CHEM1280-Notes-1-11

CHEM1280: Introduction to Organic Chemistry & Biomolecules

1.12 Aldehydes and Ketones (Chapter 12, 13)  Structure of sedative chloral hydrate and nucleophilic addition of carbonyl groups  Nobel Prize in Chemistry 1912 and Grignard reagents  Testing glucose in urine and oxidative chemical tests for aldehydes  The synthesis of aspirin: Chemistry of enol and enolate Images used in the lecture notes are mainly from Bruice, P.Y.: Essential Organic Chemistry, 2nd Ed., Pearson Education Inc. 2010; Bruice, P.Y.: Organic Chemistry, 6th Ed., Pearson Education Inc. 2011.

Carbonyl Groups

 A carbonyl group: a carbon double bonded to an oxygen.

 Compounds containing carbonyl groups are called carbonyl compounds.  An acyl group consists of a carbonyl group attached to an alkyl or an aryl group.

Naturally Occurring Aldehydes and Ketones

progesterone a female sex hormone

testosterone a male sex hormone

Nomenclature of Aldehydes  The systematic name of an aldehyde is obtained by replacing the “e” at the end of the parent hydrocarbon with “al”. The position of the carbonyl carbon does not have to be designated because it always has the 1-position.  If the aldehyde group is attached to a ring, the aldehyde is named by adding “carbaldehyde” to the name of the cyclic compound.

Nomenclature of Ketones  The systematic name of a ketone is obtained by replacing the “e” at the end of the name of the parent hydrocarbon with “one”.  The chain is numbered in the direction that gives the carbonyl carbon the smaller number. The carbonyl is assumed to be at the 1-position in cyclic ketones.  Derived names are also frequently used for ketones: the substituents attached to the carbonyl group are cited in alphabetical order, followed by “ketone”.

Nomenclature of Ketones

Nomenclature If a compound has two functional groups, the one with the lower priority is indicated by its prefix:

Sedative Chloral Hydrate

Chloral water to hydrate, sedative drug.

reacts with form chloral which is a and hypnotic Chloral

名醫馮宜亮疑開錯藥 BB失去知覺

Chloral hydrate

馮宜亮處方予一名十三個月 大男嬰的藥水濃度超標三倍， 男嬰服後失去知覺。衞生署 建議立即停用馮宜亮處方的 水合氯醛藥水。 http://orientaldaily.on.cc

Reactions of Carbonyl Groups

Aldehydes and ketones undergo nucleophilic addition reactions because the carbonyl group is attached to a group that is too strong a base (H− or R−) to be eliminated under normal conditions.

Relative Reactivities of Carbonyl Compounds Electronic factor: an alkyl group is electron donating; Steric factor: the size of groups attached to the carbonyl. The partial positive charge on the carbonyl carbon of a ketone is smaller than that of an aldehyde.

Nucleophilic Addition of Aldehydes and Ketones

A reversible nucleophilic addition reaction if the nucleophile is a weak base.

Nucleophilic Addition of Aldehydes and Ketones

An irreversible nucleophilic addition reaction if the nucleophile is a strong base.

Reactions of Aldehydes and Ketones with O Nucleophiles

Water is a poor nucleophile, and the reaction can be accelerated by an acid catalyst because the acid makes the carbonyl carbon more susceptible to nucleophilic attack.

Addition of Water to Aldehydes and Ketones The extent to which an aldehyde or a ketone is hydrated in an aqueous solution depends on the substitutents attached to the carbonyl group.

Addition of Water to Aldehydes and Ketones  Electron-donating substitutents and bulky substituents decrease the percentage of hydrate present at equilibrium.  Electron-withdrawing substituents and small substituents increase the percentage of hydrate present at equilibrium.

Addition of Alcohols to Aldehydes Hemiacetal: the product formed when one equivalent of an alcohol adds to an aldehyde Acetal: the product formed when two equivalent of an alcohol adds to an aldehyde

Addition of Alcohols to Ketones

Hemiketal: the product formed when one equivalent of an alcohol adds to a ketone Ketal: the product formed when two equivalent of an alcohol adds to a ketone

Addition of Alcohols to Aldehydes and Ketones

An acid catalyst is required for the reaction to take place at a reasonable rate because an alcohol is a poor nucleophile.

Addition of Alcohols to Aldehydes and Ketones  Acetals and ketals can be isolated if the eliminated water is removed from the reaction mixture.  Acetals and ketals are stable at basic conditions, but can be hydrolyzed back to the aldehyde or ketone in an acidic aqueous solution.

Reactions of Aldehydes and Ketones with N Nucleophiles Formation of imine and enamine is reversible

Reactions of Aldehydes and Ketones with Primary Amines Mechanism for imine formation

This is an acid-catalyzed reversible nucleophilic addition–elimination reaction.

Reactions of Aldehydes and Ketones with Secondary Amines

This is an acid-catalyzed reversible nucleophilic addition–elimination reaction.

Reactions of Carbonyl Compounds with C Nucleophiles The addition of a carbon nucleophile to a carbonyl compound is a useful reaction that forms a new C-C bond.

 Organometallic compounds are organic compounds containing carbon–metal bonds, and are applied as carbon nucleophiles.  Organolithium compounds and organomagnesium compounds are two of the most common organometallic compounds.

Nobel Prize in Chemistry 1912

Victor Grignard 1871-1935 Nancy University, France

Paul Sabatier 1854-1941 Toulouse University, France

The Nobel Prize in Chemistry 1912 was divided equally between Victor Grignard "for the discovery of the so-called Grignard reagent” and Paul Sabatier "for his method of hydrogenating organic compounds in the presence of finely disintegrated metals”.

Grignard Reagents

Grignard reagents (RMgX) have a nucleophilic carbon because the carbon is bonded to an atom that is less electronegative than carbon. Grignard Reagents are prepared from alkyl halide, vinyl halide and aryl halides.

Grignard Reagents are strong bases.

Reactions of Aldehydes and Ketones with Grignard Reagents Grignard Reagents are used to prepare alcohols.

Reactions of Aldehydes and Ketones with Grignard Reagents Reaction Mechanism

The structure of the Grignard reagent can be varied.

Reactions of Aldehydes and Ketones with Grignard Reagents

The more reactive aldehyde is protected with the diol before reaction with the Grignard reagent.

Reactions of Aldehydes / Ketones with Hydride Nucleophiles LiAlH4 and NaBH4 act as if they were donors of hydride ion (H−), and the key step is a nucleophilic addition reaction.

Nucleophilic Addition to α,β-Unsaturated Aldehydes/Ketones The β-carbon of an α,β-unsaturated carbonyl compound is an electrophilic site.

Nucleophilic Addition to α,β-Unsaturated Aldehydes/Ketones

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Nucleophilic Addition to α,β-Unsaturated Aldehydes/Ketones  Nucleophiles that form unstable addition products form conjugated addition products, because the conjugate addition is not reversible.  Nucleophiles that form stable addition products can form direct addition products or conjugate addition products.

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Nucleophilic Addition to α,β-Unsaturated Aldehydes/Ketones

Testing Glucose in Urine and Oxidative Test for Aldehydes Two simple chemical tests can indicate the presence of the aldehyde function. In both tests, the aldehyde is oxidized to the carboxylic acid.

Images are from Vollhardt, K. P. C. and Schore, N. F.: Organic Chemistry: Structure and Function 5th Ed., W. H. Freeman, 2007 and http://www.sciencephoto.com

Testing Glucose in Urine and Oxidative Test for Aldehydes

Fehling’s test can be used to determine the presence of glucose in urine. The amount of Cu2O formed is proportional to the amount of reducing sugar present in the urine. http://www.petdiabetes.com

Synthesis of Aspirin: Chemistry of Enol and Enolate

Synthesis of aspirin from phenol

Acidity of α-Hydrogens of Aldehydes and Ketones

The anion is stabilized by resonance A hydrogen bonded to an sp3 hybridized carbon that is adjacent to a carbonyl carbon is much more acidic than hydrogens bonded to other sp3 hybridized carbons (pKa for ethane is ~ 60).

Acidity of α-Hydrogens of Carbonyl Compounds Esters are less acidic than aldehydes and ketones.

Keto-Enol Tautomers Tautomers are isomers that are in rapid equilibrium.

 For most ketones, the enol tautomer is much less stable than the keto tautomer.

 Phenol is unusual in that its enol tautomer is more stable than its keto tautomer because the enol tautomer is aromatic.

Enolization

The enolization of aldehydes and ketones are reversible and catalyzed by a base or an acid.

Enol and α-Substitution Reaction of Carbonyl Compounds An enol is a better nucleophile than an alkene.

Carbonyl compounds that form enol undergo substitution reactions at the α-carbon: an α-substitution reaction

An Enolate An enolate is an ambident nucleophile (with two nucleophilic sites)

 Which nucleophilic site (C or O) reacts with an electrophile depends on the electrophile and on the reaction condition.  Protonation occurs preferentially on the O site.  When the electrophile is something other than a proton, the C site is more likely the nucleophile because negatively charged carbon is a better nucleophile than oxygen.

α-Substitution Reaction of Carbonyl Compounds Mechanism for base-catalyzed α-substitution:

Mechanism for acid-catalyzed α-substitution:

Formation of Enolates Using a strong base, such as LDA, to form an enolate

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Alkylation of Enolates

 Alkylaltion of the α-carbon of a carbonyl compound is an important reaction because it gives a way to from a C-C bond. Because the alkylation is an SN2 reaction, it works best with primary alkyl halides and methyl halides.  Two different products can be formed if the ketone is not symmetrical. The relative amounts of the two products depend on the reaction conditions.

Aldol Additions

 Because of the relatively high reactivity of aldehydes in competing aldol addition reactions, aldehydes give low yields of α-alkylation products.  Aldol additions occur more slowly with ketones because ketones are less susceptible than aldehydes to attack by nucleophiles for steric reasons.

Aldol Additions

One molecule of a carbonyl compound acts as a nucleophile, and the other carbonyl compound acts as an electrophile.

Aldol Additions An aldol addition product loses water to form an aldol condensation product.

Conjugation stabilizes the dehydrated product.

The Mixed Aldol Addition

A crossed aldol addition that forms four products is not a synthetically useful reaction because the four products are difficult to separate.

The Mixed Aldol Addition  Primarily one product can be formed if one of the carbonyl compounds does not have any α-hydrogen.

 Primarily one product can be formed by using LDA to completely deprotonate one of the carbonyl compounds:

Intramolecular Aldol Additions 1,4-Diketones afford five-member rings:

1,5- and 1,7-diketones afford six-member rings:

Reactions at the α-Carbon in Biological Systems A Biological Aldol Condensation