Nucleophiles stabilized anions

Other aryl halides that give stabilized anions can undergo nucleophilic aromatic substitution by the addition-elimination mechanism Two exam pies are hexafluorobenzene and 2 chloropyridme... 

The introduction of powerful electron-withdrawing substituents (NO2, CN, a polynitrogen heterocycle) at the a-C atom of AN stabilize anions of AN, thus facilitating their generation. At the same time, stabilization of anions of AN leads to a decrease in their reactivity and such anions act as milder nucleophilic agents. It will be seen from the following that this leads to an increase in the contribution of C-alkylation. 

Silylcuprates have been reported to undergo reactions with a number of miscellaneous Michael acceptors [65]. Conjugate addition to 3-carbomethoxy acyl pyri-dinium salts [65a] affords 4-silyl-l,4-dihydropyridines. Oxidation with p-chlorand generates a 4-acyl pyridinium salt that gives the 4-silylnicotinate upon quenching with water, and methyl 4-silyl-2-substituted dihydronicotinates upon quenching with nucleophiles (nucleophilic addition at the 6-position). The stabilized anion formed by conjugate addition to an a, j8-unsaturated sulfone could be trapped intramolecularly by an alkyl chloride [65b]. 

OTHER STABILIZED ANIONS AS NUCLEOPHILES NITRILES AND NITROMETHANE... 

Other stabilized anions as nucleophiles nitriles and nitromethane... 

Like the corresponding methylpyridines, 2- and 4-methylquinolines can be deprotonated by a base, such as sodium methoxide, forming resonance-stabilized anions (Scheme 3.9). The latter are useful in synthesis, providing nucleophilic reagents that allow extension of quinoline side chains through reactions with appropriate electrophiles. Activation of the 2-methyl group can also be achieved by the use of acetic anhydride (the same type of process occurs with 2-methylpyridine, Section 2.7.1, Worked Problem 2.3). 

The presence of a fluoroalkyl group in a of a carbonyl strongly enhances the electrophilicity and then the reactivity toward nucleophiles. The anionic tetrahedral intermediates are stabilized by the electron-withdrawing group Rf. This... 

Nevertheless, rearrangements can be suppressed, in most cases, when dediazoniation is performed in hydrogen fluoride/pyridine (48 52 w/w) mixture,308,310 since this less acidic medium stabilizes carbocations (such as the phenonium cation) to a far lesser extent and provides more nucleophilic fluoride anions which, however, cannot totally match the anchimeric assistance of the aryl or hydroxy group in tyrosine (5g) and threonine (5h). 

Fluorination has a particularly profound effect on the additions of nucleophiles to per-fluorinated alkenes where the intermediate is anionic. Such processes are dramatically assisted by the strongly stabilizing influence of perfluoroalkyl groups substituted at the incipient anionic site.66 Similar to carbocations (see Section 1.4.), the effect of fluorination in such systems is often ambiguous when monofluorination is involved. a-Halogens generally stabilize anions in the order bromine > chlorine > fluorine, which is the exact opposite to the inductive electron-withdrawing order of the substituents. This effect reflects the importance of l7t-repulsion.67... 

Many carbanionic nucleophiles that would be considered too hard to react as Michael donors can be made into effective reagents for conjugate addition reactions by appending resonance or inductively stabilizing groups to soften their intrinsic Lewis basicity. Such stabilized anionic Michael donors include enolates, alkylthio-substituted carbanions, ylides and nitro-substituted carbanions. 

While the addition-oxidation and the addition-protonation procedures are successful with ester enol-ates as well as more reactive carbon nucleophiles, the addition-acylation procedure requires more reactive anions and the addition of a polar aptotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion) but cyanohydrin acetal anions are successful. The addition of the cyanohydrin acetal anion (71) to [(l,4-dimethoxynaphthalene)Cr(CO)3] occurs by kinetic control at C-P in THF-HMPA and leads to the a,p-diacetyl derivative (72) after methyl iodide addition, and hydrolysis of the cyanohydrin acetal (equation 50).84,124-126... 

The regioselective functionalization of nitrobenzene and benzonitrile derivatives has been performed via nucleophilic aromatic substitution of hydrogen by phosphorus-stabilized carbanions.41 Lithium phosphazenes have been found to be the most suitable nucleophiles for the substitution of hydrogen in nitrobenzene. This method represents a convenient alternative to the vicarious nucleophilic substitution for the synthesis of benzylic phosphorus derivatives using phosphorus-stabilized anions that do not bear a leaving group at the carbanionic centre. 

Resonance stabilized anion less susceptible to nucleophilic attack. Can act as a nucleophile... 

Anilide 4 is lithiated selectively in ortho-position to the pivaloyl amide group.4 5 The organolithium species is generated by reaction of 4 with two equivalents of n-butyllithium below 5 °C in MTBE, since the amide proton is also acidic and is deprotonated to yield resonance-stabilized anion IS before the ort/zo-lithiation of the aromatic system with the second equivalent of n-butyllithium takes place. The resulting organolithium species 16 then undergoes nucleophilic attack of ester 176 to give dianion 18. 

The use of a metal catalyst, such as palladium, also provides for some asymmetric induction when an allylic system is treated with a stabilized anion (Scheme 22.13)82-103 or with other nucleophiles.82,87,104-111 This approach also allows for the kinetic resolution of allyl acetates.104,112... 

Solvation of anionic nucleophiles is poorer in dipolar aprotic than in dipolar protic solvents. The reason is that dipolar aprotic solvents cannot form a hydrogen bond to such nucleophiles. Consequently, anionic nucleophiles are not stabilized in dipolar aprotic... 

The normal addition process is identical to the other reactions that have been encountered so far in this chapter The nucleophile bonds to the carbonyl carbon and the electrophile bonds to the oxygen of the carbonyl group. In a conjugate addition the nucleophile bonds to the /3-carbon. The electrophile, a proton, can bond to either the a-carbon or the oxygen of the resonance stabilized anion. It actually reacts faster at the oxygen, producing an enol in an overall 1,4-addition. However, as discussed in Section 11.6, ends are less stable than the carbonyl tautomers, so the product that is isolated contains the carbonyl group. 

IZV2066). This is probably associated with the fact that during the attack of the S-nucleophile the anion is mainly stabilized by elimination of the vinyl fluorine atom, since the intermediate anion formed in this process is energetically preferable to the isomeric anion due to conjugation between the lone electron pair of the sulfur atom and the double bond. The product is of interest in syntheses of pharmaceuticals and agrochemicals. 

The chemistry of oxazolones, particularly that of 5(AH)-oxazolones (104), is full of interest. These compounds are attacked by some nucleophiles at C(2) (c/. 105), but fission of the carbonyl-oxygen bond (c/. 106), leading to ar-amino acids or their derivatives, is more usual. 5(4H)-Oxazolones react with electrophiles at C(4) or, less commonly, at C(2) by way of the resonance-stabilized anions (107), and they can function as tautomeric 1,3-dipoles (108) in cycloaddition reactions. 

First, we must determine the type of mechanism. Sodium ethoxide, a strong base and a strong nucleophile, implies the reaction involves strong nucleophiles as intermediates. We expect to see strong nucleophiles and anionic intermediates (possibly stabilized carbanions), but no strong electrophiles or strong acids, and certainly no carbocations or free radicals. 

These reactions consist of two steps. The first is the formation of a stabilized anion—usually (but not always) an enolate—by deprotonation with base. The second is a substitution reaction attack of the nucleophilic anion on an electrophilic alkyl halide. All the factors controlling SnI and Sn2 reactions, which we discussed at length in Chapter 17, are applicable here, step l formation of enolate anion step 2 alkylation (SN2 reaction with alkyl halide)... 

Nitrile-stabilized anions are so nucleophilic that they will react with alkyl halides rather well even when a crowded quaternary centre (a carbon bearing no H atoms) is being formed. In this example the strong base, sodium hydride, was used to deprotonate the branched nitrile completely and benzyl chloride was the electrophile. The greater reactivity of benzylic electrophiles compensates for the poorer leaving group. In DMF, the anion is particularly reactive because it is not solvated (DMF solvates only the Na+ cation). 

The first step is conjugate addition of the highly stabilized anion. The intermediate enolate then closes the three-membered ring by favourable nucleophilic attack on the allylic carbon. The leaving group is the sulfinate anion and the stereochemistry comes from the most favourable arrangement in the transition state for this ring closure. The product is the methyl ester of the important chrysan-themic acid found in the natural pyrethrum insecticides. 

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