Nucleophiles carbanions

In the synthesis of molecules without functional groups the application of the usual polar synthetic reactions may be cumbersome, since the final elimination of hetero atoms can be difficult. Two solutions for this problem have been given in the previous sections, namely alkylation with nucleophilic carbanions and alkenylation with ylides. Another direct approach is to combine radical synthons in a non-polar reaction. Carbon radicals are. however, inherently short-lived and tend to undergo complex secondary reactions. Escheirmoser s principle (p. 34f) again provides a way out. If one connects both carbon atoms via a metal atom which (i) forms and stabilizes the carbon radicals and (ii) can be easily eliminated, the intermolecular reaction is made intramolecular, and good yields may be obtained. 

Elimination reactions (Figure 5.7) often result in the formation of carbon-carbon double bonds, isomerizations involve intramolecular shifts of hydrogen atoms to change the position of a double bond, as in the aldose-ketose isomerization involving an enediolate anion intermediate, while rearrangements break and reform carbon-carbon bonds, as illustrated for the side-chain displacement involved in the biosynthesis of the branched chain amino acids valine and isoleucine. Finally, we have reactions that involve generation of resonance-stabilized nucleophilic carbanions (enolate anions), followed by their addition to an electrophilic carbon (such as the carbonyl carbon atoms... 

The finding that thiamine, and even simple thiazolium ring derivatives, can perform many reactions in the absence of the host apoenzyme has allowed detailed analyses of its chemistry [33, 34]. In 1958 Breslow first proposed a mechanism for thiamine catalysis to this day, this mechanism remains as the generally accepted model [35]. NMR deuterium exchange experiments were enlisted to show that the thiazolium C2-proton of thiamine was exchangeable, suggesting that a carbanion zwitterion could be formed at that center. This nucleophilic carbanion was proposed to interact with sites in the substrates. The thiazolium thus acts as an electron sink to stabilize a carbonyl carbanion generated by deprotonation of an aldehydic carbon or decarboxylation of an a-keto acid. The nucleophilic carbonyl equivalent could then react with other electro-... 

The previous sections have dealt primarily with reactions in which the new carbon-carbon bond is formed by an SN2 reaction between the nucleophilic carbanions and the alkylating reagent. Another important method for alkylation of carbon involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,/i-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. Other kinds of nucleophiles such as amines, alkoxides, and sulfide anions also react similarly, but we will focus on the carbon-carbon bondforming reactions. 

We here further demonstrate the merits of Fe -exchanged montmorillonite over the conventional homogeneous acid catalysts, applying it to other types of liquid-phase carbon-carbon bond-forming reactions between carbonyl compounds and useful nucleophilic carbanion reagents such as silyl ketene acetal (an ester... 

The addition of the nucleophilic carbanion-enolate, usually of an aldehyde, to the C=0 group of its parent compound is called an aldol condensation. The product is a /3-hydroxycarbonyl compound. In a mixed aldol condensation the carbanion-enolate of an aldehyde or ketone adds to the 0=0 group of a molecule other than its parent. The more general condensation diagramed above is termed an aldol-type condensation. Since the C, not the O, is the more reactive site in the hybrid, the enolate contributing structure is usually omitted when writing equations for these reactions. This is done even though the enolate is the more stable and makes the major contribution. 

The nucleophilic carbanion adds to the carbonyl group of acetaldehyde. 

However, difluoromethylation occurs when nucleophiles intercept difluoro-carbene generated under basic conditions, providing a route to difluoromethyl-ethers of phenols [33] and thiophenols [34]. The reaction with phosphite anion leads to the corresponding difluoromethyl phosphonate (see Sect. 2.3.2) while nucleophilic carbanions such as alkynes [35] also undergo formal alkylation, as do malonates [36,37]. An -difluoromethylaziridine was reported in a reaction with a glycine imine [38]. The scope of the established chemistry is summarised in Fig. 1. Bromodifluoromethylation occurs with a similar range of nucleophiles [39,40], and also with carbonyl-stabilised carbanions such as malonates [41,42]. 

With Functionalized Carbanions. Other nucleophilic carbanions, such as lithio-dithiane or sodiomalonate or acetylene anion react easily with epoxides. 

The condensation proceeds under the influence of strong base catalysts of which sodium ethoxide is the most common example. This is usually formed from the ethanol present in ordinary samples of ester by the action of the sodium used in the condensation. The first step in the mechanism is the removal of the a-hydrogen in ethyl acetate by the base catalyst to produce the mesomerically stabilised a-carbanion (20). The nucleophilic carbanion so formed then attacks the carbonyl carbon of a second ester molecule to produce the anion (21) which is converted into the /1-keto ester (22) by loss of an ethoxide ion. Finally (22) reacts with the ethoxide ion to produce the mesomerically stabilised /1-keto ester anion (23). 

There is no perfectly linear correlation between the basicity and nucleophilicity of carbanions [66], but higher basicity usually also implies higher nucleophilicity. Carbanions in which the negative charge is highly delocalized (e.g. diethylmalonate) will usually react more slowly with electrophiles than less extensively delocalized carbanions of similar basicity (e.g. malodinitrile) [66],... 

The C2 position of 1,3-azoles is particularly electron-deficient because of the electron-withdrawing effect of the adjacent heteroatoms. The acidity of the protons at this position is such that deprotonation can be achieved with strong bases to give nucleophilic carbanions 3.37 which can be quenched with electrophiles producing substituted 1,3-azoles 3.38. 

The combination of formyl pyrrolidine acetal 7.21 and nitrotoluene 7.19 produces electrophilic cation 7.22 and nucleophilic carbanion 7.23a,b which react together affording enamine 7.20. 

Grignard reagents provide the equivalent of a nucleophilic carbanion which can attack the electrophilic carbon of a nitrile group (Following fig.). One of the n bonds is broken simultaneously forming an intermediate imine anion that is converted to a ketone on treatment with aqueous acid. 

Organolithium reagents like CH3Li can also be used to provide the nucleophilic carbanion and the reaction mechanism is exactly the same as that described for the Grignard reaction ... 

Propyne reacts with strong bases to form a nucleophilic carbanion which displaces Br from Br2 by attacking... 

Earlier we mentioned the Wurtz reaction as being one of the simplest approaches to the formation of C-C bonds. In this reaction, the alkyl halide serves as the electrophile (carbocation equivalent) and the organometallic derivative plays the role of the nucleophile (carbanion equivalent). We have also seen that this old reaction has recently become a feasible route for the creation of C-C bonds due... 

Base catalysis operates in a similar manner. An acidic proton of a methylene adjacent to a carbonyl group may be removed by a base to generate the reactive nucleophilic carbanion (1.64). 

In these reactions the nucleophilic carbanion is produced either by deprotonation or by metal reduction of a C-halogen bond. It is interesting to note that, as in other cyclopropane formation reactions , even a sluggish nucleofuge such as EtO" can be displaced in these intramolecular nucleophilic reactions (equation 5). 

C-C bond making or breaking takes place, is only possible because of the acidity of C-2 (the C), which allows the formation of the nucleophilic carbanion. This acidity can be explained by the resonance structures which may be drawn for the alkyl-carbonyl "group" ... 

Ethoxide ion abstracts (step 1) a hydrogen ion from the a-carbon of the ester to form carbanion 1. The powerfully nucleophilic carbanion I attacks (step 2) the carbonyl carbon of a second molecule of ester to displace ethoxide ion and yield the keto ester. 

The nucleophilic carbanion can also be generated from 1-haloalkanesulfonic acid derivatives with organometallic reagents. a-Lithio a-chloro-4-mesylmorpholide reacts with various Michael acceptors to give morpholinosulfonyl-substituted cyclopropanes 5. 

The nucleophilic carbanion can also be generated from a,a-dihalomalonates or malonitriles and a suitable metal. Examples have been reported of zinc metal, magnesium metal, indium metal,dialkyltelluride, trialkylstibene, trialkylarsane, and trialkylbithmuthane mediated cyclopropanations of Michael acceptors. These reactions are closely related to the examples mentioned above. 

The reaction of an oxirane with a nucleophilic carbanion or an ylide is a versatile method for the synthesis of cyclopropanes. Oxiranes and stabilized carbanions or ylides bearing different substituents are readily prepared from a variety of starting materials. - The inherent polarity and strain of the three-membered ring makes oxiranes particularly susceptible to transformation to cyclopropanes by intermolecular ring opening. 

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