford corresponding beta-lactam 6 in higher 70% ee than that obtained by the reaction using a stoichiometric amount of the ligand. A bulkier ligand 3d bearing a phenyl group gave 81% and 6% ees in stoichiometric and catalytic reactions, respectively. Examination of the varying factors suggested the involvement of mixed aggregates as a reactive species. A working model is presented for prediction of the sense of asymmetric induction.     

Role of aggregates in Claisen acylation reactions of imidazole, pyrazole, and thioesters with lithium enolates in THF

[formula: see text] Although phenyl esters react with both monomers and dimers or tetramers of two lithium enolates in THF, the reactions of phenyl thiobenzoates are relatively much faster with the monomers. Similarly, imidazole esters react primarily with the monomers but pyrazole esters react with monomers and aggregates. The results are rationalized by a mechanism in which coordination with two lithium cations within an enolate aggregate is required for the reaction of aggregates to compete with monomers.     

A novel synthetic method for alkylidenecyclopropanes based on the reaction of magnesium cyclopropylidenes with lithium α-sulfonyl carbanions

Treatment of 1-chlorocyclopropyl phenyl sulfoxides with isopropylmagnesium chloride at low temperature gave magnesium cyclopropylidenes. The reaction of the generated carbenoids with lithium α-sulfonyl carbanions was found to afford alkylidenecyclopropanes in moderate to good yields. This reaction offers a novel, unprecedented, and versatile method for a synthesis of several alkylidenecyclopropanes from olefins in relatively short steps.     

A computational study of lithium methoxide mixed aggregates with alkyllithiums

The formation of alkyllithium-lithium methoxide mixed aggregates was modeled with the B3LYP density functional method. In the gas phase there was little tendency to form mixed dimers or trimers. Mixed tetramer formation was more energetically favorable, particularly for tert-butyllithium. THF solvation favored the formation of methyllithium and ethyllithium mixed tetramers, but not those of sec-butyllithium and tert-butyllithium. The potential for resolution of chiral alkyllithiums by mixed aggregate formation with enantiomerically pure lithium alkoxides was examined.