CN>Chapter 22CT>Carbonyl Alpha-Substitution Reactions

John E. McMurry Chapter 22 Carbonyl Alpha-Substitution Reactions Paul D. Adams University of Arkansas The Position

The carbon next to the carbonyl group is designated as being in the position Electrophilic substitution occurs at this position through either an enolate or enol ion Why this Chapter?

Many schemes make use of carbonyl substitution reactions. These reaction are one the few general methods for making C-C bonds. 22.1 KetoEnol Tautomerism

A carbonyl compound with a hydrogen atom on its a carbon rapidly equilibrates with its corresponding enol Compounds that differ only by the position of a moveable proton are called tautomers Tautomers Are Not Resonance

Forms Tautomers are structural isomers Resonance forms are representations of contributors to a single structure Tautomers interconvert rapidly while ordinary isomers do

not Enols The enol tautomer is usually present to a very small extent and cannot be isolated However, since it is formed rapidly, it can serve

as a reaction intermediate Acid Catalysis of Enolization Brnsted acids catalyze keto-enol tautomerization by protonating the carbonyl and

activating the protons Base Catalysis of Enolization

Brnsted bases catalyze keto-enol tautomerization The hydrogens on the carbon are weakly acidic and transfer to water is slow In the reverse direction there is also a barrier to the addition of the proton from water to enolate carbon

22.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions Enols behave as nucleophiles and react with electrophiles because the double bonds are electron-rich compared to alkenes General Mechanism of Addition to Enols

When an enol reacts with an electrophile the intermediate cation immediately loses the OH proton to give a substituted carbonyl compound

22.3 Alpha Halogenation of Aldehydes and Ketones Aldehydes and ketones can be halogenated at their positions by reaction with Cl2, Br2, or I2 in acidic solution Mechanism of Acid-Catalyzed

Bromination The enol tautomer reacts with an electrophile The keto tautomer loses a proton

Evidence for Rate-Limiting Enol Formation The rate of halogenation is independent of the halogen's identity and concentration In D3O+ the Hs are replaced by Ds at the same rate as halogenation

This is because the barrier to formation of the enol goes through the highest energy transition state in the mechanism Elimination Reactions of -Bromoketones -Bromo ketones can be dehydrobrominated by base treatment to yield ,-unsaturated ketones

22.4 Alpha Bromination of Carboxylic Acids Carboxylic acids do not react with Br2 (unlike aldehydes and ketones) They are brominated by a mixture of Br2 and PBr3 (Hell VolhardZelinskii reaction)

Mechanism of Bromination PBr3 converts COOH to COBr, which can enolize and add Br2 22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation

Carbonyl compounds can act as weak acids (pKa of acetone = 19.3; pKa of ethane = 60) The conjugate base of a ketone or aldehyde is an enolate ion - the negative charge is delocalized onto oxygen Reagents for Enolate Formation

Ketones are weaker acids than the OH of alcohols so a more powerful base than an alkoxide is needed to form the enolate Sodium hydride (NaH) or lithium diisopropylamide [LiN(iC3H7)2] are strong enough to form the enolate Lithium Diisopropylamide (LDA)

LDA is from butyllithium (BuLi) and diisopropylamine (pKa 40) Soluble in organic solvents and effective at low temperature with many compounds Not nucleophilic

-Dicarbonyls Are More Acidic When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced (Table 22.1) Negative charge of enolate delocalizes over both carbonyl groups

Table 22.1: Acidities of Organic Compounds 22.6 Reactivity of Enolate Ions

The carbon atom of an enolate ion is electron-rich and highly reactive toward electrophiles (enols are not as reactive) Reaction on oxygen yields an enol derivative Reaction on carbon yields an -substituted carbonyl compound 22.7 Alkylation of Enolate Ions

Base-promoted reaction occurs through an enolate ion intermediate Constraints on Enolate Alkylation SN2 reaction: the leaving group X can be chloride, bromide,

iodide, or tosylate R should be primary or methyl and preferably should be allylic or benzylic Secondary halides react poorly, and tertiary halides don't react at all because of competing elimination The Malonic Ester Synthesis For preparing a carboxylic acid from an alkyl halide while

lengthening the carbon chain by two atoms Formation of Enolate and Alkylation Malonic ester (diethyl propanedioate) is easily converted into its enolate ion by reaction with sodium ethoxide in

ethanol The enolate is a good nucleophile that reacts rapidly with an alkyl halide to give an -substituted malonic ester Dialkylation The product has an acidic -hydrogen, allowing the alkylation process to be repeated

Hydrolysis and Decarboxylation The malonic ester derivative hydrolyzes in acid and loses CO2 (decarboxylation) to yield a substituted monoacid Decarboxylation of Ketoacids

Decarboxylation requires a carbonyl group two atoms away from the CO2H Overall Conversion The malonic ester synthesis converts an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atoms

Preparation of Cycloalkane Carboxylic Acids 1,4-dibromobutane reacts twice, giving a cyclic product Three-, four-, five-, and six-membered rings can be prepared in this way Acetoacetic Ester Synthesis

Overall: converts an alkyl halide into a methyl ketone Acetoacetic Ester (Ethyl Acetoacetate)

carbon is flanked by two carbonyl groups, so it readily becomes an enolate ion This can be alkylated by an alkyl halide and also can react with a second alkyl halide Generalization: -Keto Esters

The sequence: enolate ion formation, alkylation, hydrolysis/decarboxylation is applicable to -keto esters in general Cyclic -keto esters give 2-substituted cyclohexanones Biological Alkylations Lets Work a Problem Which of the following substances would undergo

the haloform reaction? a) CH3COCH3 b) c) Acetophenone CH3CH2CHO

d) CH3CO2H e) CH3C N Answer

In the haloform reaction, there is an -substitution whereby the methyl ketone is trihalogenated at the position. The trihalomethyl group is displaced by OH. This reaction is used as a test for methyl ketones. + reactions would come from reactions a, and b; while reactions would come from c, d, and e.

Recently Viewed Presentations

  • Title of Presentation

    Title of Presentation

    Making Sense - a researcher centred approach to funder mandates Stuart Hunt, Rowena Rouse June 2014
  • Red Vinegar - UTEP SCIENCE

    Red Vinegar - UTEP SCIENCE

    pKa. Titrations . We usually measure the end point (visually) Today we get the equivalence point (pH probe) Use the data to find the greatest change and that is the eq. point


    Here it is all about the partner that is building his own environment. We salute you. You are taking a huge step your entrepreurial skills are what is driving the industry and we love you for that. What we want...
  • The Endless Frontier in Science and Technology: Role of the ...

    The Endless Frontier in Science and Technology: Role of the ...

    The Endless Frontier in Science and Technology: Role of the United States and Purdue October 1, 2007 Charles O. Rutledge, Ph.D. Vice President for Research
  • Research Methods in Clinical Psychology

    Research Methods in Clinical Psychology

    * Correlational Methods Are particular patient characteristics related to therapy outcomes? What is correlation? The issue of causality. Factor Analysis * Cross-sectional versus Longitudinal Approaches Cross-sectional Longitudinal * Experimental Method Cause and effect relationships Langer & Rodin (1976) study The...
  • Children & Families Division Director Of Children and

    Children & Families Division Director Of Children and

    Parr / Sutton CC Area Service Manager - West Sally Price ... Statutory Team South East Team Manager Caroline Watts Head of Operational Services Jean Spencer Operational Manager Damien Fitzsimmons Assessment and Statutory Team North East Team Manager Suzanne Maclachlan...
  • Canadian Bioinformatics Workshops Contains material by Wyeth

    Canadian Bioinformatics Workshops Contains material by Wyeth

    The biochemical reality is far more complex, particularly in the cells of metazoan organisms. Regulation can be considered at three levels: (1) chromatin/DNA structure, (2) interactions between multiple TFs and (3) transcription initiation. Most of the tutorial presentation will address...
  • Sylvia Plath

    Sylvia Plath

    Lying in bed at night the speaker describes the soothing sounds of the baby sleeping in a cot nearby. The images and metaphors have lost their coldness and seem more tender. The fragility of the child is evoked not as...