Aldehyde & Ketone (Compatibility Mode)

4/26/2016
Aldehydes and Ketones
Based on McMurrys Organic Chemistry, 6th edition

2003 Ronald Kluger
Department of Chemistry
University of Toronto
Based on McMurry, Organic Chemistry, Chapter 1

19, 6th edition, (c) 2003
Carbonyl Compounds
2
Based on McMurry, Organic Chemistry, Chapter
1
4/26/2016

n Aldehydes and ketones are characterized by the the
carbonyl functional group (C=O)
n The compounds occur widely in nature as
intermediates in metabolism and biosynthesis
n They are also common as chemicals, as solvents,
monomers, adhesives, agrichemicals and
pharmaceuticals

1. Naming Aldehydes and Ketones
n Aldehydes are named by replacing the terminal -e of

the corresponding alkane name with al
n The parent chain must contain the CHO group
n The CHO carbon is numbered as C1

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Nomenclature of Aldehydes

Naming Ketones
n Replace the terminal -e of the alkane name with one
n Parent chain is the longest one that contains the
ketone group
n Numbering begins at the end nearer the carbonyl
carbon

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Nomenclature of Ketones

Naming Aldehydes and Ketones

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Ketones with Common Names

Ketones and Aldehydes as Substituents

n The RC=O as a substituent is an acyl group is used
with the suffix -yl from the root of the carboxylic acid
n CH3CO: acetyl; CHO: formyl; C6H5CO: benzoyl
n The prefix oxo- is used if other functional groups are
present and the doubly bonded oxygen is labeled as a
substituent on a parent chain
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Carbonyl Structure
n Carbon is sp2 hybridized.
n C=O bond is shorter, stronger, and more
polar than C=C bond in alkenes.


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2. Preparation of Aldehydes and Ketones

n Preparing Aldehydes
n Oxidize primary alcohols using pyridinium
chlorochromate
n Reduce an ester with diisobutylaluminum
hydride (DIBAH)
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Preparing Ketones
n Oxidize a 2 alcohol
n Many reagents possible: choose for the specific
situation (scale, cost, and acid/base sensitivity)

Ketones from Ozonolysis

n Ozonolysis of alkenes yields ketones if one of the
unsaturated carbon atoms is disubstituted

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Aryl Ketones by Acylation

n FriedelCrafts acylation of an aromatic ring with an
acid chloride in the presence of AlCl3 catalyst

Methyl Ketones by Hydrating Alkynes

n Hydration of terminal alkynes in the presence of Hg2+
(catalyst)

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3. Oxidation of Aldehydes and Ketones

n CrO3 in aqueous acid oxidizes aldehydes to
carboxylic acids efficiently
n Silver oxide, Ag2O, in aqueous ammonia (Tollens
reagent) oxidizes aldehydes (no acid)
23
Hydration of Aldehydes
n Aldehyde oxidations occur through 1,1-diols
(hydrates)
n Reversible addition of water to the carbonyl group
n Aldehyde hydrate is oxidized to a carboxylic acid by
usual reagents for alcohols

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Ketones Oxidize with Difficulty

n Undergo slow cleavage with hot, alkaline KMnO4
n CC bond next to C=O is broken to give carboxylic
acids
n Reaction is practical for cleaving symmetrical ketones

4. Nucleophilic Addition Reactions of

n Nu- approaches 45 to the plane of C=O and adds
to C
n A tetrahedral alkoxide ion intermediate is produced
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Nucleophiles
n Nucleophiles can be negatively charged ( : Nu-) or
neutral ( : Nu) at the reaction site
n The overall charge on the nucleophilic species is not
considered

5. Relative Reactivity of Aldehydes

and Ketones
n Aldehydes are generally more reactive than ketones
in nucleophilic addition reactions
n The transition state for addition is less crowded and
lower in energy for an aldehyde (a) than for a ketone
(b)
n Aldehydes have one large substituent bonded to the
C=O: ketones have two

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Electrophilicity of Aldehydes and

Ketones
n Aldehyde C=O is more polarized than ketone C=O
n As in carbocations, more alkyl groups stabilize +
character
n Ketone has more alkyl groups, stabilizing the C=O
carbon inductively
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Reactivity of Aromatic Aldehydes

n Less reactive in nucleophilic addition reactions than
aliphatic aldehydes
n Electron-donating resonance effect of aromatic ring
makes C=O less reactive electrophilic than the
carbonyl group of an aliphatic aldehyde
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6. Nucleophilic Addition of H2O:

Hydration
n Aldehydes and ketones react with water to yield 1,1-
diols (geminal (gem) diols)
n Hydration is reversible: a gem diol can eliminate
water

Relative Energies
n Equilibrium generally favors the carbonyl compound
over hydrate for steric reasons
n Acetone in water is 99.9% ketone form
n Exception: simple aldehydes
n In water, formaldehyde consists is 99.9% hydrate
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Base-Catalyzed Addition of Water

n Addition of water is catalyzed by
both acid and base
n The base-catalyzed hydration
nucleophile is the hydroxide ion,
which is a much stronger
nucleophile than water

Acid-Catalyzed Addition of Water

n Protonation of C=O makes it
more electrophilic
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Addition of H-Y to C=O

n Reaction of C=O with H-Y, where Y is
electronegative, gives an addition product (adduct)
n Formation is readily reversible

7. Nucleophilic Addition of HCN:

Cyanohydrin Formation
n Aldehydes and unhindered ketones react with HCN
to yield cyanohydrins, RCH(OH)CN

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Mechanism of Formation of
Cyanohydrins
n Addition of HCN is reversible and base-catalyzed,
generating nucleophilic cyanide ion, CN
n Addition of CN- to C=O yields a tetrahedral
intermediate, which is then protonated

Uses of Cyanohydrins
n The nitrile group ( CN) can be reduced with LiAlH4
to yield a primary amine (RCH2NH2)
n Can be hydrolyzed by hot acid to yield a carboxylic
acid

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Next


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8. Nucleophilic Addition of Grignard Reagents and

Hydride Reagents: Alcohol Formation
n Treatment of aldehydes or ketones with Grignard

reagents yields an alcohol
n Nucleophilic addition of the equivalent of a carbon
anion, or carbanion. A carbonmagnesium bond is
strongly polarized, so a Grignard reagent reacts for all
practical purposes as R : - MgX +.
43
Mechanism of Addition of Grignard

Reagents
n Complexation of C=O by Mg2+, Nucleophilic addition
of R : -, protonation by dilute acid yields the neutral
alcohol
n Grignard additions are irreversible because a
carbanion is not a leaving group

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Hydride Addition
n Convert C=O to CH-OH
n LiAlH4 and NaBH4 react as donors of hydride ion
n Protonation after addition yields the alcohol

9. Nucleophilic Addition of Amines: Imine

and Enamine Formation
RNH2 adds to C=O to form imines, R2C=NR (after loss
of HOH)
R2NH yields enamines, R2N CR=CR2 (after loss of
HOH)
(ene + amine = unsaturated amine)

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Mechanism of Formation of Imines

n Primary amine adds to C=O
n Proton is lost from N and adds to O to yield a neutral
amino alcohol (carbinolamine)
n Protonation of OH converts into water as the leaving
group
n Result is iminium ion, which loses proton
n Acid is required for loss of OH too much acid blocks
RNH2
Note that overall reaction is substitution of RN for O

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Imine Derivatives
n Addition of amines with an atom containing a lone
pair of electrons on the adjacent atom occurs very
readily, giving useful, stable imines
n For example, hydroxylamine forms oximes and 2,4-
dinitrophenylhydrazine readily forms 2,4-
dinitrophenylhydrazones

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Enamine Formation
n After addition of R2NH, proton is lost from adjacent
carbon
R R R
R R R R R
O
O NH H2O N
HO +
+ R2 NH N H N C
C + H3 O+
C H C C
C C H C
H H C C H
H H H H


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10. Nucleophilic Addition of Hydrazine: The

WolffKishner Reaction
n Treatment of an aldehyde or ketone with hydrazine,

H2NNH2 and KOH converts the compound to an
alkane
n Originally carried out at high temperatures but with
dimethyl sulfoxide as solvent takes place near room
temperature
53

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11. Nucleophilic Addition of Alcohols:

Acetal Formation
n Two equivalents of ROH in the presence of an acid
catalyst add to C=O to yield acetals, R2C(OR)2
n These can be called ketals if derived from a ketone

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Formation of Acetals
n Alcohols are weak nucleophiles but acid promotes
addition forming the conjugate acid of C=O
n Addition yields a hydroxy ether, called a hemiacetal
(reversible); further reaction can occur
n Protonation of the OH and loss of water leads to an
oxonium ion, R2C=OR+ to which a second alcohol
adds to form the acetal

Uses of Acetals
n Acetals can serve as protecting groups for aldehydes
and ketones
n It is convenient to use a diol, to form a cyclic acetal
(the reaction goes even more readily)

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12. Nucleophilic Addition of Phosphorus Ylides:

The Wittig Reaction
n The sequence converts C=O is to C=C
n A phosphorus ylide adds to an aldehyde or ketone to
yield a dipolar intermediate called a betaine
n The intermediate spontaneously decomposes
through a four-membered ring to yield alkene and
triphenylphosphine oxide, (Ph)3P=O
n Formation of the ylide is shown below
59
Uses of the Wittig Reaction

n Can be used for monosubstituted, disubstituted, and
trisubstituted alkenes but not tetrasubstituted alkenes
The reaction yields a pure alkene of known structure
n For comparison, addition of CH3MgBr to
cyclohexanone and dehydration with, yields a mixture
of two alkenes
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Mechanism of the Wittig Reaction
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13. The Cannizzaro Reaction:

Biological Reductions
n The adduct of an aldehyde and OH- can transfer
hydride ion to another aldehyde C=O resulting in a
simultaneous oxidation and reduction
(disproportionation)
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The Biological Analogue of the

Canizzaro Reaction
n Enzymes catalyze the reduction of aldehydes and ketones using
NADH as the source of the equivalent of H-
n The transfer resembles that in the Cannizzaro reaction but the
carbonyl of the acceptor is polarized by an acid from the
enzyme, lowering the barrier
Enzymes are chiral

and the reactions are
stereospecific. The
stereochemistry
depends on the
particular enzyme
involved.

14. Conjugate Nucleophilic Addition to a,b-

Unsaturated Aldehydes and Ketones
n A nucleophile
can add to the
C=C double
bond of an a,b-
unsaturated
aldehyde or
ketone
(conjugate
addition, or 1,4
addition)
n The initial
product is a
resonance-
stabilized enolate
ion, which is then
protonated Based on McMurry, Organic Chemistry, Chapter 64
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Conjugate Addition of Amines

n Primary and secondary amines add to a, b-
unsaturated aldehydes and ketones to yield b-amino
aldehydes and ketones


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Conjugate Addition of Alkyl Groups:

Organocopper Reactions
n Reaction of an a, b-unsaturated ketone with a lithium
diorganocopper reagent
n Diorganocopper (Gilman) reagents from by reaction
of 1 equivalent of cuprous iodide and 2 equivalents of
organolithium
n 1, 2, 3alkyl, aryl and alkenyl groups react but not
alkynyl groups

Mechanism of Alkyl Conjugate

Addition
n Conjugate nucleophilic addition of a diorganocopper
anion, R2Cu-, an enone
n Transfer of an R group and elimination of a neutral
organocopper species, RCu

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15. Biological Nucleophilic Addition

Reactions
n Example: Many enzyme reactions involve pyridoxal phosphate
(PLP), a derivative of vitamin B6, as a co-catalyst
n PLP is an aldehyde that readily forms imines from amino groups
of substrates, such as amino acids
n The imine undergoes a proton shift that leads to the net
conversion of the amino group of the substrate into a carbonyl
group

16. Spectroscopy of Aldehydes and

Ketones
n Infrared Spectroscopy
n Aldehydes and ketones show a strong C=O peak
1660 to 1770 cm-1
n aldehydes show two characteristic CH absorptions
in the 2720 to 2820 cm-1 range.

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C=O Peak Position in the IR Spectrum

n The precise position of the peak reveals the
exact nature of the carbonyl group
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NMR Spectra of Aldehydes

n Aldehyde proton signals are at d 10 in 1H NMR -
distinctive spinspin coupling with protons on the
neighboring carbon, J 3 Hz

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Protons on Carbons Adjacent to C=O

n Slightly deshielded and normally absorb near d 2.0 to
d2.3
n Methyl ketones always show a sharp three-proton
singlet near d 2.1

13C NMR of C=O

n C=O signal is at d 190 to d 215
n No other kinds of carbons absorb in this range

19, 6th edition, (c) 2003 74
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Mass Spectrometry McLafferty

Rearrangement
n Aliphatic aldehydes and ketones that have hydrogens
on their gamma (g) carbon atoms rearrange as shown

Mass Spectroscopy: a-Cleavage

n Cleavage of the bond between the carbonyl group
and the a carbon
n Yields a neutral radical and an oxygen-containing
cation

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Enantioselective Synthesis
n When a chiral product is formed achiral reagents, we get both
enantiomers in equal amounts - the transition states are mirror
images and are equal in energy
n However, if the reaction is subject to catalysis, a chiral catalyst
can create a lower energy pathway for one enantiomer - called
an enantionselective synthesis
n Reaction of benzaldehyde with diethylzinc with a chiral titanium-
containing catalyst, gives 97% of the S product and only 3% of
the R

Summary
n Aldehydes are from oxidative cleavage of alkenes, oxidation of 1
alcohols, or partial reduction of esters
n Ketones are from oxidative cleavage of alkenes, oxidation of 2
alcohols, or by addition of diorganocopper reagents to acid chlorides.
n Aldehydes and ketones are reduced to yield 1 and 2 alcohols ,
respectively
n Grignard reagents also gives alcohols
n Addition of HCN yields cyanohydrins
n 1 amines add to form imines, and 2 amines yield enamines
n Reaction of an aldehyde or ketone with hydrazine and base yields an
alkane
n Alcohols add to yield acetals
n Phosphoranes add to aldehydes and ketones to give alkenes (the
Wittig reaction)
n ab-Unsaturated aldehydes and ketones are subject to conjugate
addition (1,4 addition)

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Thank You

A Note on the Word Betaines

n The term betaines is an extension from a specific substance (betaine)
that has permanent + and charges (as in a zwitterion) that cannot be
neutralized by proton transfers (as in normal amino acids). Webster's
Revised Unabridged Dictionary lists: Betaine \Be"ta*ine\, n. [From beta,
generic name of the beet.] (Chem.) A nitrogenous base, {C5H11NO2},
produced artificially, and also occurring naturally in beet-root molasses
and its residues. The listed pronunciation indicates it has the exact
same emphasis as cocaine.
n Cocaine \Co"ca*ine\, n. (Chem.) A powerful alkaloid, {C17H21NO4},
obtained from the leaves of coca
n So if you say co-ca-een (as this dictionary suggests) then you would
also say bee-ta-een. If you sat co-cayn then say beet-ayn.
n Whatever you say, the beta in betaine refers to beets and not a
letter in the Greek alphabet. There have been a lot of wagers on this
over the years.

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Aldehydes and Ketones

Based on McMurrys Organic Chemistry, 6th edition

Based on McMurry, Organic Chemistry, Chapter 1

Aldehydes and Ketones

Based on McMurry, Organic Chemistry, Chapter 3

1. Naming Aldehydes and Ketones

n Aldehydes are named by replacing the terminal -e of

Based on McMurry, Organic Chemistry, Chapter 4

Based on McMurry, Organic Chemistry, Chapter 5

Based on McMurry, Organic Chemistry, Chapter 6

Based on McMurry, Organic Chemistry, Chapter 7

Naming Aldehydes and Ketones

Based on McMurry, Organic Chemistry, Chapter 8

Ketones with Common Names

Based on McMurry, Organic Chemistry, Chapter 9

Ketones and Aldehydes as Substituents

Based on McMurry, Organic Chemistry, Chapter 11

Based on McMurry, Organic Chemistry, Chapter 12

Based on McMurry, Organic Chemistry, Chapter 13

Based on McMurry, Organic Chemistry, Chapter 14

Based on McMurry, Organic Chemistry, Chapter 15

Based on McMurry, Organic Chemistry, Chapter 16

Based on McMurry, Organic Chemistry, Chapter 17

2. Preparation of Aldehydes and Ketones

Based on McMurry, Organic Chemistry, Chapter 19

Ketones from Ozonolysis

Based on McMurry, Organic Chemistry, Chapter 20

Aryl Ketones by Acylation

Based on McMurry, Organic Chemistry, Chapter 21

Methyl Ketones by Hydrating Alkynes

Based on McMurry, Organic Chemistry, Chapter 22

3. Oxidation of Aldehydes and Ketones

Based on McMurry, Organic Chemistry, Chapter 24

Ketones Oxidize with Difficulty

Based on McMurry, Organic Chemistry, Chapter 25

4. Nucleophilic Addition Reactions of

Based on McMurry, Organic Chemistry, Chapter 27

5. Relative Reactivity of Aldehydes

Based on McMurry, Organic Chemistry, Chapter 28

Electrophilicity of Aldehydes and

Reactivity of Aromatic Aldehydes

6. Nucleophilic Addition of H2O:

Based on McMurry, Organic Chemistry, Chapter 31

Base-Catalyzed Addition of Water

Based on McMurry, Organic Chemistry, Chapter 33

Acid-Catalyzed Addition of Water

Addition of H-Y to C=O

Based on McMurry, Organic Chemistry, Chapter 35

7. Nucleophilic Addition of HCN:

Based on McMurry, Organic Chemistry, Chapter 36

Based on McMurry, Organic Chemistry, Chapter 37

Based on McMurry, Organic Chemistry, Chapter 38

Based on McMurry, Organic Chemistry, Chapter 39

Based on McMurry, Organic Chemistry, Chapter 40

Based on McMurry, Organic Chemistry, Chapter 41

Based on McMurry, Organic Chemistry, Chapter 42

8. Nucleophilic Addition of Grignard Reagents and

n Treatment of aldehydes or ketones with Grignard

Mechanism of Addition of Grignard

Based on McMurry, Organic Chemistry, Chapter 44

Based on McMurry, Organic Chemistry, Chapter 45

9. Nucleophilic Addition of Amines: Imine