Carbonyl functional groups in biology

Introduction
Several functional groups contain the carbonyl group
Group Biological occurence Group Biological occurence
O H

H OH O O NH2
HO
HO H HO O R'
H OH HO OH R N
H O
OH
H OH (hemiacetal form) amide
O O-
CH2OH O R N
H
R H glucose O
R O-
aldehyde carboxylate Gln at C-terminus of peptide
H O

OH O OH
Pi-O
O
R' R O
N
R O
pyridoxal phosphate OH
ester
monoacyl glycerol
CH2OH NH2
O HO OH N
O O N
O O OH O O
HO H H N
HO R' S N O P O P O N
N N O
H OH OH R S O- O-
R R' O
H H
O
ketone H OH thioester O OH
HO
(hemiketal form) O P O-
CH2OH Ac-S-CoA O-
fructose

Chapter 16 1 Chapter 16 2

In order to understand mechanisms, divide

 Structure of the Carbonyl Group
carbonyls into two groups
The carbonyl carbon is sp2 hybridized and is trigonal planar
No leaving group (Class 1):  All three atoms attached to the carbonyl group lie in one plane

O O

R H R R'
aldehyde ketone

 With leaving group (Class 2):

O O O O
R'
R Cl R O R R S
acyl chloride carboxylate anhydride thioester

O
O O
R'
R' R N
R O R OH H
ester carboxylic acid amide

Chapter 16 3 Chapter 16 4

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 The carbonyl group is polarized; there is substantial δ+ charge on OK…. Given the polarity of a carbonyl, how will it react
the carbon with a nucleophile??

O +
Nu-

Remember: Electronegativity trends from first year; these will

give you clues about reactivity

Chapter 16 5 Chapter 16 6

 Reactions of Carbonyl Compounds with Nucleophiles Let’s look at a typical nucleophile: Hydride
Carbonyl groups can undergo nucleophilic addition
 The nucleophile adds to the δ+ carbon
 The π electrons shift to the oxygen Sources of hydride (H-):
 The carbon becomes sp3 hybridized and therefore tetrahedral
 Hydride ions and carbanions are two examples of nucleophiles that react with the
carbonyl carbon
NaBH4 (sodium borohydride)
LiAlH4 (lithium aluminum hydride)

Reaction of an aldehyde and sodium borohydride to give a

primary alcohol.

O OH
1, NaBH4, ether
The formation of a tetrahedral intermediate is the first step in H H
many of the mechanisms you’ll see in this chapter (and others 2. H3O+ H
too!)

Chapter 16 7 Chapter 16 8

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 What is the mechanism?

Aldehydes and ketones (Class 1 carbonyls) react with nucleophiles

to give nucleophilic addition products.

Chapter 16 9 Chapter 16 10

What happens when we try this nucleophilic addition on a Class 2 Consider the mechanism….
carbonyl?
O O- O
H-
OCH3 OCH3 H + CH3O-
Let’s try the hydride addition on an ester: H

O
1, NaBH4, ether nucleophilic acyl substitution
OCH3 no reaction
2. H3O+
The aldehyde generated goes on to be reduced further to the
primary alcohol while the alkoxide gets protonated in the
NaBH4 not a strong enough reducing agent for esters
workup.
(explanation to come)… need LiAlH4
O O- OH
O OH H- H2O
1, LiAlH4, ether
H H H
OCH3 + CH3-OH H H
2. H3O+

H2O
How did this happen??? CH3O- CH3OH

Chapter 16 11 Chapter 16 12

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Reaction type #2 - Nucleophilic Acyl Substitutions
You’ll see these two mechanism throughout the course with a
(nucleophilic addition followed by elimination)
number variations on these themes. Important to remember:
many different reactions with essentially the same mechanism.
δ-

Reaction type #1 - Addition to aldehydes/ketones O O- - X: O
1st step is addition (nucleophilic attack) δ+
R X X R Nu
δ- Nu
O O- Nu
δ+
Nu
Nu
2nd step protonation

H+
O- OH

Nu Nu

Chapter 16 13 Chapter 16 14

Chapter 16
Aldehydes and Ketones I. Nucleophilic

Nomenclature of Aldehydes and Ketones (16.2)
Addition to the Carbonyl Group

Physical Properties (16.3)

Chapter 16 16

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Ch. 16.6 Ch. 16.4

 Relative Reactivity: Aldehydes versus Ketones
Synthesis of Aldehydes

Aldehydes are generally more reactive than ketones
 Aldehydes by Oxidation of 1o Alcohols
Primary alcohols are oxidized to aldehydes by PCC

Chapter 16 17 Chapter 16 18

Ch. 16.4 Ch. 16.4

Reduction to an aldehyde can be accomplished by using a more

Synthesis of Aldehydes reactive carboxylic acid derivatives such as an acyl chloride, ester
 Aldehydes by Reduction of Acyl Chlorides, Esters and or nitrile and a less reactive hydride source
 The use of a sterically hindered and therefore less reactive aluminum hydride
Nitriles reagent is important
Reduction of carboxylic acid to aldehyde is impossible to stop at
the aldehyde stage
 Aldehydes are much more easily reduced than carboxylic acids

Chapter 16 19 Chapter 16 20

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Ch. 16.4 Ch. 16.4

Acid chlorides react with lithium tri-tert-butoxyaluminum hydride

at low temperature to give aldehydes

Chapter 16 21 Chapter 16 22

Ch. 16.4 Ch. 16.5

Reduction of an ester to an aldehyde can be accomplished at low
Synthesis of Ketones (review - also see Ch. 8)
temperature using DIBAL-H
 As the carbonyl re-forms, an alkoxide leaving group departs  Ketones from Alkenes, Arenes, and 2o Alcohols
Ketones can be made from alkenes by ozonolysis

Chapter 16 23 Chapter 16 24

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Ch. 16.5 Ch. 16.6

(review - see
Nucleophilic Addition to the Carbonyl Groups

Synthesis of Ketones also Ch. 12)  (See also Chapter 12.1, and Introductory lecture)

Addition of a nucleophile to a carbonyl carbon occurs because of

the δ+ charge at the carbon
Ketones can be made from 2o alcohols by oxidation

Chapter 16 25 Chapter 16 26

Ch. 16.6 Ch. 16.6

Nucleophilic Addition to the Carbonyl Groups

An acid catalyst is used to facilitate reaction of weak nucleophiles
with carbonyl groups
Addition of strong nucleophiles such as hydride or Grignard  Protonating the carbonyl oxygen enhances the electrophilicity of the carbon

reagents result in formation of a tetrahedral alkoxide intermediate

 The carbonyl π electrons shift to oxygen to give the alkoxide
 The carbonyl carbon changes from trigonal planar to tetrahedral

Chapter 16 27 Chapter 16 28

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Ch. 16.6 Ch. 16.7

Addition of Water to Aldehydes or

Ketones
Dissolving aldehydes (or ketones) in water causes formation of an
equilibrium between the carbonyl compound and its hydrate
 The hydrate is also called a gem-diol (gem i.e. geminal, indicates the presence of
two identical substituents on the same carbon)

Chapter 16 29 Chapter 16 30

Ch. 16.7 Ch. 16.9

The equilibrum favors a ketone over its hydrate because the
The Addition of Hydrogen Cyanide
tetrahedral ketone hydrate is sterically crowded
Aldehydes and ketone react with HCN to form a cyanohydrin
 A catalytic amount of cyanide helps to speed the reaction

Chapter 16 31 Chapter 16 32

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Ch. 16.9 Ch. 16.9

The cyano group can be hydrolyzed or reduced

Reduction of a cyanohydrin produces a
 Hydrolysis of a cyanohydrin produces an α-
hydroxycarboxylic acid (Sec. 18.8H)
β-aminoalcohol

Chapter 16 33 Chapter 16 34

review - from Ch. 12 review - from Ch. 12

 Reaction of Grignard Reagents with Carbonyl

Compounds
Nucleophilic attack of Grignard reagents at carbonyl carbons is
the most important reaction of Grignard reagents
 Reaction of Grignard reagents with aldehydes and ketones yields a new carbon-
carbon bond and an alcohol

Chapter 16 35 Chapter 16 36

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Ch. 16.5 Ch. 16.7

 Ketones from Nitriles
The Addition of Alcohols: Hemiacetals and

Organolithium and Grignard reagents add to nitriles to form
ketones
Acetals
 Hemiacetals
An aldehyde or ketone dissolved in an alcohol will form an
equilibrium mixture containing the corresponding hemiacetal
 A hemiacetal has a hydroxyl and alkoxyl group on the same carbon
 Acylic hemiacetals are generally not stable, however, cyclic five- and six-
membered ring hemiacetals are

Chapter 16 37 Chapter 16 38

Ch. 16.7 Ch. 16.7

Hemiacetal formation is catalyzed by either acid or base  Acetals

An aldehyde (or ketone) in the presence of excess alcohol and an
acid catalyst will form an acetal
 Formation of the acetal proceeds via the corresponding hemiacetal
 An acetal has two alkoxyl groups bonded to the same carbon

Chapter 16 39 Chapter 16 40

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Ch. 16.7 Ch. 16.7

Acetal formation from ketones and simple alcohols is less

favorable than formation from aldehydes
 Formation of cyclic 5- and 6- membered ring acetals from ketones is, however,
favorable
 Such cyclic acetals are often used as protecting groups for aldehydes and
ketones
 These protecting groups can be removed using dilute aqueous acid

Acetals are stable when isolated and purified

Acetal formation is reversible
 An excess of water in the presence of an acid catalyst will hydrolyze an acetal to
the corresponding aldehyde (or ketone)

Chapter 16 41 Chapter 16 42

Ch. 16.7 Ch. 16.7

 Acetals as Protecting Groups  Thioacetals

Acetal protecting groups are stable to most reagents except Thioacetals can be formed by reaction of an aldehyde or ketone
aqueous acid with a thiol
Example: An ester can be reduced in the presence of a ketone  Thioacetals can be converted to CH2 groups by hydrogenation using a catalyst
such as Raney nickel
protected as an acetal  This sequence provides a way to remove an aldehyde or ketone carbonyl oxygen

(BF3 is a Lewis acid)

Chapter 16 43 Chapter 16 44

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