Carbonyl compounds* (Aldehydes and ketones) i. Nucleophilic addition, Electromeric effect,

1. 03
NUCLEOPHILIC
ADDITION
REACTION
02
CARBONYL
COMPOUNDS
01
NUCLEOPHILESSEM-II,FYPOC-I

2. 03
CHEMISTRY OF
CARBONYL
COMPOUNDS
02
TYPES OF
NUCLEOPHILES
01
NUCLEOPHILESCONTENT
that donates an
electron pair
Weak
&
Strong
Polar
Nature
© Dr. Atul R. Bendale

3. NUCLEOPHILES
All molecules or ions with a free pair of electrons or at least one pi bond
can act as nucleophiles.
Because nucleophiles donate electrons, they are by definition Lewis bases.
Nucleophilic describes the affinity of a nucleophile to the nuclei.
Neutral nucleophilic reactions with solvents such as alcohols and water are
named solvolysis.
Nucleophiles may take part in nucleophilic substitution, whereby a
nucleophile becomes attracted to a full or partial positive charge.
Nucleophiles are “electron rich” compounds, also known as “positive-
charge loving”, or “nucleus loving”.
Definition: A nucleophile is a chemical species that donates an electron
pair to form a chemical bond in relation to a reaction.
© Dr. Atul R. Bendale

4. 01
Strong Nucleophiles
Usually anions with
a full negative
charge(with negative
charged O, N, and C
atoms are strong
nucleophiles)
Examples:
NaOCH3 , LiCH3 ,
NaOH or KOH,
NaCN or KCN,
NaCCR (acetylide
anion), NaNH2,
NaNHR, NaNR2,
NaI, LiBr, KI, NaN3,
RO⁻, OH⁻, RLi,
RC≡C:⁻, and NH₂⁻
02
Weak Nucleophiles
· Typically neutral
molecules
· Participate in SN1-
type substitutions
Examples: H2O, ROH,
H2S, RSH
In above examples Pink colored compounds are
examples of Strong Nucleophile
In above examples Blue colored compounds are
examples of Weak Nucleophile
© Dr. Atul R. Bendale

5. CARBONYL
Before we consider in detail the reactivity of aldehydes and ketones, we need to look back and remind
ourselves of what the bonding picture looks like in a carbonyl. Carbonyl carbons are sp2 hybridized, with the
three sp2 orbitals forming soverlaps with orbitals on the oxygen and on the two carbon or hydrogen atoms.
These three bonds adopt trigonal planar geometry. The remaining unhybridized 2p orbital on the central
carbonyl carbon is perpendicular to this plane, and forms a ‘side-by-side’ pbond with a 2p orbital on the
oxygen.
The carbon-oxygen double bond is polar: oxygen is more electronegative than carbon, so
electron density is higher on the oxygen side of the bond and lower on the carbon side. Recall that
bond polarity can be depicted with a dipole arrow, or by showing the oxygen as holding a partial
negative charge and the carbonyl carbon a partial positive charge.
© Dr. Atul R. Bendale

6. NUCLEOPHILESATTACKSONCARBONYL
After the carbonyl is attacked by the nucleophile, the negatively charged oxygen has the capacity to act as a
nucleophile. However, most commonly the oxygen acts instead as a base, abstracting a proton from a nearby
acid group in the solvent or enzyme active site.
There are three fundamental events in a nucleophilic addition reaction:
Overall reaction can be summarized as
Attack of Nucleophile on carbonyl carbon
Formation of the new s bond between the nucleophile, Nu, to the electrophilic C of the C=O group
•Breaking of the p bond to the O resulting in the formation of an intermediate alkoxide
•Protonation of the intermediate alkoxide to give an alcohol derivative
© Dr. Atul R. Bendale

7. NUCLEOPHILESATTACKSONCARBONYL
Depending on the reactivity of the nucleophile, there are two possible general scenarios:
•Strong nucleophiles (anionic) add directly to the C=O to form the intermediate alkoxide. The alkoxideis then
protonated on work-up with dilute acid.
•Weaker nucleophiles (neutral) require that the C=O be activated prior to attack of the Nu.
This can be done using a acid catalyst which protonates on the Lewis basic O and makes the system more
electrophilic.
1. Nucleophile attack first
2. Protonation second
1. Protonation first
2. Nucleophile attack second
© Dr. Atul R. Bendale

8. NUCLEOPHILICADDITIONEXAMPLES
Addition of water
The addition of water to an aldehyde results in the formation of a hydrate
The formation of a hydrate proceeds via a nucleophilic addition mechanism.
1. Water, acting as a nucleophile, is attracted to the partially positive carbon of the carbonyl group, generating an oxonium ion
2. The oxonium ion liberates a hydrogen ion that is picked up by the oxygen anion in an acid‐base reaction
Small amounts of acids and bases catalyze this reaction. This occurs because the addition of acid causes a protonation of the
oxygen of the carbonyl group, leading to the formation of a full positive charge on the carbonyl carbon, making the carbon a
good nucleus. Adding hydroxyl ions changes the nucleophile from water (a weak nucleophile) to a hydroxide ion (a strong
nucleophile). Ketones usually do not form stable hydrates.
Example of Nucleophilc addition. No-1
© Dr. Atul R. Bendale

9. Addition of alcohol
Reactions of aldehydes with alcohols produce either hemiacetals (a functional group
consisting of one —OH group and one —OR group bonded to the same carbon)
or acetals (a functional group consisting of two —OR groups bonded to the same
carbon), depending upon conditions. Mixing the two reactants together produces the
hemiacetal. Mixing the two reactants with hydrochloric acid produces an acetal. For
example, the reaction of methanol with ethanal produces the following results
A nucleophilic substitution of an OH group for the double bond of the carbonyl
group forms the hemiacetal through the following mechanism:
1. An unshared electron pair on the alcohol's oxygen atom attacks the carbonyl
group
2. The loss of a hydrogen ion to the oxygen anion stabilizes the oxonium ion formed in
Step 1
3. The oxonium ion is lost from the hemiacetal as a molecule of water.
4. A second molecule of alcohol attacks the carbonyl carbon that is forming the
protonated acetal
5. The oxonium ion loses a proton to an alcohol molecule, liberating the acetal
Example of Nucleophilc addition. No-2
© Dr. Atul R. Bendale
NUCLEOPHILICADDITIONEXAMPLES

10. Addition of hydrogen cyanide
The addition of hydrogen cyanide to a carbonyl group of an aldehyde or most
ketones produces a cyanohydrin. Sterically hindered ketones, however, don't
undergo this reaction
The mechanism for the addition of hydrogen cyanide is a straightforward
nucleophilic addition across the carbonyl carbony oxygen bond.
Addition of ylides (the Wittig reaction)
The reaction of aldehydes or ketones with phosphorus ylides produces alkenes
of unambiguous double‐bond locations. Phosphorous ylides are prepared by
reacting a phosphine with an alkyl halide, followed by treatment with a base.
Ylides have positive and negative charges on adjacent atoms.
The following illustration shows the preparation of 2‐methylbutene by a Wittig
reaction.
Addition of organometallic reagents
Grignard reagents, organolithium compounds, and sodium alkynides react
with formaldehyde to produce primary alcohols, all other aldehydes to
produce secondary alcohols, and ketones to produce tertiary alcohols.
Example of Nucleophilc addition. No-3
© Dr. Atul R. Bendale
NUCLEOPHILICADDITIONEXAMPLES

11. Addition of ammonia derivatives
Aldehydes and ketones react with primary amines to loose water
molecule, form a class of compounds called imines (R-N=CH2)
The mechanism for imine formation proceeds through the following steps:
1. An unshared pair of electrons on the nitrogen of the amine is attracted
to the partial‐positive carbon of the carbonyl group
2. A proton is transferred from the nitrogen to the oxygen anion
3. The hydroxy group is protonated to yield an oxonium ion, which
easily liberates a water molecule.
4. An unshared pair of electrons on the nitrogen migrate toward the
positive oxygen, causing the loss of a water molecule.
5. A proton from the positively charged nitrogen is transferred to water,
leading to the imine's formation
Example of Nucleophilc addition. No-4
© Dr. Atul R. Bendale
NUCLEOPHILICADDITIONEXAMPLES

12. Addition of ammonia derivatives
Some other examples:
Oximes, 2,4‐dinitrophenylhydrazones, and
semicarbazones are often used in qualitative
organic chemistry as derivatives for aldehydes
and ketones.
© Dr. Atul R. Bendale
NUCLEOPHILICADDITIONEXAMPLES

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