Electrophilic Substitution

▪ The -H is weakly acidic;

▪ Enol (or enolate) formation makes the -C react like a Nu: with an
electrophile (E+); therefore:
▪ Electrophilic substitution occurs at this position

Nu:

-H is substituted by
an E (electrophile)

Nu:
 α-Halogenation of Aldehydes and Ketones
▪ Aldehydes and ketones can be halogenated at their α- positions by
reaction with Cl2, Br2, or I2 as E+ in acidic solution:

stops at mono-
substituted product
Mechanism of Acid-Catalyzed Halogenation

less basic
X
another round of substitution?

▪ Under acidic conditions, only one -hydrogen is substituted for

a bromine, IF you are using 1 eq. of Br2.
▪ Reason: Br- is electron-withdrawing, decreases the basicity of
the oxygen on the C=O, makes protonation more difficult.
 α-Halogenation of Aldehydes and Ketones
▪ Aldehydes and ketones can also be halogenated at their α- positions by
reaction with Cl2, Br2, or I2 in basic solution:

• CANNOT stop at the mono-substituted product;

• Use excess of Br2 to obtain fully substituted product.

• An even more reactive

species;
• This H is even more
acidic

▪ Reason: Br- is electron-withdrawing, increases the acidity of

the α-H, thereby making the next deprotonation easier.
α-Halogenation of Aldehydes and Ketones

acidic basic

NaOH Br Br

NaOH

Use 1 eq. of Cl2 or Br2 Use excess of Cl2 or Br2

Elimination Reactions of -Bromo-ketones
▪ -Bromo ketones can be dehydrobrominated by base treatment
to yield , -unsaturated ketones (which is quite stable)

X strong
base

Br2 radical reaction

hv selective for 3º H
 Haloform (CHX3) Reaction
▪ A tri-halo compound is formed from a methyl ketone by
electrophilic substitution;
▪ The product is cleaved by hydroxide (basic condition) with -CX3
as a leaving group.

• -CX
3is a relatively good leaving
group (X groups stabilizes the
negative charge).

• needs to be -CH3, other alkyl groups haloform

(e.g. –CH2R) do not work very well;
• since it has less number of halogens
to stabilize the carbon anion.
 Alpha Bromination of Carboxylic Acids:
The Hell–Volhard–Zelinski (HVZ) Reaction

▪ Carboxylic acids do NOT react well with Br2

→ With base, the R-COOH becomes R-COO-, thus no enolate can be
formed;

with base an enolate with 2

negative charges,
too unstable
 Alpha Bromination of Carboxylic Acids:
The Hell–Volhard–Zelinski (HVZ) Reaction

▪ Carboxylic acids do NOT react well with Br2

→ With base, the R-COOH becomes R-COO-, thus no enolate can be
formed;
→ With acid, the basicity of the oxygen of C=O is reduced (due to the
electron-withdrawing effect of the 2nd oxygen) and cannot be easily
protonated; thus, it is also difficult to generate the enol.

not sufficiently basic to

be protonated
X

with acid with base an enolate with 2

negative charges,
enolate too unstable
 Alpha Bromination of Carboxylic Acids:
The Hell–Volhard–Zelinski (HVZ) Reaction
▪ Carboxylic acids can be brominated by a mixture of Br2 and PBr3
(HVZ reaction)

deprotonation and
hydrolysis back to acid
converted to acyl bromide

▪ Br is much less EN than O;

▪ The oxygen of the C=O is more basic and can be
protonated more easily;
▪ The enol can be formed.
α-Halogenation of Aldehydes and Ketones

acidic basic

NaOH Br Br

NaOH

Use 1 eq. of Cl2 or Br2 Use excess of Cl2 or Br2

HVZ reaction haloform reaction

Use 1 eq. of Cl2 or Br2 Use excess of Cl2 or Br2

 Reagents for Enolate Formation
electrophiles

• Only a small amount of enolate ion is formed

→ HO- is not basic enough.

or NaH

▪ Sodium hydride (NaH) or lithium diisopropylamide

(LDA) are strong enough to form the enolate
 Reagents for Enolate Formation
• The two bulky isopropyl groups make the N highly sterically hindered;
• LDA is a poor Nu: for steric reason;
• LDA is a good base (H is small enough to be captured by N);
• LDA can be used for deprotonation but will NOT attack C=O directly.

X
H

▪ Sodium hydride (NaH) or lithium diisopropylamide (LDA) are

strong enough to form the enolate
 Reagents for Enolate Formation
• The two bulky isopropyl groups make the N highly sterically hindered;
• LDA is a poor Nu: for steric reason;
• LDA is a good base (H is small enough to access N);
• LDA can be used for deprotonation but will not attack C=O directly.

NaH

▪ Sodium hydride (NaH) or lithium diisopropylamide (LDA) are

strong enough to form the enolate
 Alkylating an Enolate Ion

alkyl halide
enolate (nucleophile) (electrophile)

• This method can be used to alkylate the α-carbon of:

ketones, esters, and nitriles.

→ Aldehydes, however, rarely give high yields of desired alkylation

products (other reaction possibilities we will discuss later)
 Constraints on Enolate Alkylation

alkyl halide
enolate (nucleophile) (electrophile)

▪ SN2 reaction: R should be primary, methyl, allylic or benzylic R-X

▪ Secondary halides react poorly;
▪ Tertiary halides do not react at all because of the competing
elimination reaction.
Direct Alkylation with LDA
Two Products can be Formed if the
Ketone is not Symmetrical.
major
 Kinetic and Thermodynamic Products
the kinetic the thermodynamic
enolate enolate
less hindered site, this enolate is more stable
deprotonation at this site (more substituted C=C)
is faster
-OH
LDA

• The kinetic product is the major product when using strong, bulky
base (e.g. LDA)
• The thermodynamic product is the major product when using weak,
unhindered base (e.g. HO−)
 Practice

• what are the major products of the reactions of

these substrates with LDA or NaOH?
 Practice

-OH
LDA
-OH

-OH LDA LDA

-OH LDA -OH LDA

no reaction

• what are the major products of the reactions of

these substrates with LDA or NaOH?
 It is more than regioselectivity…

LDA -OH
1 eq. 1 eq. 1 eq.
1 eq. ~ 0.1% eq.

• How to form the thermodynamic enolate more efficiently?

• Answer: form an enol instead….

 Enolate/enol and Enamine
1 eq. 1 eq. 1 eq.
1 eq.

1 eq.
enolate as the Nu: enol as the Nu:

• Use enamine to obtain the thermodynamic enol

1 eq. ~1 eq.

this is a stable species,

1 eq. and it can be formed thermodynamic product
with high efficiency
 Enolate/enol and Enamine

• An additional step of hydrolysis in aqueous acid to

obtain the alkylation product and the amine

• Similar to LDA, alkylation of an aldehyde or a ketone using an

enamine yields the alkylated product

• But it is the thermodynamic product.

• An additional hydrolysis step is needed.

Kinetic and Thermodynamic Products

enamine formation/
LDA hydrolysis

strong basic condition mild acidic condition

 The Stork Reaction
▪ Enamine adds to an ,-unsaturated carbonyl acceptor
▪ The product is hydrolyzed to a 1,5-dicarbonyl compound

direct addition or conjugate

addition…???
α,β-Unsaturated Aldehydes and Ketones

Grignard reagent, hydride

Br-, CN-, HS-, RO-, RNH2

and Gilman reagent

enolate and enol

 The Stork Reaction
▪ Enamine adds to an ,-unsaturated carbonyl acceptor
▪ The product is hydrolyzed to a 1,5-dicarbonyl compound

X
▪ Direct addition of the enol is also
reversible; thus,

▪ C=C in the enamine prefers conjugate

addition.
 Forming the More Stable Enolate

C=C in the enolate also

prefers conjugate addition

• –OH or –OCH3 is used in these reactions;

• They form thermodynamically more stable enolates;
 Forming the More Stable Enolate

• –OH or –OCH3 is used in these reactions;

• They form thermodynamically more stable enolates;

1. These enolates are stable, so

weaker bases can be used (e.g.,
NaOH);

2. Also because of their stability, the

1,2-addition is reversible.

3. They prefer 1,4- conjugate

addition.
stable enolates
 Forming the More Stable Enolate

• –OH or –OCH3 is used in these reactions;

• They form thermodynamically more stable enolates;
▪ Another round of alkylation is
difficult, since the product is
already very crowded, the steric
hindrance is too high for further
reactions

stable enolates
 Michael Addition
• The definition of Michael addition is actually very broad:

donors

R-NH2, R-SH

acceptors
(an α,β-unsaturated system)
 Electrophilic Substitution
δ+
alkyl halide: R-Br (alkylation) ,-unsaturated system: Michael, Stork
halogens: Br-Br, Cl-Cl (halogenation) δ+ δ+
δ+

δ+

NaOH, CH3ONa, etc.

(for stabilized enolate)
LDA

aldol addition

2º amine
 Aldol Addition
C=C prefers conjugate addition

enolate X

Michael addition

carbonyl compounds can be both the

electrophile and nucleophile

• Aldol addition: one molecule of the carbonyl carbon is

an electrophile and the other is a nucleophile
 Aldol Addition

homodimerization:
 Aldol Addition
• Aldehyde:

▪ A small amount of base is used to generate a

small amount of enolate
▪ After the addition, the basic catalyst is
regenerated
• Ketone:

all steps are reversible.

 Aldol Addition

▪ Aldol reaction is reversible;

▪ The product is more sterically crowded than the reactant;
▪ Therefore… equilibrium favors the ketone/aldehyde...
Aldol Addition

how can we make the

aldol addition reaction
useful?

convert to a more stable product