Stereochemistry of Nucleophilic Additions

One of the most important aspects of nucleophilic addition to carbonyl compounds is the stereochemistry of these additions. Controlling the stereochemistry can lead to diaste-reoselective syntheses. Although a complete analysis of this topic is more appropriate for a textbook on synthetic organic chemistry, a few examples are instructive here, because they nicely tie together several of our structure-reactivity principles. 

Addition reactions of a nucleophile such as a hydride or Grignard reagent to a carbonyl adjacent to a stereocenter are stereoselective (see Section 6.9 for the definition). Many chemists have provided rationalizations for the observed products. 

Cram s model, B. Karabatsos model, and C. the Felkin-Ahn model for nucleophilic addition to a carbonyl. 

Let s now return to the attack on 4-f-butylcyclohexanone. The C-H bonds labeled (a) in Eq. 10.34 can similarly donate toward the developing a orbital as the hydride nucleophile adds anti to them. The alternative approach can be stabilized by C-C bonds aligned with the developing a orbital, but the alignment is not as favorable. 

Reversible reductions lead to similar product ratios as irreversible reactions on locked cyclohexanone rings. 

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If the carbanion has even a short lifetime, 6 and 7 will assume the most favorable conformation before the attack of W. This is of course the same for both, and when W attacks, the same product will result from each. This will be one of two possible diastereomers, so the reaction will be stereoselective but since the cis and trans isomers do not give rise to different isomers, it will not be stereospecific. Unfortunately, this prediction has not been tested on open-chain alkenes. Except for Michael-type substrates, the stereochemistry of nucleophilic addition to double bonds has been studied only in cyclic systems, where only the cis isomer exists. In these cases, the reaction has been shown to be stereoselective with syn addition reported in some cases and anti addition in others." When the reaction is performed on a Michael-type substrate, C=C—Z, the hydrogen does not arrive at the carbon directly but only through a tautomeric equilibrium. The product naturally assumes the most thermodynamically stable configuration, without relation to the direction of original attack of Y. In one such case (the addition of EtOD and of Me3CSD to tra -MeCH=CHCOOEt) predominant anti addition was found there is evidence that the stereoselectivity here results from the final protonation of the enolate, and not from the initial attack. For obvious reasons, additions to triple bonds cannot be stereospecific. As with electrophilic additions, nucleophilic additions to triple bonds are usually stereoselective and anti, though syn addition and nonstereoselective addition have also been reported. 

Backwall and coworkers have extensively studied the stereochemistry of nucleophilic additions on 7r-alkenic and ir-allylic palladium(II) complexes. They concluded that nucleophiles which preferentially undergo a trans external attack are hard bases such as amines, water, alcohols, acetate and stabilized carbanions such as /3-diketonates. In contrast, soft bases are nonstabilized carbanions such as methyl or phenyl groups and undergo a cis internal nucleophilic attack at the coordinated substrate.398,399 The pseudocyclic alkylperoxypalladation procedure occurring in the ketonization of terminal alkenes by [RCC PdOOBu1], complexes (see Section 61.3.2.2.2)42 belongs to internal cis addition processes, as well as the oxidation of complexed alkenes by coordinated nitro ligands (vide in/ra).396,397... 

It has however been suggested by Cieplak (9) that the stereochemistry of nucleophilic addition to cyclohexanone is determined by a combination of steric and stereoelectronic effects. According to this interesting model, steric hindrance favors the equatorial approach while electron donation favors the axial approach. The stereoelectronic effect favors the axial approach because the axial C —H bonds next to the carbonyl group (C — Ha and Cn-Ha) are better electron donors than the Cn-C-j and Cc-Cfi a bonds (cf 7A 7 and 7A-8). J... 

Cieplak, A. S. Stereochemistry of nucleophilic addition to cyclohexanone. The importance of two-electron stabilizing interactions. J. Am. Chem. Soc. 1981, 103, 4540-4552. 

The stereochemistry of nucleophilic additions to cycloheptanone has been studied by quantum mechanical calculations.160 Employing a Monte Carlo search, 1000 conformations were generated and minimized. The five lowest conformers, labelled A, B, C, D and E, are shown below with their relative energies. The global minimum A is a chair with the carbonyl on the two-carbon stern fragment. The twist conformer B is almost as stable. The three remaining conformers can be roughly characterized as chairs with the carbonyl located at the bow. 

Tetrahydropyridinium salts, stereochemistry of nucleophilic addition to 84MI28. 

The stereochemistry of nucleophilic addition of Grignard reagents to unsaturated organic substrates has been addressed by Kahn and associates [11]. They identify three factors ... 

The theoretical study by Khan et al. [13] on the stereochemistry of nucleophilic addition of organometallics to unsaturated substrates can also be applied to conjugated systems. Of the three major factors affecting the orientation of the nucleophile to the substrate (see Chapter 16), the ability of the substrate to discriminate between the nucleophilic and electrophilic character of the Grignard reagent is the one most susceptible to influence by conjugation with an adjacent 7r-system. They concluded that the accessible electrophilic site (the metal) is the source of the stereochemical preference for the electron-rich olefin face. 

A special class of acyclic diastereoselective reactions involves the use of chiral auxiliaries to control the absolute stereochemistry of nucleophilic additions at carbonyl centers. This process takes advantage of steric and/or electronic factors within the chiral adjuvant to promote nucleophilic addition from one face of the molecule, and thereby generate one predictable diastereomer. Removal of the auxiliary, in the best cases, generates enantiomerically pure products, as well as the recyclable chiral adjuvant. The end result of this process is the synthesis of enantiomerically pure products via diastereoselective reactions. 

The stereochemistry of nucleophilic addition is especially relevant to the mechanism of the Pd(II)-catalyzed conversion of ethylene and water to acetalydehyde. The mechanism originally proposed involved hydroxide attack at Pd followed by migration to coordinated ethylene ... 

Stereoselective Nucleophilic Additions to Acyclic Carbonyl Groups The stereochemistry of nucleophilic addition to acyclic aldehydes and ketones is influenced by nearby substituents. A particularly important case occurs when there is a stereogenic center adjacent to the carbonyl group. As a result of the adjacent substituent, two diastereomers can be formed, depending on the direction of the approach of the nucleophile. The stereoselectivity of addition can be predicted on the basis of a conformational model of the TS. The addition reaction has been studied with several kinds... 

Section 18.11 Stereochemistry of Nucleophilic Addition Reactions Re and S Faces... 

Matsukura, M., K.Takahashi, M. Kawamoto, S. Ishiguro, and H. Matsushita Identification of 3-hydroxy-4,5-di-methyl-2-(57/)-furanone (Sotolone) in roasted tobacco volatiles Agr. Biol. Chem. 49 (1985) 3335-3337. Matsumoto, T., G. Sakata, Y. Tachibana, and K. Fukui Stereochemistry of nucleophilic addition. fV. Condensation of 2,2,6-trimethylcyclohexanone with tert-butyl acetate in the presence of lithium amide Bull. Chem. Soc. Japan 45 (1972) 1147-1152. 

Stereoisomeric l,2-Bis-(arylmercapto)-ethenes and Corresponding Sulfones. Journal of the American Chemical Society, 76, 5745-5747. (e) Truce, W. E., Simms, J. A. (1956). Stereospecific Reactions of Nucleophilic Agents with Acetylenes and Vinyl-typ Halides. IV. The Stereochemistry of Nucleophilic Additions of Thiols to Acetylenic Hydrocarbons. Journal of the American Chemical Society, 78, 2756-2759 (f) Modena, G. (1971). Reactions of nucleophiles with ethylenic substrates. Accounts of Chemical Research, 4,73SO. 

The 1950s saw the beginning of empirical generalizations about the stereochemistry of nucleophilic additions to chiral carbonyl compounds. The reaction in Fig. 1 is an example of such a process. 

The stereochemistry of nucleophilic addition to activated triple bonds is related to the nature of the activating groups. In the case of the trifluoro-methyl substituted acetylenes where activation is by the inductive effect alone, addition is predominantly trans, e.g. methoxide-catalysed addition of methanol to hexafluorobut-2-yne gives (57). Addition is also observed... 

Truce WE, Simms JA. Stereospecific reactions of nucleophilic agents with acetylenes and vinyl-type halides. IV. The stereochemistry of nucleophilic additions of thiols to acetylenic hydrocarbons. J. Am. Chem. Soc. 1956 78 2756-2759. 

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