Enolate ion

1 X-Substituted Allyl Anions. Allyl anions with alkyl substituents almost always react with carbonyl electrophiles at the more substituted a position, as in the reaction of the prenyl Grignard reagent with aldehydes to give the product 4.39, presumably because the metal attaches itself preferentially to the less-substituted end of the allyl system and then delivers the electrophile in a six-membered transition structure 4.38. In contrast, alkylation of a similar anion with an alkyl halide gives mainly the product 4.40 of y attack, which is normal for an X-substituted allyl anion when a cyclic transition structure is not involved. 

The coefficients in the HOMO can be estimated using the simple arguments developed earlier [see (Section 2.1.2.3) page 64], as in Fig. 4.3. The HOMO of an X-substituted allyl anion will have some of the character of ijj2 of the allyl anion, which is symmetrical, but it will also have some of the character of a carbanion conjugated to an allyl anion, in other words i/ 3 of butadiene, which has the larger coefficient on C-4, corresponding to the y position. 

2 C-Substituted Allyl Anions—Pentadienyl Anions. Allyl anions with C-substituents also suffer both a attack and y attack, as illustrated by the reactions of the open-chain C-substituted anions 4.41, and 4.42. Simple predictions based on the 7i orbitals suggest that the C-substituted system should be equally reactive at the a and y carbons, since mixing any amount of i/ 3 of the pentadienyl anion 

7r-electron populations c2 for the HOMO converted to c2 values using the 

33 Z-Substituted Allyl Anions—Dienolate Ions. Z-Substituted allyl anions 4.45a are typified by dienolate ions 4.45b, which is how they are best drawn. They almost always react faster at the a carbon than at the y carbon, both with soft and hard electrophiles. 

As before, we must not forget how much solvent effects may be the dominant influence in the regioselec-tivity. There is ample evidence that both the alkylation and the acylation of enolate ions in the gas phase take place, more often than not, on oxygen,301 the site that solvents protect. However, frontier orbital effects have been used to explain those gas phase reactions, and there are several, in which the enolate ion is attacked on carbon.302 

1 X-substituted AUyl Anions. The allyl-lithium reagents 4.53-4.56 are relatively simple examples of X-substituted allyl anions. With oxygen303,304 or nitrogen305,306 substituents, 4.53 and 4.54, y alkylation is almost always the major pathway, but with sulfur, while y alkylation is known307 4.55, a alkylation is much more common 4.56.308,309 

The anomalous results with the sulfur-containing anions can also be explained. The stabilisation of an anion adjacent to sulfur is by overlap with the neighbouring SC bond (Section 2.2.3.2) and not by overlap with the lone pairs. If this is operating in the dithian-stabilised anion 4.56, it is no longer an X-substituent, but a Z-substituent, since the S—C bond is polarised away from the sulfur. Allyl anions with a Z-substituent are 

From this point on, the regioselectivity of substituted allyl anions is much less regular, and somewhat less explicable. For a start, X-substituted allyl anions react with carbonyl electrophiles with a selectivity. This is explicable, but it is determined by the site of coordination by the metal, not by the frontier orbitals. We can contrast the reaction of the oxygen-substituted lithium anion 4.57 with an alkyl halide, which is y selective, as usual, and the reaction of the zinc anion 4.58 with a ketone, which is a selective.304 The oxygen substituent coordinates to the zinc cr-bound at the y position, and the aldehyde is then delivered to the a position in a six-membered cyclic transition structure 4.59. The same reaction with the lithium reagent 4.57 gives a 50 50 mixture of a and y products, and so lithium is not so obviously coordinated in the way that the zinc is. This type of reaction is often brought under control in the sense 4.59 for synthetic purposes by 

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The acetoacetate enolate ion (A in frame 54) is a reagent for the synthon B, the acetone anion. We shall discover how to add the COiEt activating group later. 

The altematiye condensation to giye A does not happen because A cannot form a stable enolate ion, whereas TM 219 can. Zhur. Obshchei Khim., 1957, 27, 742 Chem. Abs.. 1957. 51, 16313. 

The key intermediate m this process the conjugate base of the carbonyl compound IS referred to as an enolate ion because it is the conjugate base of an enol The term... 

Step 2 A water molecule acts as a Brpnsted acid to transfer a proton to the oxygen of the enolate ion... 

The slow step m base catalyzed enolization is formation of the enolate ion The second step proton transfer from water to the enolate oxygen is very fast as are almost all proton transfers from one oxygen atom to another... 

Write the structure of the enolate ion derived from each of the... 

Enolate ions of p dicarbonyl compounds are useful intermediates m organic synthesis We shall see some examples of how they are employed m this way later m the chapter... 

Rapid halogenation of the a carbon atom takes place when an enolate ion is generated m the presence of chlorine bromine or iodine... 

As m the acid catalyzed halogenation of aldehydes and ketones the reaction rate is mde pendent of the concentration of the halogen chlorination brommation and lodmation all occur at the same rate Formation of the enolate is rate determining and once formed the enolate ion reacts rapidly with the halogen... 

Only the a hydrogens are replaced by deuterium m this reaction The key intermediate IS the enolate ion formed by proton abstraction from the a carbon atom of cyclopen tanone Transfer of deuterium from the solvent D2O to the enolate gives cyclopentanone containing a deuterium atom m place of one of the hydrogens at the a carbon... 

Each act of proton abstraction from the a carbon converts a chiral molecule to an achi ral enol or enolate ion The sp hybridized carbon that is the chirality center m the start mg ketone becomes sp hybridized m the enol or enolate Careful kinetic studies have established that the rate of loss of optical activity of sec butyl phenyl ketone is equal to Its rate of hydrogen-deuterium exchange its rate of brommation and its rate of lodma tion In each case the rate determining step is conversion of the starting ketone to the enol or enolate anion... 

The point was made earlier (Section 5 9) that alcohols require acid catalysis in order to undergo dehydration to alkenes Thus it may seem strange that aldol addition products can be dehydrated in base This is another example of the way in which the enhanced acidity of protons at the a carbon atom affects the reactions of carbonyl com pounds Elimination may take place in a concerted E2 fashion or it may be stepwise and proceed through an enolate ion... 

The nucleophilic portion of the reagent (Y m HY) becomes bonded to the p carbon For reactions carried out under conditions m which the attacking species is the anion Y an enolate ion precedes the enol... 

Alkylation occurs by an 8 2 mechanism m which the enolate ion acts as a nucleophile toward the alkyl halide... 

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

Reactions of Aldehydes and Ketones That Involve Enol or Enolate Ion Intermediates... 

A reaction of great synthetic val ue for carbon-carbon bond for mation Nucleophilic addition of an enolate ion to a carbonyl group followed by dehydration of the 3 hydroxy aldehyde yields an a p unsaturated aldehyde... 

You have already had considerable experience with carbanionic compounds and their applications in synthetic organic chemistry The first was acetyhde ion m Chapter 9 followed m Chapter 14 by organometallic compounds—Grignard reagents for example—that act as sources of negatively polarized carbon In Chapter 18 you learned that enolate ions—reactive intermediates generated from aldehydes and ketones—are nucleophilic and that this property can be used to advantage as a method for carbon-carbon bond formation... 

The present chapter extends our study of carbanions to the enolate ions derived from esters Ester enolates are important reagents m synthetic organic chemistry The stabilized enolates derived from p keto esters are particularly useful... 

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

Section 21 9 Michael addition of the enolate ions derived from ethyl acetoacetate and diethyl malonate provides an alternative method for preparing their a alkyl derivatives... 

Enolate ion (Section 18 6) The conjugate base of an enol Enolate ions are stabilized by electron delocalization... 

Two techniques have been described for producing trimethylsilyl enol ethers from aldehydes or ketones (10) reaction of (CH2)2SiCl and (C2H3)2N in DMF and reaction of LiN(C2H3)2, which generates enolate ions in the presence of... 

Reversible electron addition to the enone forms the radical anion. Rate determining protonation of the radical anion occurs on oxygen to afford an allylic free radical [Eq. (4b) which undergoes rapid reduction to an allylic carbanion [Eq. (4c)]. Rapid protonation of this ion is followed by proton removal from the oxygen of the neutral enol to afford the enolate ion [Eq. (4c)]. 

Reduction of linearly conjugated 4,6-dien-3-ones with lithium-ammonia yields either 5-en-3-ones or 4-en-3-ones depending upon the work-up procedure. Protonation of the dienyl carbanion intermediate (58) occurs at C-7 to give ultimately the enolate ion (59) kinetic protonation of (59) occurs largely at C-4 to give the 5-en-3-one (60). ... 

The preferential exchange of the 6 -hydrogen under strongly acidic conditions is attributed to the formation of a A -dienol intermediate (29) which then undergoes deuterium attack from the -side at C-6. In contrast, in neutral or alkaline media the exchange proceeds via an enolate ion intermediate in which deuterium addition occurs in the following order C-4 >... 

Generally, methylation of enolate ions with isotopically tagged methyl iodide is a satisfactory labeling procedure. For example, application of this method has given the C-18 labeled steroids, (244) and (245) (see above), 17 -acetoxy-4jS-trideuteriomethyl-4a-methyl-l9-norandrost-5-en-3-one (264) and 19- C-testosterone acetate (268). Methylation of the anion derived from 17jS-acetoxy-4-methyl-l9-norandrost-4-en-3-one (263) with d3-methyl iodide occurs predominantly at C-4, yielding mainly the 4)S-trideuterio-methyl derivative (264) and about 10% of the corresponding C-4 epimer... 

Mazur " obtained 2a-alkyl-5a-H (3) or 4 -alkyl-5 -H products (6) by direct alkylation of either 5a-H (1) or 5 -H-3-keto steroids (4) with alkyl halides under basic conditions. In general, formation and alkylation of the more stable enolate ion is observed in this procedure. 

Tnfluoroacetonitrile oxide also reacts with stabilized enolate ions, such as that derived from 2,4-pentanedione, to give good yields of 1,3-dipolar adducts [38] (equation 38). 

In the presence of bases such as hydroxide, methoxide, and ethoxide, these p-diketones aie converted completely to their enolate ions. Notice that it is the methylene group flanked by the two caibonyl groups that is deprotonated. Both caibonyl groups paitici-pate in stabilizing the enolate by delocalizing its negative chaige. 

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