Mixed aggregates of 1-methoxyallenyllithium with lithium chloride.

A combined computational and (13)C NMR study was used to investigate the formation of mixed aggregates of 1-methoxyallenyllithium and lithium chloride in tetrahydrofuran (THF) solution. The observed and calculated chemical shifts, as well as the calculated free energies of mixed aggregate formation (MP2/6-31+G(d)), are consistent with the formation of a mixed dimer as the major species in solution. Free energies of mixed dimer, trimer, and tetramer formation were calculated by using the B3LYP and MP2 methods and the 6-31+G(d) basis set. The two methods generated different predictions of which mixed aggregates will be formed, with B3LYP/6-31+G(d) favoring mixed trimers and tetramers in THF solution, and MP2/6-31+G(d) favoring mixed dimers. Formation of the sterically unhindered mixed dimers is also consistent with the enhanced reactivity of these compounds in the presence of lithium chloride. The spectra are also consistent with some residual 1-methoxyallenyllithium tetramer, as well as small amounts of higher mixed aggregates. Although neither computational method is perfect, for this particular system, the calculated free energies derived using the MP2 method are in better agreement with experimental data than those derived using the B3LYP method.

Rearrangement reactions of lithiated oxiranes.

The first computational study of the rearrangement reactions of oxiranes initiated by lithium dialkylamides is presented. Aside from the well-known carbenoid insertion pathways, both ß-elimination and α-lithiation have been suggested as the exclusive mechanism by which oxiranes react in the presence of organolithium bases. The products of the former are allyl alcohols (and, in some cases, dienes) and are ketones in the case of the latter. The computational studies reported in this work indicate that both mechanisms could be simultaneously operational. In particular, our work shows that the allyl alcohols from ß-elimination are unlikely to undergo 1,3-hydrogen transfer to the vinyl alcohols and thus to the ketones, suggesting that ketones are formed through the opening of the oxirane ring after α-substitution. Elimination of LiOH from the lithiated allyl alcohol is found to result in the diene product. Low activation barriers for ß-elimination are offered as the explanation for the few special cases where the allyl alcohol is the dominant or exclusive product. These findings are consistent with the product distributions observed in several experiments.

Carbenoid alkene insertion reactions of oxiranyllithiums.

The first computational investigations of the carbenoid reactions of α-lithiated dimethyl ether (methoxymethyllithium) and the intramolecular and intermolecular reactions of lithiated epoxides with the alkene double bond to yield cyclopropane rings are presented. These reactions represent the full spectrum of known carbenoid pathways to cyclopropanation. The reaction of Li-CH(2)-O-CH(3) with ethylene proceeds exclusively through a two-step carbolithiation pathway, the intramolecular reaction of 1,2-epoxy-5-hexene follows either the carbometalation or a concerted methylene transfer pathway (the former is energetically more favorable), and the reaction of lithiated ethylene oxide (oxiranyllithium) with ethylene, the main focus of this paper, appears to proceed exclusively by the methylene transfer mechanism. In the case of these latter reactions, the free energy of activation for cyclopropanation tends to decrease with the higher aggregation states. Formation of tetramers or higher aggregates is favorable in nonpolar solvents, but in strongly coordinating solvents such as tetrahydrofuran (THF), steric factors appear to limit aggregate sizes to the dimer. In the case of 1,2-epoxy-5-hexene, consideration of competing reaction pathways provide an explanation for the observed product distribution.

A computational study of lithium cuprate mixed aggregates.

Lithium dialkylcuprates may potentially form mixed aggregates with many species in solution. Those include excess alkyllithium used to prepare the cuprate, lithium halide, and lithium cyanide from cuprate preparation and from coupling reactions with alkyl halides, higher order cuprates, and species resulting from incomplete cuprate reactions. The M06 DFT method was used to elucidate the structures and energies of formation of potential mixed aggregates. A comparison was made to available experimental data.

Nitrogen dynamics and reactivity of chiral aziridines: generation of configurationally stable aziridinyllithium compounds.

Diastereomeric oxazolinylaziridines (R,R)-9 and (R,S)-9 have been regioselectively lithiated at the α-position with respect to the oxazolinyl ring. The resulting aziridinyllithium compounds proved to be chemically and configurationally stable under the experimental conditions used, thus furnishing, upon trapping with electrophiles, chiral 2,2-disubstituted aziridines, in contrast to the corresponding α-lithiated oxazolinyloxiranes that have been reported to be chemically stable but configurationally unstable. This peculiar behavior of the nitrogen-bearing heterocycle has been rationalized on the basis of DFT calculations and the observed dynamics of the aziridine nitrogen atom. The DFT analysis allowed the disclosure of a solvent-dependent differing stability of diastereomeric lithiated aziridines (R,R)-9-Li and (R,S)-9-Li, suggesting η(3)-coordinated oxazolinylaziridinyllithium compounds as likely intermediates. Such intermediates could be the result of a dynamically controlled lithiation that relies on the preliminary formation of a complex between the lithiating agent and the oxazolinyl ring. According to this model, the competing complexation of the lithiating agent by the lone pair of electrons on the aziridine nitrogen would cause addition to the oxazoline C=N bond, thus ending up with the formation of oxazolidines, which are precursors of useful chiral ketoaziridines. The proposed model has been also supported by estimating the nitrogen inversion barrier by dynamic NMR spectroscopic experiments.

Nickel-catalyzed alkyl coupling reactions: evaluation of computational methods.

The B3LYP, M06, M06L, M062X, MPW1K, and PBE1PBE DFT methods were evaluated for modeling nickel-catalyzed coupling reactions. The reaction consists of a nucleophilic attack by a carbanion equivalent on the nickel complex, S(N)2 attack by the anionic nickel complex on an alkyl halide, and reductive elimination of the coupled alkane product, regenerating the nickel catalyst. On the basis of CCSD(T)//DFT single-point energies, the B3LYP, M06, and PBE1PBE functionals were judged to generate the best ground state geometries. M06 energies are generally comparable or superior to B3LYP and PBE1PBE energies for transition state calculations. The MP2 and CCSD methods were also evaluated for single-point energies at the M06 geometries. The rate-determining step of this reaction was found to be nucleophilic attack of a L(2)NiR anion on the alkyl halide.

Computational strategies for reactions of aggregated and solvated organolithium carbenoids.

This study explores the degree to which GGA, meta-GGA, hybrid GGA, and hybrid meta-GGA functionals of density functional theory (DFT), when used with the 6-31+G(d) basis set, are able to reproduce the MP2/6-31+G(d) structures and energetics of the species involved in the reactions of halomethyllithium carbenoids with ethylene. While many popular DFT functionals have been parametrized and/or benchmarked using various databases, the scarcity of experimental structural and energetic information for organolithium compounds has resulted in their exclusion from these training and test sets. In this work, we first establish a set of practical benchmark reaction energetics against which the performance of DFT methods for larger molecules can be compared. Next, we examine the performance of 13 DFT functionals spanning the second, third, and fourth rungs of the "Jacob's ladder" using 84 molecules and 78 reactions. The main conclusions are (a) the meta-hybrid GGA M06-2X is the best functional among the set for organolithium chemistry, (b) the hybrid GGA PBE1PBE consistently yields equilibrium and transition-state geometries that are very close to the MP2 predictions, and (c) MP2//M06-L or MP2//PBE1PBE model chemistries are excellent low-cost alternatives to the costly MP2. However, this work also showed that the very popular B3LYP functional is a rather poor choice for these systems.

Lithium cuprate coupling reactions: evaluation of computational methods for determination of the reaction mechanisms.

Several computational methods were evaluated for determining the gas-phase reaction mechanisms of lithium dimethylcuprate and dimethylcuprate anion with chloromethane and vinyl chloride. These methods include the B3LYP and M06 density functional theory (DFT) methods, the unscaled and spin-component-scaled Moller-Plesset perturbation theory (MP2, SCS-MP2, and SCSC-MP2), CCSD, and CCSD(T). The reaction of interest is an oxidative addition of the alkyl or vinyl halide to the Cu(I) species, resulting in a Cu(III) intermediate, which undergoes reductive elimination with coupling of the two alkyl fragments. Three possible oxidative addition pathways were examined, a concerted addition to Cu(I), an S(N)2-like reaction of Cu on the alkyl halide, and a radical mechanism. A concerted reductive elimination step was also investigated.

Gas phase and solution structures of 1-methoxyallenyllithium.

A combined computational and (13)C NMR study was used to determine the solution structures of 1-methoxyallenyllithium. The gas phase calculations indicated that this species is aggregated as a hexamer. The NMR spectra in THF solution, together with the calculated aggregation energies and chemical shifts, are consistent with a dimer-tetramer equilibrium.

A computational study of lithium ketone enolate aggregation in the gas phase and in THF solution.

The aggregation state of several lithium enolates were calculated in the gas phase and in THF solution by the B3LYP DFT and MP2 methods. The gas phase free energies of aggregate formation were underestimated by the DFT calculations, compared to those obtained by the G3MP2 method, although DFT did correctly predict the hexamer to be the major gas phase species. The DFT calculations correctly predicted the tetramer to be the major species in THF, while MP2 underestimated the stability of the tetramer relative to the dimer.

Aggregation of alkyllithiums in tetrahydrofuran.

Density functional theory was used to examine the solvation number and aggregation state of several alkyllithium compounds in clusters with tetrahydrofuran molecules coordinated to each lithium atom. We then made the microsolvation approximation and approximated the bulk free energy of solvation by the free energy of clustering with solvent molecules in the gas phase. The trends in the computed results are in reasonable agreement with the available experimental data.

Solvent and temperature effects on the reduction and amination reactions of electrophiles by lithium dialkylaminoborohydrides.

The influence of temperature and solvent effects on the reduction and amination mechanisms of iodomethane by lithium N,N-diisopropylaminoborohydride (iPr-LAB) was examined in varying concentrations of THF and dioxane. The reactions of benzyl chloride and trimethylsilyl chloride with iPr-LAB in THF were also studied. The amination of iodomethane is favored over reduction at low and room temperatures in pure THF and with increasing the amount of dioxane in THF. At higher temperatures, the reduction reaction appears to compete with the amination. In dioxane solvent, however, iodomethane yields exclusively the amination product regardless of temperature. On the other hand, reduction by iPr-LAB to the aminoborane is the only product observed in THF when benzyl chloride and trimethylsilyl chloride are used. To understand the solvent effects on the product distribution, ab initio and density functional theory (DFT) calculations were used to examine the mechanisms of reduction and amination of chloromethane and bromomethane by lithium dimethylaminoborohydride (LAB) in THF and dioxane. The results of these calculations show that the relative reaction barrier heights are significantly affected by the nature of the coordinated solvent molecule and thus lend support to the experimental observations.

Novel diborane-analogue transition structures for borane reactions with alkyl halides.

Ab initio and DFT calculations were performed to examine the mechanisms of reduction of alkyl halides and formaldehyde by borane. With alkyl halides, the optimized transition structure geometry resembled diborane, with a pair of hydrogen atoms bridging the boron and carbon atoms by three-center-two-electron bonds. A similar transition structure was found for the reduction of formaldehyde, although it was not the lowest-energy transition structure. Solvation by dimethyl ether or dimethyl sulfide disrupted this bridging with chloromethane, while both ligands dissociated from borane during the reduction of formaldehyde. The high calculated activation free energies of alkyl halide reduction are consistent with their observed lack of reactivity with borane.

Gas-phase reactions of lithium dimethylaminoborohydride and related species.

[reaction: see text] Ab initio and density functional theory (DFT) calculations were used to examine the mechanisms of reduction and amination of chloromethane by lithium dimethylaminoborohydride (LAB) in the gas phase. For comparison, the amination of chloromethane by lithium dimethylamide and the reduction by borane, diborane, and borohydride ions were also examined. The reduction of chloromethane by LAB occurred most readily from a conformation that allowed coordination of the lithium atom to the chloride leaving group, and the most favorable amination pathway occurred by a backside attack of the nitrogen nucleophile on chloromethane.

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 oxiranyllithium.

[reaction: see text] Computational methods were used to determine the structure, bonding, and aggregation states of oxiranyllithium in the gas phase and in THF solution, at 200 and 298 K. THF solvation was modeled by microsolvation with explicit THF ligands, forming a supermolecule that includes the oxiranyllithium aggregate and its first solvation shell. Because oxiranyllithium has a chiral center, two diastereomeric dimers were formed, the RR and the RS, along with their enantiomers. Similarly, three diastereomers of the tetramer were formed, the RRRR, RRRS, and RRSS and their enantiomers. Oxiranyllithium was found to exist predominantly as the tetramer in the gas phase, while the dimer was the dominant species in THF solution. The relative concentrations of the different stereoisomers were calculated from equilibrium constants.

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.

Structure, bonding, and solvation of lithium vinylcarbenoids.

[reaction: see text] Molecular modeling was used to determine the structure of lithium vinylcarbenoids in the gas phase and in THF solution. Solvent effects were modeled by microsolvation with explicit THF ligands on each of the lithium atoms. The carbenoid geometries are dependent on the heteroatom and on solvation. The calculations predict 1-chlorovinyllithium and 1-bromovinyllithium to be a mixture of monomer and dimer at 200 K and mostly monomer at higher temperatures, whereas the 1-fluoro-, 1-methoxy-, and 1-dimethylaminovinyllithium are predicted to be dimeric in solution.

N,O-dilithio-2-(N-methylamino)ethanol: an intramolecular mixed aggregate.

Density functional theory and infrared spectroscopy were used to determine the structure of N,O-dilithio-2-(N-methylamino)ethanol, a mixed intramolecular aggregate. The calculations indicated that the cyclic form of this compound is more stable than the open form, and that conclusion is consistent with the infrared spectra. The solid-state spectra showed lower Li-N and Li-O vibrational frequencies than were calculated for the gas phase, which is consistent with coordination of lithium to electronegative atoms on adjacent molecules in the solid state.

Structure, bonding, and solvation of dilithiodiamines.

Computational methods were used to determine the structure of dilithiodiamines and the effects of solvation by ethereal solvents. Solvation was examined by the use of microsolvation with explicit dimethyl ether or THF ligands and by the combined use of microsolvation and the IEFPCM continuum solvent model. It was determined that each of the compounds studied exists exclusively as a bridged intramolecular dimer, both in the gas phase and in solution. Thermodynamic properties were calculated at 200 and 298 K to estimate the effect of temperature on the cyclization energies. Infrared spectroscopy was used to confirm the proposed intramolecular dimer structures.