Chemistry
Enolate Ion
An enolate ion is a reactive intermediate in organic chemistry that forms when a base deprotonates a carbonyl compound, creating a negatively charged carbon atom. Enolate ions are important in organic synthesis as they can undergo various reactions, such as alkylation and condensation, to form new carbon-carbon bonds. These reactions are key in the production of many organic compounds.
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12 Key excerpts on "Enolate Ion"
eBook - PDF- William H. Brown, Thomas Poon(Authors)
- 2016(Publication Date)
- Wiley(Publisher)
1 What Are Enolate Anions, and How Are They Formed? 507 508 C H A P T E R 1 5 Enolate Anions This type of enolate anion reaction occurs among esters in the Claisen (Section 15.3A) and Dieckmann condensations (Section 15.3B). Enolate anions undergo nucleophilic addition to a carbon–carbon double bond if the double bond is conjugated with the carbonyl group of an aldehyde, a ketone, or an ester: 3-Buten-2-one (Methyl vinyl ketone) Enolate anion of diethyl propanedioate (Diethyl malonate) EtO – Na + EtOH EtOOC COOEt O EtOOC COOEt O – + – this new C C bond is formed This type of enolate anion reaction is called the Michael reaction (Section 15.5). 15.2 What Is the Aldol Reaction? A. Formation of Enolate Anions of Aldehydes and Ketones Treatment of an aldehyde or a ketone containing an acidic α‐hydrogen with a strong base, such as sodium hydroxide or sodium ethoxide, gives an enolate anion as a hybrid of two major contributing structures: An enolate anion ) d i c a r e g n o r t s ( ) d i c a r e k a e w ( pK a 15.7 pK a 20 H C H O C CH 3 H C H O CCH 3 Na H 2 O CH 3 O CCH 3 NaOH – – Given the relative acidities of the two acids in this equilibrium, the position of equilibrium lies considerably to the left. However, the existence of just a small amount of enolate anion is enough to allow the aldol reaction to proceed. B. The Aldol Reaction Addition of the enolate anion derived from an aldehyde or a ketone to the carbonyl group of another aldehyde or ketone is illustrated by these examples: Ethanal Ethanal 3-Hydroxybutanal (Acetaldehyde) (Acetaldehyde) Propanone Propanone 4-Hydroxy-4-methyl-2-pentanone (Acetone) (Acetone) (a β-hydroxyketone) CH 3 OH β C CH 3 C α H 2 O C CH 3 NaOH CH 3 O C CH 3 + H CH 2 O C CH 3 (a β-hydroxyaldehyde) CH 3 O β C H H C α H 2 O C H NaOH CH 3 O C H + H C H 2 O C H 15
eBook - PDF- William H. Brown, Thomas Poon(Authors)
- 2017(Publication Date)
- Wiley(Publisher)
For this reason both reactions proceed quantitatively Use of a base that is weaker than the ensuing enolate anion results in an equilibrium in which the enolate exists in very small concentrations. pK a 20 pK a 15.7 Sodium hydroxide Enolate + NaOH + + HOH – CH 3 C CH 3 CH 3 C CH 2 O O Na the stronger acid and base reside on the right side of the equation, causing the equilibrium to favor the reactants C. The Use of Enolate Anions to Form New C C Bonds Enolate anions are important building blocks in organic synthesis, and we will study their use as nucleophiles to form new carbon–carbon bonds. In overview, they participate in three types of nucleophilic reactions. Enolate anions function as nucleophiles in carbonyl addition reactions: R O R R An enolate anion A ketone A tetrahedral carbonyl addition intermediate this new C C bond is formed nucleophilic addition to a carbonyl carbon R R O R O R O R R R – + – This type of enolate anion reaction is particularly useful among reactions of aldehydes and ketones in the aldol reaction (Section 15.2). Enolate anions function as nucleophiles in nucleophilic acyl substitution reactions: O O O RO R O OR (1) (2) + + – RO – O O – OR OR R RO R An enolate anion An ester A tetrahedral carbonyl addition intermediate Product of nucleophilic acyl substitution R R R this new C C bond is formed 1 5 . 1 What Are Enolate Anions, and How Are They Formed? 507 This type of enolate anion reaction occurs among esters in the Claisen (Section 15.3A) and Dieckmann condensations (Section 15.3B). Enolate anions undergo nucleophilic addition to a carbon–carbon double bond if the double bond is conjugated with the carbonyl group of an aldehyde, a ketone, or an ester: 3-Buten-2-one (Methyl vinyl ketone) Enolate anion of diethyl propanedioate (Diethyl malonate) EtO – Na + EtOH EtOOC COOEt O EtOOC COOEt O – + – this new C C bond is formed This type of enolate anion reaction is called the Michael reaction (Section 15.5).
eBook - PDF- David R. Klein(Author)
- 2020(Publication Date)
- Wiley(Publisher)
Enolate Enol H Nuc H O H H Nuc O Nuc H H H O ⊕ ⊝ ⊝ O This type of reaction is called a conjugate addition, or a 1,4-addition, because the nucleophile and the proton have added across the ends of a conjugated π system. Conjugate addition reactions were first discussed in Section 17.4 when we explored the reactivity of conjugated dienes. A major differ- ence between conjugate addition across a diene and conjugate addition across an enone is that the latter produces an enol as the product, and the enol rapidly tautomerizes to form a carbonyl group. H O Nuc H H O Nuc H Tautomerization After the reaction is complete, it might appear that the two groups (shown in red) have added across the α and β positions in a 1,2-addition. However, the actual mechanism likely involves a 1,4-addition followed by tautomerization to give the ultimate product shown. With this in mind, let’s now explore the outcome of a reaction in which an Enolate Ion is used as a nucleophile to attack an α,β-unsaturated aldehyde or ketone. In general, enolates are less reactive than Grignard reagents but more reactive than lithium dialkyl cuprates. As such, both 1,2-addition and 1,4-addition are observed, and a mixture of products is obtained. In contrast, doubly stabilized enolates are sufficiently stabilized to produce 1,4-conjugate addition exclusively. O O O O H O 2) 1) KOH 3) H 3 O + H O In this case, the starting diketone is deprotonated to form a doubly stabilized Enolate Ion, which then serves as a nucleophile in a 1,4-conjugate addition. This process is called a Michael reaction. The doubly stabilized enolate is called a Michael donor, while the α,β-unsaturated aldehyde is called a Michael acceptor. Michael donor O O Michael acceptor H O δ+ ⊝ A variety of Michael donors and acceptors are observed to react with each other to produce a Michael reaction. Table 22.2 shows some common examples of Michael donors and acceptors.
eBook - PDF- David R. Klein(Author)
- 2021(Publication Date)
- Wiley(Publisher)
The α position is first deprotonated to form an Enolate Ion, fol- lowed by expulsion of a hydroxide ion to produce α,β unsaturation. This two-step process, which is different from the elimination reactions we saw in Chapter 7, is called an E1cb mechanism. Unlike an E1 process, in which the intermediate is a cation, the intermediate in this case is an anion (an enolate). This enolate is formed via deprotonation, so it is a conjugate base (thus the letters “cb”), and the “1” indicates that the reaction is first order (see Section 5.5 for a description of first-order reactions). 1014 CHAPTER 21 Alpha Carbon Chemistry: Enols and Enolates In cases where two stereoisomeric π bonds can be formed, the product with fewer steric interac- tions is generally the major product. H O H O Major H O + Minor NaOH Heat In this example, formation of the trans π bond is favored over formation of the cis π bond. The driving force for an aldol condensation is formation of a conjugated system. The reaction conditions required for an aldol condensation are only slightly more vigorous than the conditions required for an aldol addition reaction. Usually, an aldol condensation can be achieved by simply performing the reaction at an elevated temperature. In fact, in some cases, it is not even possible to isolate the β-hydroxyketone. As an example, consider the following case: O O NaOH O OH Not isolated In this case, the aldol addition product cannot be isolated. Even at moderate temperatures, only the condensation product is obtained, because the condensation reaction involves formation of a highly conjugated π system. Even in cases where the aldol addition product can be isolated (by performing the reaction at a low temperature), the yields for condensation reactions are often much greater than the yields for addition reactions.
- Jacob Zabicky, Zvi Rappoport(Authors)
- 2009(Publication Date)
- Wiley(Publisher)
Enolates can be synthesized 9–11 and isolated 12 – 14 or used in situ 3, 4, 15, 16 efficiently under kinetic control 17 , whereas under thermodynamic control 18 enolate for- mation is reversible 19 – 22 , and therefore for efficient product formation the product(s) generally needs to be more stable than the starting precursor(s) 23 . By far, the majority of enolate chemistry is dominated by the reformation of the more thermodynamically favoured (typically by ca 40 kJ mol −1 for simple aldehydes and ketones) 24 carbonyl (C=O) group through either reprotonation 25 – 27 or by addition to an electrophile 28 – 35 . The chemistry of carbonyl groups and their enolates are a near-perfect marriage where neither can be divorced from one another 36 . This chapter is primarily concerned with keto–enol equilibrium and the chemistry of dissociated enols (enoxides) 37 and lithium enolates. The acid–base aspects of the chemistry of other metal enolates (e.g. silyl enol ethers 38 – 43 , boron enol ethers 44 – 51 , aluminium 52 , tin 53 – 55 , gallium 56 , bismuth 57, 58 , zinc 59 – 70 , rhodium 71 , palladium 72 – 82 , manganese 83, 84 , copper 85 , nickel 86, 87 , magnesium 88 – 90 , titanium 91 – 108 , molybdenum 109 , zirconium 110, 111 and ammonium 112, 113 enolates) have been reported elsewhere. III. CHEMISTRY OF ENOLS AND ENOLATES A. Enol Formation Carbonyl-containing molecules, such as 1, with an α-carbon – hydrogen C(2sp 3 )–H(1s ) hybridized bond can exist as an enol tautomer 2, and their relative proportions depend on the relative stability of each tautomeric component (Scheme 1) 114 – 120 . For saturated carbonyl-containing molecules, like 1, the amount of enol content 2 is quite low (<1%; K E 1; pK E 0) 24, 121, 122 .
eBook - ePub- David John Ager, Michael B. East(Authors)
- 2020(Publication Date)
- CRC Press(Publisher)
Chapter 5ENOLATE REACTIONS OF CARBONYL COMPOUNDS
The carbonyl group is extremely versatile for the introduction of functionality. The powerful transformation of nucleophilic addition to afford an alcohol derivative was discussed in Chapter 4 . The reactions of functionalized carbonyl compounds are discussed in Chapter 6 , although some examples have been included in this chapter to avoid unnecessary fragmentation.The emphasis of this chapter is placed on the introduction of an additional substituent, such as a heteroatom or alkyl group, at the carbon atom next to the carbonyl group of a simple compound. The aldol reaction and its analogs are discussed in Chapter 7 . This demarcation has resulted in some duplication as a chiral auxiliary that allows both high selectivity for the reaction of a ketone equivalent with an alkyl halide and aldehyde will appear in this chapter and the one on the aldol reaction. Some fragmentation of topics has also occurred: as an example, the synthesis of α-amino acids by reaction of a carboxylic enolate derivative with a nitrogen electrophile will be found in this chapter, while the alkylation reactions of glycine derivatives are discussed in Chapter 6 .The incorporation of nitrogen, through the utilization of imines, enamines, and hydrazones, has allowed for the introduction of a large number of chiral auxiliaries to be used in alkylation-type chemistry. The appropriate chemistry, in keeping with the limitations outlined above, is also discussed in this chapter.The chemistry of chiral bases, especially with regard to enolate formation, continues to expand. A section in this chapter discusses the general usage of this approach and its closely related asymmetric protonation methodology.5.1. ENOL ETHERS AND ENOLATE FORMATION
The chemistry of enol ethers and enolate formation are closely related as the preparation of the former often proceeds by way of the latter. As we are concerned with asymmetric methodology, there will be little discussion of the chemistry of enols, as their formation and reactions are often under thermodynamic control — although this can be useful in cyclic systems.1
eBook - ePubModern Organic Synthesis
An Introduction
- George S. Zweifel, Michael H. Nantz, Peter Somfai(Authors)
- 2017(Publication Date)
- Wiley(Publisher)
6 Formation of Carbon–Carbon Single Bonds via Enolate AnionsHydrogen atoms at a position alpha to a carbonyl, nitrile, or sulfonyl group are relatively acidic (Table 6.1 ). The acidity of the C–H bond in these compounds is due to a combination of the inductive electron-withdrawing effect of the neighboring functionality and resonance stabilization of the anion that is formed by removal of the α-proton. Since these anions possess carbanionic reactivity, they undergo a host of carbon–carbon bond-forming reactions at the α-carbon by alkylation with R–X, addition to RR′CO, or by acylation with RC(O)X.16.1 1,3-Dicarbonyl Compounds
The acidities of 1,3-dicarbonyl compounds are sufficiently high that they can be substantially converted to their conjugate bases by oxyanions such as hydroxide and alkoxides (case A below). Treatment of 1,3-dicarbonyl compounds with amines will form the corresponding enolate species in equilibrium with the dicarbonyl compound (case B).Approximate pKa Values of Carbonyl, Nitrile, and Sulfonyl Compounds2Table 6.1In contrast, deprotonation with sodium hydride (usually in THF or DME as solvent) transforms 1,3-dicarbonyl compounds to enolate species irreversibly by loss of H2 (case C). The selection of base and solvent for alkylation, acylation, or condensation reactions of 1,3-dicarbonyl compounds must take into account whether the overall reaction requires the presence of a conjugate acid for participation in an equilibrium process (see Knoevenagel Condensation).Malonates
Alkylation
Mono- and dialkylations of malonate esters (malonic ester synthesis) generally are performed in an alcoholic solution of a metal alkoxide.3 When the dialkylated product is desired, two identical or different electrophiles can be introduced by careful choice of reaction conditions. The alkylation works well with RCH2 X (X = I, Br, OTs), PhCH2 X (X = Cl, Br) and even with unhindered sec alkyl bromides.4
eBook - PDF- T. W. Graham Solomons, Craig B. Fryhle, Scott A. Snyder(Authors)
- 2017(Publication Date)
- Wiley(Publisher)
The reasons for the unusual acidity of the α hydrogens of carbonyl compounds are straightforward. • The carbonyl group is strongly electron withdrawing, and when a carbonyl com- pound loses an α proton, the anion that is produced, called an enolate, is stabilized by delocalization. A B Resonance structures for the delocalized enolate C C B – O H O C C – C C O – + H—B Two resonance structures, A and B, can be written for the enolate. In structure A the negative charge is on carbon, and in structure B the negative charge is on oxygen. Both structures contribute to the hybrid. Although structure A is favored by the strength of its carbon–oxygen π bond relative to the weaker carbon–carbon π bond of B, structure B 18.2 KETO AND ENOL TAUTOMERS 813 makes a greater contribution to the hybrid because oxygen, being highly electronegative, is better able to accommodate the negative charge. We can depict the enolate hybrid in the following way: O C C δ– δ– Hybrid resonance structure for an enolate When this resonance-stabilized enolate accepts a proton, it can do so in either of two ways: it can accept the proton at carbon to form the original carbonyl compound in what is called the keto form or it may accept the proton at oxygen to form an enol (alkene alcohol). • The enolate is the conjugate base of both the enol and keto forms. Enolate O H A proton can add here. A proton can add here. or C C Enol form Keto form O + HB δ– δ– + – B C C HO + – B C C A calculated electrostatic potential map for the enolate of acetone is shown below. The map indicates approximately the outermost extent of electron density (the van der Waals surface) of the acetone enolate. Red color near the oxygen is consistent with oxygen being better able to stabilize the excess negative charge of the anion. Yellow at the carbon where the α hydrogen was removed indicates that some of the excess negative charge is localized there as well.
eBook - PDF- David R. Klein(Author)
- 2016(Publication Date)
- Wiley(Publisher)
In general, enolates are less reactive than Grignard reagents but more reactive than lithium dialkyl cuprates. As such, both 1,2-addition and 1,4-addition are observed, and a mixture of products is obtained. In contrast, doubly stabilized enolates are sufficiently stabilized to produce 1,4-conjugate addition exclusively. O O O O H O 2) 1) KOH 3) H 3 O + H O In this case, the starting diketone is deprotonated to form a doubly stabilized Enolate Ion, which then serves as a nucleophile in a 1,4-conjugate addition. This process is called a Michael reaction. The doubly stabilized enolate is called a Michael donor, while the α,β-unsaturated aldehyde is called a Michael acceptor. Michael donor O O Michael acceptor H O δ+ ⊝ 988 CHAPTER 21 Alpha Carbon Chemistry: Enols and Enolates A variety of Michael donors and acceptors are observed to react with each other to produce a Michael reaction. Table 21.2 shows some common examples of Michael donors and acceptors. Any one of the Michael donors in this table will react with any one of the Michael acceptors to give a 1,4-conjugate addition reaction. TABLE 21.2 A LIST OF COMMON MICHAEL DONORS AND MICHAEL ACCEPTORS R 2 CuLi MICHAEL DONORS MICHAEL ACCEPTORS O O OEt O O R NO 2 C O N EtO OEt O O H O δ+ δ+ δ+ δ+ δ+ δ+ O OEt O NH 2 O C N NO 2 ⊝ ⊝ ⊝ ⊝ ⊝ CONCEPTUAL CHECKPOINT 21.35 Identify the major product formed when each of the follow- ing compounds is treated with Et 2 CuLi followed by mild acid: (a) O (b) CN (c) OEt O 21.36 Predict the major product of the three following steps and show a mechanism for its formation: O 2) 1) KOH 3) H 3 O + ? O O 21.37 In the previous section, we learned how to use diethyl mal- onate as a starting material in the preparation of substituted car- boxylic acids (the malonic ester synthesis). That method employed a step in which the enolate of diethyl malonate attacked an alkyl halide to give an alkylation product.
eBook - PDF- Michael Bryant Smith(Author)
- 2013(Publication Date)
- CRC Press(Publisher)
75 4 Enolate Anion and Related Reactions An important general strategy for the preparation of amino acids involves generating a carbanion from an acid derivative and subsequent reaction with another suitably functionalized derivative. This reaction may be the conjugate addition discussed in Chapter 3, Section 3.2.2, but alkylation or acyl addition reactions may also be used. When appropriate functionality is present, these reactions constitute a useful route to non-α -amino acids. 4.1 ACID, ESTER, AND MALONATE ENOLATE ANION REACTIONS The reaction of an ester bearing an α -hydrogen atom with a nonnucleophilic base such as lithium diisopropylamide (LDA) generates the corresponding enolate anion. 1 Modern techniques allow generation of both mono- and dianions of carboxylic acids. Such enolate anions undergo C-alkylation and C-condensation reactions. An example of an ester enolate alkylation reaction first treated methyl 2-methyl-propanoate with lithium diisopropylamide to generate the enolate anion, and then with 4-bromobutanenitrile to give 1 . 2 Catalytic hydrogenation of the cyano group gave methyl 6-amino-2,2-dimethylhexanoate ( 2 ). In this case, the nitrile was the amine surrogate and the ester was the acid precursor. CO 2 Me N NH 2 CO 2 Me CO 2 Me Br 1. LDA, THF –78°C 2. –70°C 0°C H 2 , Ni (R) EtOH, 100°C 90 atm, 1 h 1 2 69% 37% C N C The enolate alkylation reaction that generated 1 used cyano as a nitrogen sur-rogate (see Chapter 1, Section 1.1.3). Other nitrogen surrogates may also be used in enolate alkylation reactions. An example is the reaction of the sodium enolate of diethyl 2-methyl malonate with phthalimide derivative 3 . This displacement reaction was followed by removal of the phthalimidoyl group, hydrolysis of the ester moieties, and decarboxylation to give 2-methyl-6-aminohexanoic acid ( 4 ). 3 Phthalimide 1 was prepared by reaction of 1,4-dibromobutane with potassium phthalimide. 3 The length 1 See Smith, M.B. Organic Synthesis , 3rd ed.
eBook - PDFOrganic Chemistry as a Second Language
Second Semester Topics
- David R. Klein(Author)
- 2019(Publication Date)
- Wiley(Publisher)
After all, it looks like the nucleophile and the H have added across the C===C bond: O Nuc H O You need to draw the entire mechanism in order to see why we call it a 1,4-addition. Now that we know the difference between a 1,2-addition and a 1,4-addition, let’s take a look at what happens when our attacking nucleophile is an enolate. If an α,β-unsaturated ketone is treated with an enolate, a mixture of products is obtained. Not only do we observe both possibilities (the enolate attacking the carbonyl group, or the enolate attacking the β position), but it gets even more complicated. The product of the 1,4-addition is a ketone, which can be attacked again by an enolate. You can get crossed aldol condensations, and all sorts of unwanted products. So, we can’t use an enolate to attack an α,β-unsaturated ketone. The enolate is simply too reactive, and we observe a mixture of undesired products. 258 CHAPTER 8 ENOLS AND ENOLATES The way around this problem is to create an enolate that is more stabilized. A more stable enolate will be less reactive, and therefore, it will be more selective in what it reacts with. But how do we make a more stabilized enolate? We have actually already seen such an example in this chapter. Consider the following enolate: O O We argued that this enolate is more stable than a regular enolate, because the negative charge is delocalized over two carbonyl groups. If we use this enolate to attack an α,β-unsaturated ketone, we find that the predominant reaction is a 1,4-addition: O O O O O O 1,4-addition H 3 O + O O O We said earlier that a 1,4-addition is also called a Michael addition. In order to get a Michael addition, you need to have a stabilized nucleophile, like the stabilized enolate shown in the reaction above. This stabilized enolate is called a Michael donor. There are many other examples of Michael donors.
- David R. Klein(Author)
- 2017(Publication Date)
- Wiley(Publisher)
LDA is a strong, sterically hindered base, so deprotonation will occur at the less substituted position. Deprotonation at that position results in the following kinetic enolate: 872 CHAPTER 21 21.54. Deprotonation at the highlighted γ position results in an anion that has three resonance structures. The negative charge is spread over one oxygen atom and two carbon atoms: 21.55. Deprotonation at the carbon changes the hybridization state of the carbon from sp 3 (tetrahedral) to sp 2 (planar). When the position is protonated once again, the proton can be placed on either side of the planar carbon, resulting in racemization: 21.56. In acidic conditions, the carbonyl group is first protonated, resulting in a resonance-stabilized cation that is deprotonated at the position to give an enol. The enol is then protonated at the position, followed by deprotonation. Once again, racemization occurs because the chiral center becomes planar (achiral) when the enol is formed. Subsequent tautomerization back to the ketone allows for protonation to occur on either face of the planar enol, giving a racemic mixture. O Me H O H Me H O H Me O H Me H O Me H H O H H H O H H O H H H O H [H + ] CHAPTER 21 873 21.57. Each of the starting aldehydes has an position that can be deprotonated, giving two possible enolates: So, there are two nucleophiles in solution, as well as two electrophiles (acetaldehyde and pentanal), giving rise to the following four possible products. In each case, a wavy line is used to indicate the bond that was formed as a result of the aldol addition reaction: 21.58. Hexanal has an position that bears protons, but the position of benzaldehyde does not bear any protons. As such, only one enolate can form under these conditions: This enolate is present in solution together with two electrophiles (hexanal and benzaldehyde), giving rise to the following two possible products.
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