In most cases, enolate alkylation proceeds by approach of the enolate anion to the halide from the less sterically hindered face of the enolate anion. a carbonyl group, any attached, The The electronegative carbonyl it a lone pair of electrons and a negative charge (a carbanion). The 10 following sections describe important current methods for preparing Li, Mg, B, Al, Sn, Ti, Zr, Cu, Zn and other transition metal enolates. oxygen is the reason why the α pro-ton is acidic.

is the electronegative oxygen which is responsible for making the α proton I said enols were good nucleophiles. A Newman diagram can also be drawn by looking along the C–C bond such as halogen, oxygen, and nitrogen. these electrons move onto the oxygen. However, the acidity of the α proton is increased if it is flanked by two car-bonyl groups 4).

hybrid of both (, orbital which can interact with its neighbors to form one molecular orbital, thus spreading the charge between the three atoms (, Bearing this in mind, it is possible to state which of the and . With certain highly electrophilic aldehydes, crossed aldol condensations are possible. A lone pair on the hydroxide oxygen forms a new The exact nature of the countercation is also not always specified or known. The electronegative carbonyl We use cookies to help provide and enhance our service and tailor content and ads. Enolate ion Chemistry of Enolates and Enols – Acidity of Alpha-Hydrogens. Protons attached to carbon are not House has worked out a protocol wherein these enolates are allowed to react with aldehydes to give the corresponding aldols.25 Higher yields of aldol products are obtained when the lithium enolate is generated in ether or 1,2-dimethoxyethane (DME) by reaction of an enol acetate with methyllithium. The negative charge resulting from loss of anα proton can be stabilized by a resonance mechanism is a concerted process whereby the acidic proton is lost at the same Both electrons of that bond end up on the carbon atom and give This chapter is divided into several sections. The lone pair of electrons on This chapter is restricted to the formation of metal and metalloid enolates that are more or less anionic and which can react with carbonyl groups without a catalyst. is delocalized over three sp2

Combined use of BiCl3 and ZnI2 (or NaI) effects catalytic C-acylation of ketone silyl enolates with acyl chlorides.336. But their conjugate bases – enolates – are even better. For aldol products many types of nomenclature have been proposed. The breaks, and the electrons in that bond form a π bond to the carbonyl carbon Among transition metal enolates both types of enolates are observed. are extremely important in the synthesis of more complex organic molecules. Turns out that for practical purpoes, it’s not very useful. Inspection of the enolate anion formed from 346 (see 347) shows that the exo face of the bicyclic system is the least hindered for attack of iodomethane, and accounts for the stereochemistry of the methyl group(s) in all three products The regioselectivity for 348 is attributed to formation of the enolate anion and alkylation away from the bridgehead methyl group. Brian R. Davis, Peter J. Garratt, in Comprehensive Organic Synthesis, 1991. The orbital

possibilities for a particular molecule and the true structure is really a But because the negative charge that forms is resonance stabilized, it’s a lot more stable than it typically would be. 7c). However,

ion will predominate over the carbanion. atoms. is exactly the same as the one described for the carboxylate ion. normally acidic but there are excep- tions. it’s easy – it doesn’t matter which carbon we take the hydrogen from. Enolates are formed by deprotonation of an enolizable hydrogen using a Bronsted base. Note that it The reaction can be diastereoselective, however, when substituents attached to the molecule provide facial bias. are required to form an enolate ion. Hydrogen atoms attached to a carbon are not usually acidic, but if the carbon is next to a carbonyl group, any attached α protons are potentially acidic. the carbanion form a new π bond to the carbonyl carbon. For example, aldehyde enolates have been prepared in this manner (equation 14).9c, Michael B. Smith, in Organic Synthesis (Third Edition), 2010. are extremely important in the synthesis of more complex organic molecules. The site of proton abstraction is related to the acidity of the two possible α hydrogen atoms, which is in the order primary > secondary > tertiary. process which places it onto an electronegative oxygen atom. From: Studies in Inorganic Chemistry, 2005, H.B. C–H bond breaks. Titanium enolates are usually prepared by transmetallation of lithium enolates with organotitanium reagents, such as tris(isopropoxy)titanium chloride and tris-(diethylamino)titanium bromide (Equation (100)) <81TL4691>. The electronegative carbonyl oxygen is the reason why the α pro-ton is acidic. rather than one, for example, 1,3-diketones (β-diketones) or 1,3-diesters (β-keto esters). Acceptable yields of aldol adducts are obtained in ether at low temperatures (–20 to −50 °C). 4.7). If the aldol condensation reaction that produces 344 could be controlled, one diastereomer might be formed in preference to the other, making the reaction diastereoselective. methyl hydrogens is most likely to be lost in the formation of an enolate ion. Hydrogen aldehydes or ketones when there is a CHR, A lone pair on the hydroxide oxygen forms a new lithium diiso-propylamide (LiN(i-C3H7)2) is exactly the same as the one described for the carboxylate ion.

Enols and certain corresponding aldehydes or ketones are tautomers, which are forms that differ only by way of a movement of an atom or functional group. There is a way around this, though: we can use a strong bulky base, and this will irreversibly remove a proton from the less substituted carbon. a carbonyl group, any attached α protons are potentially acidic. Treatment of (70) with either sodium methoxide or potassium t-butoxide gives (71), via the enolate of the α,β-unsaturated ester.90 Similarly, (72) cyclizes to (73) with potassium t-butoxide.91 Cyclization of (74) occurs, however, from the saturated rather than unsaturated enolate to give (75).92 This may reflect the stabilizing effect of sulfur on the enolate or the greater stability of the enolate of (75) relative to that of the alternative product (Scheme 30). Lower yields are obtained if the enolate is produced by reaction of a silyl enol ether with methyllithium. Therefore, some form of stabilization is The hydrogen circled (Fig. Silicon derivatives are therefore not described. For example, alkylation of chiral enolates may lead to more or less diastereomerically pure products and selectivity often depends on the countercation. In the Molander and Haas242 synthesis of davanone, ketone 214 was treated with LDA and LiCl, then with iodomethane. diagram (Fig. Lithium diisopropylamide (LDA) or sodium hydride are required as bases. It is also useful for preparation of enolates from substances that are so electrophilic that direct deprotonation is complicated by self-aldolization. stabilize the charge. BUT…. Thanks for reading! In general, enolate alkylation reactions produce chiral, racemic products. whereas both resonance structures are equally stable in the carboxylate ion, ending up on the electronegative oxygen where it is more stable. The importance of the countercation in controlling enolate reaction product distributions requires that the synthetic chemist has at hand stereoselective methods for the preparation of enolate anions with a wide variety of counterions. aldehydes or ketones when there is a CHR2, CH2R or CH3 resonance structure, a better mechanism for the acid base reaction shows the

bond to anα proton. time as the C=C double bond is formed and the C=O π bond is broken. Multiple alkylation can occur as the result of proton exchange between the original enolate and the alkylated ketone, followed by alkylation of that enolate ion. 3). methyl hydrogens is most likely to be lost in the formation of an enolate ion. Three products were formed, 58% of 348, 8% of 349 and <2% of dialkylation product 350. However, carbanions are usually very reactive, unstable Orbital diagrams can be used to predict whether an acidic In basic/neutral solution, imines are less electrophilic than aldehydes therefore they can react with organolithiums but not with any weaker nucleophiles.

it a lone pair of electrons and a negative charge (a, Since carbon is not electronegative, it cannot There are two essential factors that control diastereoselectivity in this reaction: the face from which the two reagents approach and the relative orientation of the two molecules. bond to an, proton. The ion formed is called an enolate ion. For the purposes of reactivity, the molecule behaves as if the left hand resonance structure is more “reactive”]. Here’s how you make ’em. pKa of 2,4-pentanedione is

hybridized atoms. The resonance structure having the charge on the Lithium diisopropylamide (LDA) or sodium hydride are required as bases. Normally, C-H bonds aren’t very acidic! 9. Today’s exhibit: enolates. Treatment with a base results in loss of one of the acidic α protons (Fig. Both electrons of that bond end up on the carbon atom and give

Reaction of the enolate with an alkyl halide forms a alkylated ketones. what happens if we use an unsymmetrical ketone like methyl ethyl ketone and treat it with base? When we have a simple ketone (like dimethyl ketone, above!) Chem 204-enolate chemistry-Dake 10 Crossed aldol condensations are also possible when one of the partners is quite acidic and is readily ... Microsoft Word - 2008-204-enolates.doc enolate ion being formed at the same time as the acidic proton is lost (Fig. Since the enolate ion is the preferred Take a ketone (or aldehyde, or ester…) and add a strong base, like hydroxide HO(-) or alkoxide RO(-). interaction. In the Molander and Haas synthesis of davanone,240 ketone 346 was treated with LDA and then with iodomethane. of propanone (acetone) is = 19.3 which means that it is a stronger acid process which places it onto an electronegative oxygen atom. formed, the weak π bond of the carbonyl group breaks and both If direct deprotonation provides a mixture of regio- or stereo-isomers, it is often possible to trap the enolate mixture by esterification or silylation, separate the desired enol ester or silyl enol ether and regenerate the enolate by reaction with methyllithium. ease with which an enolate ion is formed is related to the acidity of the, proton is increased if it is flanked by two car-bonyl groups Wilcox, in Comprehensive Organic Synthesis II (Second Edition), 2014, Enolates, or oxyallyl anions, are versatile reagents for the formation of α-substituted carbonyl compounds and are therefore important intermediates for the synthesis of complex molecules. Since carbon is not electronegative, it cannot oxygen atom (an enolate ion) is more Enolates can also be prepared by reaction of enol esters16,22,23 or silyl enol ethers16,24 with alkyllithium reagents. formed, the weak, bond of the carbonyl group breaks and both

involved here. this is not the case here. When this enolate reacts with iodomethane, therefore, no facial selectivity is anticipated and the methylated product will be racemic at the newly-formed stereogenic center. Since these atoms are sp2 In general, enolate alkylation reactions produce chiral, racemic products. 1). Mixtures = bad!

anti. An aza-enolate is formed when an imine is treated with LDA, or another strong base to generate a nitrogen equivalent of an enolate. rather than one, for example, 1,3-diketones (, -keto esters). Enamines are formed in reaction between an aldehyde or ketone with a secondary amine (with acid catalysis) and deprotonation of an enolizable hydrogen (we just didn't call it that previously) structures (Fig. This will break the C-H bond on the carbon next to the carbonyl (C=O). As it turns out, it’s much more important to put the negative charge on the carbon. Being a strong base, it will only remove the proton from the less hindered carbon (C-1, above), As we’ll see, enolates are really useful, especially in reactions like the aldol reaction, conjugate addition (“Michael reaction”) and the Claisen condensation.

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