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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

BB

Chloral hydrate

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 additionelimination


reaction.

Reactions of Aldehydes and Ketones with Secondary Amines

This is an acid-catalyzed reversible nucleophilic additionelimination


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


carbonmetal 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 ,-Unsaturated Aldehydes/Ketones


The -carbon of an ,-unsaturated carbonyl compound is an electrophilic site.

Nucleophilic Addition to ,-Unsaturated Aldehydes/Ketones

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Nucleophilic Addition to ,-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 ,-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

Fehlings 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 -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 -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 -Substitution Reaction of Carbonyl Compounds


An enol is a better nucleophile than an alkene.

Carbonyl compounds that form enol undergo substitution reactions at the


-carbon: an -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.

-Substitution Reaction of Carbonyl Compounds


Mechanism for base-catalyzed -substitution:

Mechanism for acid-catalyzed -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 -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 -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 -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 -Carbon in Biological Systems


A Biological Aldol Condensation

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