CHEM-332

Rahman S. Z. Saleem
Department of Chemistry & Chemical Engineering, SBASSE
Lahore University of Management Sciences

Lecture

06
Sep 24, 2019
 Why Nucleophile Attacks Carbonyl Carbon ?
Bonding in formaldehyde

polarization

Look at the hybridization states of carbonyl carbon and oxygen.

Identify HOMO and LUMO for such reactions
 Let’s first look at the order of reactivity

Order of reactivity

Why an aldehyde has a greater partial positive charge on its carbonyl carbon than does a ketone ?
 Nucleophilic Addition to Carbonyl Group

Can you identify

nucleophilic and
electrophilic centers

Additions to carbonyl groups generally consist of two mechanistic steps:

1. Nucleophilic attack on the carbonyl group
(More important, generally rate determining step) formation of C-C σ at the expense of C=O π bond
2. Protonation of the resulting anion
 Change in the Hybridization State of Carbonyl Carbon

sp2 (trigonal planer) sp3 (tetrahedral)

Why C=O π-bond is broken? What orbital-type interaction is involved?

 Whats is the Role of Acid?

sp-orbital with lone electron pair is available both on carbon and nitrogen. sp-orbital on C is the
HOMO and attacks the carbonyl C.
Cyanohydrin Formation is Reversible

Aqueous base completely

decomposes the cyanohydrins
 Reactivity

Aldehydes are more reactive than ketones due to steric and electronic reasons
 Cyanohydrin in synthesis

Can you draw the structure of “other reagents” in below mentioned reactions to form
fluvalinate and cypermethrin ?
Further, which molecular orbital of cyanohydrin is acting as HOMO and which molecular orbital
of the other reagent is acting as LUMO?
Cyanohydrin in synthesis

Carbon chain elongation

 Cyanohydrin in synthesis

?
PMAA

ACH Methyl methacrylic acid

Methacrylic acid is produced industrially on a large scale as a precursor to its esters, especially
methyl methacrylate (MMA) and poly(methyl methacrylate) (PMMA).
The co-polymer methyl methacrylate-butadiene-styrene (MBS), used as a modifier for PVC
The methacrylates have numerous uses, most notably in the manufacture of polymers
These are also used as cement in total hip replacement and total knee replacement
 The Angle of Nucleophilic Attack on Carbonyl Carbon
Burgi - Dunitz Trajectory

This is the major factor for higher rate of

reactions for aldehydes than for ketones
for such type of reactions.

Though nucleophile attacks at a particular angle, feel free to draw

curly arrows in any direction ……..
 Nucleophilic Attack by “Hydride” on Aldehydes and Ketones

NaH can not be used as a source of hydride ion

Due to higher electron density, it always acts as a base and attracts the proton.

The addition of hydride to carbonyl group can, however, lead to the formation of alcohol
BUT what should be the source of hydride?
 Nucleophilic Attack by “Hydride” on Aldehydes and Ketones

NaBH4, a water soluble salt, is an attractive option for such reactions ……

Hydrogen is added to carbonyl carbon forming an electron deficient BH3 and an oxyanion, which can stabilize
BH3 to form a tetravalent boron anion. This boron anion can transfer another hydrogen to another carbonyl
compound and the process can, in principle, continue till all four “H” atoms of NaBH4 are transferred to four
carbonyl molecules.
 Hydride Addition or Reduction of Carbonyl Group
More Examples

NaBH4 reacts 400

then in isopropanol
times faster with
 Hydride Addition or Reduction of Carbonyl Group
More Examples

NaBH4, being a weaker reducing agent, selectively reduces only the aldehyde, ketones and imines.
 Hydride Addition or Reduction of Carbonyl Group

LiAlH4 is a stronger reducing agent. It can not be used in water/alcohol solvents due to violent reaction and
reduces many other reducible groups including esters, amides, nitro, carboxylic acids etc…

H=2.1

B=2.0

Al=1.5
 Hydride Addition or Reduction of Carbonyl Group

NaBH3CN is even a weaker reducing agent than NaBH4 and can selectively reduce imines in the presence of
aldehydes and ketones (Borch reaction). This is due to electron withdrawing nature of CN in NaBH3CN.

Sodium cyanoborohydride
 Nucleophilic Attack by “Hydride” on Aldehydes and Ketones in
Biological System

In the laboratory, the conversion of an aldehyde or ketone to an alcohol is generally carried out using NaBH4.
In biological pathways, however, NADH (reduced nicotinamide adenine dinucleotide) or the closely related
NADPH (reduced nicotinamide adenine dinucleotide phosphate) is the most frequently used hydride-ion
donor. An example that occurs in the pathway by which organisms synthesize fatty acids is the conversion of
acetoacetyl ACP (acyl carrier protein) to 3-hydroxybutyryl ACP.