Stereochemistry of a cyclohexyllithium reagent. A case of higher configurational stability in strongly coordinating media

Reich, Hans J.; Medina, Marco A.; Bowe, Michael D.

doi:10.1021/ja00053a071

Cited by 54 publications

(41 citation statements)

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“…The meso organolithium shown in Figure 11 is an example of an organolithium which is configurational stabile for only a few minutes at −78 °C. 47 The rate of epimerization of this lithiohydrocarbon was accelerated by lithium iodide and was strongly dependent on the total organolithium concentration, suggesting that the inversion involves a dimeric (or possibly higher) aggregate in the transition state. Consistent with this hypothesis is the fact that the tridentate ligand, PMDTA, which would be expected to inhibit aggregation, retards the rate of epimerization by a factor of 20, and increases the half life from 9 minutes to greater than two hours at −78 °C.…”

Section: Relative Rates: Inversion Vs Substitutionmentioning

confidence: 93%

“…Lithium salts sometimes facilitate inversion of organolithiums. 47 An asymmetric synthesis would use an enantiopure organolithium. Since the Hoffmann test uses racemic organolithium, it assumes that the aggregation state of enantiopure and racemic organolithiums are the same, and that the kinetics of reactions of electophiles with homochiral and heterochiral aggregates (or monomers in equilibrium with them) are the same.…”

Section: Competing Inversion and Substitution: The Hoffmann Testmentioning

confidence: 99%

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Overview of Carbanion Dynamics and Electrophilic Substitutions in Chiral Organolithium Compounds

Gawley

2010

Topics in Stereochemistry

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Section: Relative Rates: Inversion Vs Substitutionmentioning

confidence: 93%

Section: Competing Inversion and Substitution: The Hoffmann Testmentioning

confidence: 99%

Overview of Carbanion Dynamics and Electrophilic Substitutions in Chiral Organolithium Compounds

Gawley

2010

Topics in Stereochemistry

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“…Our goal was therefore to increase the configurational stability of such organolithium compounds by some modification, which obviously would require knowledge of the enantiomerization mechanism. Calculations" ' 1 and experiments [12] were carried out on the epimerizationtenantiomerization of alkyllithium compounds, suggesting an associative process between two or more alkyllithium entitites. However, the enantiomerization of a-heterosubstituted alkyllithium compounds 1 may also be described by other mechanistic schemes.…”

mentioning

confidence: 99%

Chiral Organometallic Reagents, XVI. Enantiomerization of α‐Thio‐, α‐Seleno‐, and α‐Telluro‐Substituted Alkyllithium Compounds; Kinetic and Mechanistic Studies

et al. 1995

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The rate of enantiomerization of the racemic a-phenylsele-in those sterically hindered systems. Similar steric effects noalkyllithium compound 6 has been determined by dy-were detected for the enantiomerization of the corresponding namic NMR spectroscopy in [D,]THF. The enantiomerization a-arylthio-and a-aryltelluroalkyllithium compounds ?j and rate was found to be first order with respect to monomeric 6 7f, but are absent with the a-arylsilyl-substituted alkyland to show no conspicuous solvent dependence (diethyl lithium compound 7 0 . This finding, along with the fact that ether; toluene + 1 eq. of THF) or change upon addition of the phenyltelluro-(?e), phenylseleno-(6), and phenylthio-alLiC104. The marked steric effects on the enantiomerization kyllithium compounds (irg) have essentially the same enanrate found with the a-duryl-and a-mesityl-selenoalkyl-tiomerization barrier, lead us to propose that in these cases a lithium compounds 7 c and 7d suggest that rotation about the reorganization within the contact ion pair is the rate limiting carbanion-selenium bond may be the rate-determining step step for the enantiomerization.a-Heterosubstituted alkyllithium compounds 1 are d' synthonsL21 in organic synthesis, and since the entity 1 is chiral, these compounds are of interest as chiral building blocks for stereoselective synthesis.Accordingly, attention was focused on their configurational stability: Various studies showed that o~y g e n -[~.~] and amino-sub~tituted[~I derivatives of 1 are configurationally stable on a macroscopic time scale, i.e. for ca. 10 min at -78 "C. On the other hand, ~u l f u r -[~~~~~] and seleno-L9] substituted derivatives of 1 are configurationally labile on this time scale. However, fast (e.g. intramolecular) trapping reactions are sometimes faster than enantiomerization in such cases[6,'01. Such species may be called configurationally stable on a microscopic time scale. Our goal was therefore to increase the configurational stability of such organolithium compounds by some modification, which obviously would require knowledge of the enantiomerization mechanism. Calculations" ' 1 and experiments [12] were carried out on the epimerizationtenantiomerization of alkyllithium compounds, suggesting an associative process between two or more alkyllithium entitites. However, the enantiomerization of a-heterosubstituted alkyllithium compounds 1 may also be described by other mechanistic schemes. For this reason, the groups of H. J. Reich and ourselves initiated studies on the enantiomerization mechanism of alkyllithium compounds 1 with X = SR, SeR, and SiR3. In this paper we detail our results. Results and DiscussionA limitation of all mechanistic studies is, that they rely on proposed reaction pathways, which can be disproven by experiments but not proven. A non-associative mechanism for the enantiomerization of 1 may involve the following steps:The first step may be described as a decoordination of the carbanion from the lithium to form a contact ion pair. This would allow a relative motion...

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“…Organolithium compounds devoid of heteroatoms have little configurational stability [531,543,544]. Thus, lithiation of (-)-2-iodooctane with sBuLi at -70 C in Et 2 O followed by treatment with CO 2 after 2 min led to 80% racemized 2-methyloctanoic acid [545].…”

Section: Organolithium Compoundsmentioning

confidence: 99%

The Alkylation of Carbanions

Dörwald

2004

Side Reactions in Organic Synthesis

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The deprotonation of organic compounds by strong, non-nucleophilic bases followed by C-alkylation with a suitable electrophile has become one of the most predictable and straightforward methods for formation of C-C bonds. The popularity of this chemistry is also a consequence of the often-seen close resemblance of feasible structural modifications by a deprotonation/alkylation strategy to an unsophisticated retrosynthetic analysis of a given target compound. Other reactions, which involve, for instance, substantial rearrangement of the carbon framework (e.g. Cope rearrangement, fragmentations, ring contractions or enlargements) are usually more difficult to take into account during retrosynthetic analysis.LDA and related, sterically hindered, lithium dialkylamides, first investigated by Levine [1], have completely replaced the more nucleophilic sodium amide, which had been the base of choice for many years [2]. Because the reactivity of an organometallic compound depends to a large extent on its state of aggregation (i.e. on the solvent and on additives) and on the metal, transmetalation of the lithiated intermediates and the choice of different solvents and additives emerged as powerful strategies for fine-tuning the reactivity of these valuable nucleophiles.In this chapter the alkylation of carbanions with simple carbon electrophiles will be discussed, with special emphasis on the structure-reactivity relationship of the carbanion and on side reactions. In this context the term "carbanion" refers to an intermediate prepared by in-situ deprotonation of an organic compound, followed by optional cation exchange (transmetalation), which tends to be alkylated at carbon by soft electrophiles such as MeI or PhCHO. This type of reactivity is characteristic of enolates with an ionic M-O bond or for organometallic compounds with a strongly polarized or ionic M-C bond, M typically being an alkali metal, Mg, Cu, or Zn. Carbanions can, alternatively, also be prepared by halogen-metal exchange [3-8], sulfoxide-or sulfone-metal exchange [9-13], or by transmetalation of stannanes. The most suitable reagents for performing such metalating exchange reactions are organometallic compounds with a metal-bound secondary or tertiary alkyl group, such as tBuLi, sBuLi, iPr 2 Zn [14, 15], or iPrMgHal [6]. These reagents are thermodynamically less stable than organometallic compounds with primary alkyl 5 146 Scheme 5.1. Approximate relative rates of proton transfer in water at thermoneutrality (DpK a = 0) [35, 39, 51]. 147 Scheme 5.2. The effect of fluorine on the acidity of organic compounds [24, 62-65]. 148 Scheme 5.3. Dependence of the reactivity of carbanions on their basicity [68, 72-74]. Regioselectivity of Deprotonations and AlkylationsThe organic chemist is occasionally confronted with the problem that a compound has several differrent X-H groups of similar pK a . If only one of these is to be alkylated, one option would be to perform a regioselective deprotonation. This can sometimes be achieved by exploiting small differences be...

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Stereochemistry of a cyclohexyllithium reagent. A case of higher configurational stability in strongly coordinating media

Cited by 54 publications

References 1 publication

Overview of Carbanion Dynamics and Electrophilic Substitutions in Chiral Organolithium Compounds

Overview of Carbanion Dynamics and Electrophilic Substitutions in Chiral Organolithium Compounds

Chiral Organometallic Reagents, XVI. Enantiomerization of α‐Thio‐, α‐Seleno‐, and α‐Telluro‐Substituted Alkyllithium Compounds; Kinetic and Mechanistic Studies

The Alkylation of Carbanions

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