LESSON 3

NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP

 Introduction to Aldehydes and Ketones
 General mechanism of nucleophilic addition reactions
 Oxygen nucleophiles
1. Addition of water
2. Addition of Alcohols
 Sulfur Nucleophiles
 Nitrogen Nucleophiles
1. Addition of primary amines
2. Addition of secondary amines: enamines

 Hydrogen Nucleophiles
 Carbon Nucleophiles
1. Addition of organometallic compounds
2. Addition of phosphorous ylides: Wittig reaction
3. Addition of cyanide: cyanohydrin formation
4. Addition of acetylides
  Introduction to Aldehydes and Ketones

Aldehydes and ketones are responsible for many flavors and odors:

Many important biological compounds also exhibit the carbonyl group, including progesterone and
testosterone, female and male sex hormones.
Nomenclature of aldehydes and ketones: a review
Some simple aldehydes and ketones has common names, as for example:

When naming the parent, the suffix “-al” indicates the presence of an aldehyde group, while the
suffix “-one” indicates the presence of a ketone group.

Simple ketones to be named as alkyl alkyl ketones. For

example, 3-hexanone can also be called ethyl propyl ketone:

The main chain of an aldehyde or a ketone is the longest chain that includes the carbon atom of the
carbonyl group, which is assigned number 1, despite the presence of alkyl substituents, π bonds, or
hydroxyl groups. Examples:
 General mechanism of nucleophilic addition reactions:
The electrophilicity of a carbonyl group derives from
resonance effects as well as inductive effects:

Therefore, it is susceptible to be attacked by a nucleophile; the hybridization state of the carbon

atom changes as a result of the process:

In general, aldehydes are more reactive than ketones toward nucleophilic attack.
Nucleophilic Addition to the carbonyl can be under basic or under acidic conditions:
1.- Basic conditions:

2.- Acidic conditions:

In acidic conditions, the first step plays an important

role. Specifically, protonation of the carbonyl group
generates a very powerful electrophile:
There is a wide variety of nucleophiles that can attack to the carbonyl. We will see
nucleophiles (indicated in red) based on oxygen, sulfur, nitrogen, hydrogen and carbon:
 Oxygen Nucleophiles
1. Addition of water: when an aldehyde or ketone is treated with water in the presence of either
acidic or basic conditions, the carbonyl group is converted into a geminal diol.

Base-Catalyzed Hydration:

Geminal diol

Acid-Catalyzed Hydration:
2. Addition of alcohols: acetal formation
In acidic conditions, an aldehyde or ketone will react with two molecules of alcohol to form
an acetal.

Acetal
Acetal

The presence of acid catalyst is necessary because the nucleophile is weak. Common acids
used for this purpose include p-toluenesulfonic acid (TsOH) and sulfuric acid (H2SO4):
Mechanism:

Hemiacetal

Acetal
Aldehydes are readily converted into acetals by
treatment with two equivalents of alcohol in
acidic conditions:

However, for most ketones, the equilibrium

favors reactants rather than products. In this
case, formation of the acetal can be favored by
removing the water that is formed by
distillation.

A compound containing two OH groups can be used, forming a cyclic acetal.

To convert an acetal back into the corresponding

aldehyde or ketone, it is simply treated with water in
the presence of an acid catalyst. As a consequence,
acetals can be used as protecting groups.
Treatment of the acetal with aqueous acid to
afford the corresponding aldehyde or ketone is a
hydrolysis reaction, because bonds are cleaved
(shown with red wavy lines) by treatment with
water.
Mechanism:
 Sulfur Nucleophiles

In acidic conditions, an aldehyde or ketone will react with two equivalents of a thiol to form a
thioacetal. The mechanism is analogous to acetal formation, with sulfur atoms taking the place of
oxygen atoms.
If a compound with two SH groups is used, a cyclic thioacetal is formed:
 Applications
Acetals as Prodrugs

Prodrug: pharmacologically inactive compounds that are converted by the body into
active compounds.

Fluocinonide is a prodrug that contains an acetal group and is sold in a cream used for
the topical treatment of eczema and other skin conditions.
Drugs containing OH groups typically exhibit low dermal permeability (they are not
readily absorbed by the skin). To resolv this problem, two OH groups can be
temporarily converted into an acetal. The acetal prodrug is capable of penetrating the
skin more deeply, because it lacks the OH groups. Once the prodrug reaches the
affected area, the acetal group is slowly hydrolyzed, thereby releasing the active drug.
 Nitrogen Nucleophiles
1. Primary Amines
In mildly acidic conditions, an aldehyde or ketone will react with a primary amine to form an
imine:

Imines: compounds that

possess a C=N double bond.

Many different primary amines RNH2 will react with aldehydes and ketones, including compounds
in which R is not an alkyl group. Examples:

An oxime A hydrazone
Mechanism:

Imine
2. Secondary Amines: formation of enamines
In acidic conditions, an aldehyde or ketone will react with a secondary amine R2NH to
form an enamine, compounds in which the nitrogen lone pair is delocalized by the
presence of an adjacent C=C double bond.
Mechanism of enamine formation:
 The mechanism of
enamine formation is
identical to the
mechanism for imine
formation except for the
last step:

Imines and enamines also undergo hydrolysis when treated with aqueous acid. The intermediates
involved in imine and enamine hydrolysis are the same as the intermediates involved in imine and
enamine formation, but in reverse order.
 Hydrogen Nucleophiles
When treated with a hydride reducing agent,
such as lithium aluminum hydride (LiAlH4) or
sodium borohydride (NaBH4), aldehydes and
ketones are reduced to alcohols:

With NaBH4 :
With LiAlH4 (LAH) :

When an unsymmetrical ketone is reduced with a hydride reducing agent, such as LiAlH4 or NaBH4, a
new chiral center is generated, and a pair of stereoisomers is obtained. Example:
 Carbon Nucleophiles
1. Organometallic compounds
Compounds containing a bond between a
carbon atom and a metal (C−M) are called
organometallic compounds.
The carbon atom is more electronegative than the metal to which it is attached, so it is electron rich.
The magnitude of the partial charge (δ–) on the carbon atom will depend on the identity of the metal.
Both organolithium (RLi) and organomagnesium (RMgX) compounds exhibit a C−M bond with a high
degree of ionic character. They behave very much like carbanions.

Carbanions are strong bases and

strong nucleophiles. In fact, RLi
and RMgX are among the
strongest bases and strongest
nucleophiles, reacting with
electrophiles such as carbonyl
compounds (aldehydes, ketones,
esters, carbon dioxide, etc) and
epoxides. They’re also very strong
bases and will react with acidic
hydrogens (such as alcohols,
water, and carboxylic acids).
 Organolithium reagents can be prepared by treating an organohalide (RX) with two equivalents of Li
in a nonpolar solvent, such as hexane or diethyl ether. The R group of the organohalide can be alkyl,
aryl, or vinyl:

Grignard reagents can be prepared by treating an organohalide (RX) with Mg in an ether solvent, such
as diethyl ether, which results in the insertion of magnesium into the C−X bond:
Grignard reagents (RMgX) and organolithium reagents (RLi) reacts rapidly with water to give a
hydrocarbon (RH):

When treated with a Grignard reagent, aldehydes and ketones are converted into alcohols,
accompanied by the formation of a new C−C bond.

General mechanism:
When treated with carbon dioxide,
Grignard reagents give carboxylic acids
(carboxylation of Gridnard reagents):

Mechanism:

Example:
2. Cyanohydrin Formation
When treated with a mixture of HCN KCN
and cyanide ions (from KCN),
aldehydes and ketones are converted
into cyanohydrins, which are
characterized by the presence of a
cyano group and a hydroxyl group
connected to the same carbon atom:

Mechanism:
The process is reversible. However,
for most aldehydes and unhindered
ketones, the equilibrium favors
formation of the cyanohydrin:

HCN is a liquid at room temperature and is extremely hazardous to handle because it is highly
toxic and volatile (b.p. = 26°C). To avoid the dangers associated with handling HCN, cyanohydrins
can also be prepared by treating a ketone or aldehyde with potassium cyanide and an alternate
source of protons, such as HCl:
3. Wittig Reaction
Georg Wittig, a German chemist, was awarded the 1979 Nobel Prize in Chemistry for his work with
phosphorus compounds and his discovery of a reaction with enormous synthetic utility. This
reaction is called the Wittig reaction:

The reaction converts a ketone or

aldehyde into an alkene by forming a
new C=C bond at the location of the
carbonyl group:
An ylide (iluro) is a neutral molecule that contains a
negatively charged atom (C− in this case) directly
attached to a positively charged heteroatom (P+ in
this case):

Phosphorus ylide

A Wittig reagent can be prepared in two steps from an alkyl halide:

Example:

Wittig mechanism:
The Wittig reaction allows two molecular segments to be connected through a C=C.

1.
O retro
Br
Br
2. O
4. Acetylides: nucleophilic addition to Carbonyls

Terminal alkynes are much more acidic than most other hydrocarbons. It can be attributed to the
stability of the acetylide anion, which has the unpaired electrons in an sp hybridized orbital. The
stability results from occupying an orbital with a high degree of s-orbital character.

Acetylide anions will add to aldehydes and ketones to form alkoxides, which upon protonation give
the corresponding alcohols.

Example:
Synthetic Strategies
 applications

Well over 1500 species of plants are known to make compounds containing a cyanide group
covalently bonded to a sugar (usually glucose).
The plants make these compounds as a repellent to herbivores. In general, the cyanide
functional group is non-toxic as long as it is covalently bonded to an organic molecule. However,
the cyanide ion is released when an animal eats the plant and metabolizes the cyanide
containing compounds to yield HCN.
In order to eat cassava tubers safely, humans have developed methods to process the tubers by
cooking, soaking, fermenting, or drying them in order to release HCN gas prior to consumption.

Example: cassava plant

(mandioca, yuca)

Linamarin
 applications

CARVONE
With the exception of their ability to rotate the polarized light, enantiomers mostly present
UNIVERSITY OF VIGO
the same chemical and physical properties (melting point, boiling point, density, and so on),
but they behave differently in chiral environments, that is, in the presence of other chiral
molecules or objects.
For example, carvone can be isolated from nature in both enantiomeric forms R and S, but from
different resources. Enantiomer R is the main constituent of the oil from several species of mint
while enantiomer S appears in caraway seeds oil. They smell differently because our
olfactory receptors also contain chiral molecules, so they behave differently in the presence
of different enantiomers.

(S) Spearmint: (S)-carvone

(R)

CARVONE

Careway: (R)-carvone