22: Carbonyl Alpha-Substitution Reactions
- Page ID
- 448790
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\(\newcommand{\avec}{\mathbf a}\) \(\newcommand{\bvec}{\mathbf b}\) \(\newcommand{\cvec}{\mathbf c}\) \(\newcommand{\dvec}{\mathbf d}\) \(\newcommand{\dtil}{\widetilde{\mathbf d}}\) \(\newcommand{\evec}{\mathbf e}\) \(\newcommand{\fvec}{\mathbf f}\) \(\newcommand{\nvec}{\mathbf n}\) \(\newcommand{\pvec}{\mathbf p}\) \(\newcommand{\qvec}{\mathbf q}\) \(\newcommand{\svec}{\mathbf s}\) \(\newcommand{\tvec}{\mathbf t}\) \(\newcommand{\uvec}{\mathbf u}\) \(\newcommand{\vvec}{\mathbf v}\) \(\newcommand{\wvec}{\mathbf w}\) \(\newcommand{\xvec}{\mathbf x}\) \(\newcommand{\yvec}{\mathbf y}\) \(\newcommand{\zvec}{\mathbf z}\) \(\newcommand{\rvec}{\mathbf r}\) \(\newcommand{\mvec}{\mathbf m}\) \(\newcommand{\zerovec}{\mathbf 0}\) \(\newcommand{\onevec}{\mathbf 1}\) \(\newcommand{\real}{\mathbb R}\) \(\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}\) \(\newcommand{\laspan}[1]{\text{Span}\{#1\}}\) \(\newcommand{\bcal}{\cal B}\) \(\newcommand{\ccal}{\cal C}\) \(\newcommand{\scal}{\cal S}\) \(\newcommand{\wcal}{\cal W}\) \(\newcommand{\ecal}{\cal E}\) \(\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}\) \(\newcommand{\gray}[1]{\color{gray}{#1}}\) \(\newcommand{\lgray}[1]{\color{lightgray}{#1}}\) \(\newcommand{\rank}{\operatorname{rank}}\) \(\newcommand{\row}{\text{Row}}\) \(\newcommand{\col}{\text{Col}}\) \(\renewcommand{\row}{\text{Row}}\) \(\newcommand{\nul}{\text{Nul}}\) \(\newcommand{\var}{\text{Var}}\) \(\newcommand{\corr}{\text{corr}}\) \(\newcommand{\len}[1]{\left|#1\right|}\) \(\newcommand{\bbar}{\overline{\bvec}}\) \(\newcommand{\bhat}{\widehat{\bvec}}\) \(\newcommand{\bperp}{\bvec^\perp}\) \(\newcommand{\xhat}{\widehat{\xvec}}\) \(\newcommand{\vhat}{\widehat{\vvec}}\) \(\newcommand{\uhat}{\widehat{\uvec}}\) \(\newcommand{\what}{\widehat{\wvec}}\) \(\newcommand{\Sighat}{\widehat{\Sigma}}\) \(\newcommand{\lt}{<}\) \(\newcommand{\gt}{>}\) \(\newcommand{\amp}{&}\) \(\definecolor{fillinmathshade}{gray}{0.9}\)When you have completed Chapter 22, you should be able to
- fulfill all of the detailed objectives listed under each individual section.
- design multi‑step syntheses in which the reactions introduced in this unit are used in conjunction with any of the reactions described in previous units.
- solve road‑map problems that require a knowledge of carbonyl alpha‑substitution reactions.
- define, and use in context, the key terms introduced.
Alpha‑substitution reactions are the third major type of reaction that you will study in your investigation of the chemistry of carbonyl compounds. As you will see, these reactions proceed through the formation of the enol form of the carbonyl compound.
After a brief review of keto‑enol tautomerism, we begin our discussion of alpha‑substitution reactions by looking at the methods in which the enol form of the carbonyl compound is directly involved. After discussing the factors that influence the formation and stability of enolate anions, we will examine some halogenation reactions in which an enolate ion is formed as an intermediate.
The chapter concludes with a study of the alkylation of enolate anions. These reactions are of tremendous use in organic syntheses, as they provide a method of forming new carbon‑carbon bonds, and hence facilitate the laboratory preparation of increasingly complex compounds.
- 22.0: Why This Chapter?
- As with nucleophilic additions and nucleophilic acyl substitutions, many laboratory schemes, pharmaceutical syntheses, and biochemical pathways make frequent use of carbonyl α-substitution reactions. Their great value comes from the fact that they constitute one of the few general methods for forming carbon–carbon bonds, thereby making it possible to build larger molecules from smaller precursors. In this chapter, we’ll see how and why these reactions occur.
- 22.1: Keto-Enol Tautomerism
- The page on keto-enol tautomerism describes the equilibrium between keto (carbonyl) and enol (alkene with an alcohol) forms of carbonyl compounds. This process involves the transfer of a proton and the movement of a double bond, affecting the compound's reactivity and stability. Factors like solvent and temperature can influence the tautomeric ratio. Understanding this equilibrium is crucial for predicting reaction outcomes in organic synthesis.
- 22.2: Reactivity of Enols- α-Substitution Reactions
- The page discusses the reactivity of enols in substitution reactions. Enols, which are formed from carbonyl compounds, can act as nucleophiles, enabling them to participate in various substitution reactions. Their reactivity is influenced by factors like sterics and electronics. Key reactions include enolate formation and nucleophilic attack, leading to products such as alpha-substituted carbonyl compounds. Understanding these mechanisms is essential for manipulating carbonyl chemistry.
- 22.3: Alpha Halogenation of Aldehydes and Ketones
- The page on alpha halogenation of aldehydes and ketones explains how carbonyl compounds, specifically aldehydes and ketones, undergo substitution at the alpha carbon when exposed to halogens (chlorine, bromine, or iodine) under acidic or basic conditions. The reaction replaces one hydrogen from the alpha position with a halogen, forming alpha-halo aldehydes or ketones. This process is important in organic synthesis, as it can lead to further transformations.
- 22.4: Alpha Bromination of Carboxylic Acids
- The section on alpha bromination of carboxylic acids describes how these acids react with bromine in the presence of a base, leading to the substitution of an alpha hydrogen with a bromine atom. This reaction is particularly notable in the presence of enol forms of carboxylic acids, which enhance reactivity. The process is essential for synthesizing alpha-bromo carboxylic acids, which can be further transformed in various organic synthesis applications.
- 22.5: Acidity of Alpha Hydrogen Atoms- Enolate Ion Formation
- The section on the acidity of alpha hydrogen atoms explains that these hydrogens are more acidic than other hydrogens due to the stabilization of the resulting enolate ion. When an alpha hydrogen is removed by a strong base, it forms an enolate, which serves as a key intermediate in various organic reactions, including nucleophilic additions and substitutions. This characteristic is crucial for many synthetic pathways in organic chemistry.
- 22.6: Reactivity of Enolate Ions
- Enolate ions, which are nucleophilic species formed from carbonyl compounds with alpha-hydrogens, can engage in various reactions, such as alkylation and condensation, making them valuable in synthesizing complex organic molecules. Their reactivity depends on the stability of the enolate formed, influenced by factors like substitution and resonance. Understanding enolate reactivity is essential for harnessing their potential in organic synthesis.
- 22.7: Alkylation of Enolate Ions
- The section on alkylation of enolate ions explains how enolates can react with alkyl halides to form carbon-carbon bonds through nucleophilic substitution. This process typically involves treating the enolate with a suitable electrophile, leading to the formation of alkylated products. The choice of electrophile and conditions influences the reaction's efficiency and outcome, making alkylation a valuable method in organic synthesis.
- 22.8: Chemistry Matters—Barbiturates
- The section discusses barbiturates, a class of drugs derived from barbituric acid, known for their sedative and anesthetic properties. These compounds can be synthesized through the alkylation of urea and are used to treat anxiety, insomnia, and seizure disorders. The text also highlights the importance of understanding the chemistry of barbiturates, including their potential for dependence and overdose.
- 22.10: Summary
- The summary section reviews key concepts of carbonyl alpha-substitution reactions, highlighting the significance of keto-enol tautomerism and the reactivity of enolate ions. It emphasizes the importance of understanding how alpha-hydrogens influence acidity and the mechanisms of nucleophilic substitutions. The section also encapsulates various synthetic applications and the role of enolate ions in organic synthesis.
- 22.11: Summary of Reactions
- This section summarizes various carbonyl alpha-substitution reactions, including keto-enol tautomerism, nucleophilic acyl substitution, and the reactivity of enolate ions. It discusses key reactions such as alpha halogenation, alkylation, and condensation reactions, along with their significance in organic synthesis. The importance of understanding these reactions for the formation of carbon-carbon bonds and their applications in creating complex molecules is also highlighted.