Nucleophiles enolates

Chapters 1 and 2. Most C—H bonds are very weakly acidic and have no tendency to ionize spontaneously to form carbanions. Reactions that involve carbanion intermediates are therefore usually carried out in the presence of a base which can generate the reactive carbanion intermediate. Base-catalyzed condensation reactions of carbonyl compounds provide many examples of this type of reaction. The reaction between acetophenone and benzaldehyde, which was considered in Section 4.2, for example, requires a basic catalyst to proceed, and the kinetics of the reaction show that the rate is proportional to the catalyst concentration. This is because the neutral acetophenone molecule is not nucleophihc and does not react with benzaldehyde. The much more nucleophilic enolate (carbanion) formed by deprotonation is the reactive nucleophile. 

Because they re negatively charged, enolate ions act as nucleophiles and undergo many of the reactions we ve already studied. For example, enolates react with primary alkyl halides in the SK2 reaction. The nucleophilic enolate ion displaces halide ion, and a new C-C bond forms ... 

Perhaps the single most important reaction of enolate ions is their alkylation by treatment with an alkyl halide or tosylate, thereby forming a new C-C bond and joining two smaller pieces into one larger molecule. Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction and displaces the leaving group by backside attack. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Exactly the same kind of conjugate addition can occur when a nucleophilic enolate ion reacts with an ,j6-unsaturated carbonyl compound—a process known as the Michael reaction. 

Michael reactions take place by addition of a nucleophilic enolate ion donor to the /3 carbon of an a,(3-unsaturated carbonyl acceptor, according to the mechanism shown in Figure 23.7. 

A carbonyl condensation reaction takes place between two carbonyl partners and involves both nucleophilic addition and -substitution steps. One carbonyl partner (the donor) is converted by base into a nucleophilic enolate ion, which adds to the electrophilic carbonyl group of the second partner (the acceptor). The donor molecule undergoes an a substitution, while the acceptor molecule undergoes a nucleophilic addition. 

There have been several studies of the stereochemistry of conjugate addition reactions. If there are substituents on both the nucleophilic enolate and the acceptor, either syn or anti adducts can be formed. 

These enolates are important in organic synthesis in providing a source of nucleophilic enol for use in aldol and related reactions, and this is covered in Volume 9. 

In almost the same manner, tandem hydroformylation/aldol condensation aldol condensation of ketoolefins, such as p,y-unsaturated ketones, gives a single cyclization product under acid catalysis. Similar to the stepwise reaction, the in situ generated aldehyde preferentially acts as the electrophilic carbonyl component, while the ketone acts as the nucleophilic enol to form the five-membered ring product. Subsequent dehydration and hydrogenation of the resulting enone readily occurs under the reductive reaction conditions used (Scheme 30) [84],... 

C4 is nucleophilic (enol ether), and CIO is electrophilic. The Lewis acid makes CIO more electrophilic by coordinating to 013. After conjugate addition, 08 traps the C3 carbocation. Proton-Li+ exchange gives the product. 

In this report the authors describe a surprising solvent effect on enantioselectivi-ties. Alcoholic solvents afford the opposite enantiomer using the same enantiomeric series of catalyst Eq. 9. This profound effect is presumably due to hydrogen bonding in the transition state on the nucleophilic enol and/or the carbonyl acceptor Eq. 10. These electrostatic interactions can be visualized with Models E and F. Although the enantioselectivity is reversed the values remain lower than when toluene is used. 

Conjugate addition can also be carried out by completely forming the nucleophilic enolate under kinetic conditions. Ketone enolates formed by reaction with LDA in THF react with enones to give 1,5-diketones (entries 1 and 2, Scheme 1.12). Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,/J-unsaturated esters (entry 5, Scheme 1.12). 

The cycloaddition of A Af-dimethylethenamine with triethyl ethenetricarboxylate proceeds even faster but the corresponding cyclobutane is not stable. The less nucleophilic enol ethers and thioenol ethers are less reactive and require higher temperatures and longer reaction times although the cycloaddition products are obtained in respectable yields.30... 

Enol or Arene Double Bonds as Nucleophiles Enolate alkylation has been a powerful... 

So far we have used the same molecule to provide both nucleophilic (enolate) and electrophilic (carbonyl) components. This... 

In making a four carbon chain from two two-carbon units we used a nucleophilic enolate and an electrophilic carbonyl group. This theme of the two components is universal to this section. 

The second complication arises if the alkyl compound reacts with both carbon and oxygen of the nucleophilic enolate anion. The carbon product is the result of C-alkylation, whereas the oxygen product is the result of O-alkylation ... 

The Cinchona alkaloid-derived thiourea (112), has been developed as an organocat-alyst for conjugate addition of a wide range of nucleophilic enol species to enones. The reaction is characterized by high enantioselectivities and mild reaction condition.160... 

Using electrospray ionization mass spectrometry in both positive and negative ion modes, the on-line scanning of the Morita-Baylis-Hillman reaction in the presence of imidazolium ionic liquids has been investigated. The interception of several supramolecular species indicated that ionic liquids co-catalyse the reactions by activating the aldehyde toward nucleophilic enolate attack and by stabilizing the zwitterionic species that act as the main intermediates.175... 

In origin, the Mannich reaction is a three-component reaction between an eno-lizable CH-acidic carbonyl compound, an amine, and an aldehyde producing / -aminocarbonyl compounds. Such direct Mannich reactions can encompass severe selectivity problems since both the aldehyde and the CH-acidic substrate can often act as either nucleophile or electrophile. Aldol addition and condensation reactions can be additional competing processes. Therefore preformed electrophiles (imines, iminium salts, hydrazones) or nucleophiles (enolates, enamines, enol ethers), or both, are often used, which allows the assignment of a specific role to each car-... 

The second type of reaction which is commonly associated with carbonyl compounds involves the generation of a nucleophilic enol or enolate ion. Although the conversion of a ketone to the tautomeric enol does not necessarily involve any other species, the generation of an enolate requires a base (Fig. 3-4). In this latter reaction, the putative nucleophile may act as a general base. 

Figure 6-17. The formation of a C-C bond using a Claisen-type condensation. A nucleophilic enol, enolate or enamine reacts with the electrophilic carbon of a carbonyl compound or an imine.

We now have a continuous piece of carbon skeleton with two OH groups and a ketone. No doubt we shall make this by forming a C-C bond. But which one We know that ketones can form nucleophilic enolates so disconnecting the bond between C-4 and C-5 is a good choice because one starting material 3 is symmetrical. As we plan to use an enolate we need to make 3 nucleophilic and therefore 4 must be electrophilic so we write plus and minus charges to show that. 

The second point was made in chapter 6 where we said Very electrophilic compounds such as acid chlorides or aldehydes tend to prefer direct addition while less electrophilic compounds such as esters or ketone tend to do conjugate addition. That remains true and the same idea applies to the enolates very nucleophilic enolates such as lithium enolates tend to prefer direct addition while less nucleophilic enols and enolates such as enamines or 1,3-dicarbonyl compounds tend to do conjugate addition. 

Current understanding of the reaction suggests that an unprecedented mechanism is operating. Unlike in classical Lewis acid catalysed reactions [28], the metal complex does not activate the carbonyl moiety but is understood to enhance the degree of enolisation and thus create the necessary nucleophilic enol structure for reaction with the fluorinating agent [29]. 

With an aromatic aldehyde as the electrophilic partner, the nucleophilic enolate ion can also be derived from a ketone or a nitrile. As illustrated in the following examples, this enables the aldol condensation to be used to form a wide variety of compounds ... 

Again the best approach is to identity the site where the nucleophilic enolate anion forms, the a-carbon with the most acidic hydrogen. This carbon becomes bonded to the carbonyl carbon of the ester electrophile in the final product. 

The key idea of the Zimmerman-Traxler model is that aldol additions proceed via six-membered ring transition state structures. In these transition states, the metal (a magnesium cation in the case of the Ivanov reaction) coordinates both to the enolate oxygen and to the O atom of the carbonyl compound. By way of this coordination, the metal ion guides the approach of the electrophilic carbonyl carbon to the nucleophilic enolate carbon. The approach of the carbonyl and enolate carbons occurs in a transition state structure with chair conformation. C—C bond formation is fastest in the transition state with the maximum number of quasi-equatorially oriented and therefore sterically unhindered substituents. 

As one sees, not even a single molecule of the most reactive enolate F is present in the reaction flask, and it can be concluded safely that the Knoevenagel reaction does not proceed via enolate F. The second most nucleophilic species is enolate E, and its concentration is 1015 times smaller than the concentration of the least nucleophilic enolate D. The enolate D also does not occur in high concentration, but at least there is 10 s mole of this species for every mole of malonic acid employed. Based on these numbers, it would seem reasonable to assume that the malonic acid monoenolate D is the most effective nucleophile in the Knoevenagel condensation under consideration. 

Neither of these reactants is a strong enough nucleophile to attack the other. If ethoxide removes an a proton from methylcyclohexanone, however, a strongly nucleophilic enolate ion results. 

Only a small amount of the nucleophilic enolate ion is formed hydroxide is not basic enough to enolize an aldehyde completely. Each molecule of enolate is surrounded by molecules of the aldehyde that are not enolized and so still have the electrophilic carbonyl group intact Each enolate ion will attack one of these aldehydes to form an alkoxide ion, which will be protonated by the water molecule formed in the first step. 

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