KIM3203 (contd)

KIMIA SEBATIAN
KARBONIL
29 SEPTEMBER 2013

Acetals Formation
An alcohol acts as the nucleophile instead of
water.

2 equiv

2 equiv

SKAM26.Unimamail.com
R

R = H or Alkyl

Notice that the reaction is under equilibrium and

that it is acid catalyzed.

7 -2

Acetals Formation

Common acid :-

p-toluenesulfonic acid (TsOH)

Sulfuric acid

[H+] = acid is catalyst

7 -3

Acetals Formation (Part 1)

The mechanism for acetal formation can be divided into
two parts, the first of which is addition of one
equivalent of alcohol to form the hemiacetal.

Hemiacetal

7 -4

Acetals Formation (Part 2)

Convert the hemiacetal
into an acetal

7 -5

Mechanism

7 -6

Acetals Formation
Aldehydes

Ketone

7 -7

Acetals Equilibrium Control

Acetals can be attached and removed fairly easily.

Example:

Both the forward and reverse reactions are acid

catalyzed.

7 -8

Acetals- Protecting Groups

protecting groups for aldehydes and ketones.
Suppose we wish to selectively reduce the ester to an
alcohol in compound A, leaving the ketone untouched.
Because ketones are more readily reduced, methyl-5hydroxyhexanoate is formed instead.
To solve this problem, we can use a protecting group to
block the more reactive ketone carbonyl.

ProtectionDeprotection Process
The overall process requires three steps.
[1] Protect the interfering functional groupthe ketone
carbonyl.
[2] Carry out the desired reaction.
[3] Remove the protecting group.

10

Acetals Protecting Groups

Fill in necessary reagents or intermediates.

711

Acetals Protecting Groups

Fill in necessary reagents or intermediates.

712

ANSWER

713

Cyclic Hemiacetals
Cyclic hemiacetals containing five- and six-membered
rings are stable compounds that are readily isolated.

14

Formation of Cyclic Hemiacetals

Cyclic hemiacetals are formed by intramolecular
cyclization of hydroxy aldehydes.

15

Acid-Catalyzed Hemiacetal Formation

Hemiacetal formation is catalyzed by both acid and base.

16

Intramolecular Hemiacetal Formation

Intramolecular cyclization of a hydroxy aldehyde forms a
hemiacetal with a new stereogenic center, so that an
equal amount of two enantiomers results.

Cyclic hemiacetals can be converted to acetals by

treatment with an alcohol and acid.

17

Intramolecular Hemiacetal Formation

18

Cyclic Hemiacetals
In the conversion of hemiacetals to acetals, the overall
result is the replacement of the hemiacetal OH group
by an OCH3 group.
Thus, when a compound with both an alcohol OH and a
hemiacetal OH is treated with an alcohol and acid, only
the hemiacetal OH reacts to form the acetal.

19

Nucleophilic Addition of R
Treatment of an aldehyde or ketone with either an
organolithium (RLi) or Grignard reagent (RMgX)
followed by water forms a 1, 2, or 3alcohol containing
a new CC bond.

Nucleophilic addition of the carbanion-like species

occurs via a two-step mechanism.

20

Grignard Example
O
H
O
O

1) BrMg
3 equivalents
2) dilute HCl (aq)

Identify the nucleophile.

Will the reaction be more effective under acidic or under
basic conditions? WHY?
Show a complete mechanism (Mechanism 20.10). Three
equivalents of the Grignard are necessary.
Analyze the reversibility or irreversibility of each step.
Describe necessary experimental conditions.
Why are there two steps in the reaction?

Nucleophilic Addition of CN
Treatment of an aldehyde or ketone with NaCN and a
strong acid such as HCl adds the elements of HCN
across the CO bond, forming a cyanohydrin.
The mechanism involves the usual two steps of
nucleophilic additionnucleophilic attack followed by
protonation.

22

Hydrolysis of Cyanohydrins
Cyanohydrins can be reconverted to carbonyl
compounds by treatment with base.
This process is just the reverse of the addition of
HCN: deprotonation followed by elimination of CN.

The cyano group of a cyanohydrin is readily

hydrolyzed to a carboxy group by heating with
aqueous acid or base.

23

Wittig Reaction
The Wittig reaction uses a carbon nucleophile (the Wittig
reagent) to form alkenesthe carbonyl group is
converted to a C=C.

24

Wittig Reagents
is an organophosphorus reagent.
A typical Wittig reagent has a phosphorus atom
bonded to three phenyl groups, plus another alkyl
group that bears a negative charge.

25

 A Wittig reagent is an ylide, a species that contains two

oppositely charged atoms bonded to each other, with
both atoms having octets.
Phosphorus ylides are also called phosphoranes.
Formation of an Ylide

26

Synthesis of Wittig Reagents

Wittig reagents are synthesized by a two-step procedure.

27

Wittig Reagents

28

Wittig Reaction

The Wittig mechanism

The formation of the especially stable

triphenylphoshine oxide drives the equilibrium
forward.
20 29

Comparison of Alkene Formation Methods

Addition of a Grignard reagent followed by dehydration
gives a mixture of products with the desired compound
being the minor product.

Using the Wittig reaction to achieve the same synthesis

gives only the desired compound.

30

IMINES

31

Formation of Imines
Amines are classified as 1, 2, or 3 by the number of
alkyl groups bonded to the nitrogen atom.

Treatment of an aldehyde or a ketone with a 1 amine

affords an imine (also called a Schiff base).

32

Imine Properties
Because the N atom of an imine is surrounded by three
groups (two atoms and a lone pair), it is sp2 hybridized,
making the CNR bond angle 120, (not 180).
Imine formation is fastest when the reaction medium is
weakly acidic (pH 45).

33

Imine formation

20 34

Role of Acidity in Imine Formation

In imine formation, mild acid is needed for protonation
of the hydroxy group to form a good leaving group.
Under strongly acidic conditions, the reaction rate
decreases because the amine nucleophile is protonated.
With no free electron pair, it is no longer a nucleophile,
and so nucleophilic addition cannot occur.

35

Formation of Enamines
A 2 amine reacts with an aldehyde or ketone to give an
enamine.
Enamines have a nitrogen atom bonded to a CC double
bond.

36

37

Formation of Imines vs. Enamines

38

Hydrolysis of Imines and Enamines

Because imines and enamines are formed by a
reversible set of reactions, both can be converted back
to carbonyl compounds by hydrolysis with mild acid.
The is the exact reverse of the mechanismmechanism
of hydrolysis written for formation of imines and
enamines.

39

Primary Amine Nucleophiles vs. Secondary

Amine Nucleophiles
A proton transfer alleviates
the +1 charge in both
mechanisms. The difference
occurs in the LAST step.

For 1 amines (Mechanism 20.6):

the NITROGEN atom loses a
proton directly.
For 2 amines (Mechanism 20.7):
a neighboring CARBON atom
loses a proton.

20 40

Wolff-Kishner Reduction

Reduction of a carbonyl to an alkane:

20 41

Wolff-Kishner Reduction

In general, carbanions are unstable and reluctant

to form.

20 42

Mechanism Strategies

Note the many similarities between the acid catalyzed

mechanisms we have discussed:

Carbonyl is protonated first:




Makes the carbonyl more electrophilic

Avoids negative formal charge on the intermediate

Avoid high energy intermediate with two formal charges

Acid protonates leaving group so that it is stable and neutral
upon leaving
Last step of mechanism involves a proton transfer forming a
neutral product

Overall: under acidic conditions, reaction

species should either be neutral or have a +1
formal charge.
20 43

Mechanism Strategies Sulfur

Nucleophiles

Under acidic conditions, thiols react nearly the

same as alcohols. Examples:

20 44

Mechanism Strategies Alternative to

Wolff-Kishner

Conditions to convert a ketone into an alkane:

1. A thioacetal is formed via an acid catalyzed

nucleophilic addition mechanism.
2. Raney Ni transfers H2 molecules to the thioacetal
converting it into an alkane.

20 45

THE END..

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