CHEM 330
Topics Discussed on Oct 16
Deprotonation of α,β-unsaturated (= conjugated) carbonyl compounds
Important: bases cannot abstract protons connected to the olefinic α-position of
a conjugated carbonyl compound, because resonance interactions force the C=O
and C=C π-systems to be coplanar As a result, the dihedral angle θ between the
axis of the olefinic α-C–H s bond and the axis of the lobes of the π*C=O orbital is ca. 90°.
There is no overlap between σC–H and π*C=O orbitals à no deprotonation is possible
bases cannot abstract these protons
O
H
H
Me
dihedral angle
θ ≈ 90°
no overlap!
O
O
H
OEt
axis of the
large lobe
of the π*C=O
orbital
axis of the
C–H bond
Definition of α, β, γ, … carbons of an α,β-unsaturated carbonyl compound
generic α,β-unsaturated
carbonyl compound
O
β
R1
R2
α
γ
Principle of vinylogy (= "vinyl analogy"): the interposition of a C=C unit between the
components of a functional group generates a new chemical entity, which retains the chemical
characteristics of the original
Examples:
an enolizable carbonyl
compound: deprotonation
is possible because of
resonance delocalization
of (–) charge on the
eletronegative O atom
B:
:B
O
C
H
CH2
H
O
C C=C–CH2
O
an ester: it undergoes hydrolysis to
an acid and an alcohol when treated C OR
with, e.g. aqueous HCl
a vinylogous ester: reacts with aq.
HCl like the original
H3O+
O
C C=C–OR
a vinylog of the original:
resonance delocalization
of (–) charge on the O
atom still possible through
the C=C bond: can undergo
deprotonation
O
C OH + HOR
O
C C=C–OH + HOR
H3O+
Deprotonation of α,β-unsaturated esters: conversion of, e.g., ethyl crotonate into a dienolate
O
a base (e.g, LDA) can
remove one of these
protons, because ....
H
H
O
OEt
H
:B
H
OEt
H
the anion is resonance-stabilized,
just like an ordinary enolate
O
OEt
a dienolate
lecture of Oct 16
p. 2
Normal O-reactivity of dienolates of conjugated esters with, e.g., TMS-Cl:
O
O–Li
LDA
OEt
–78 °C
O–SiMe3
TMS-Cl
OEt
OEt
dienolate
Definition of α, β, γ, etc., positions of a dienolate:
α
γ
dienolate of a generic
α,β-unsaturated
carbonyl compound
OLi
β
R1
R2
Potential C-reactivity of a dienolate at the α-carbon or at the γ-carbon, e.g.:
OLi
β
R1
R2
α
γ
+ CH3I
β
could
form
R1
α
O
R2
γ
prod. of α-alkylation
& / or
R1
γ
O
β
R2
α
prod. of γ-alkylation
Principle: the nucleophilic C-reactivity of dienolates is expressed selectively at the α-carbon.
This is true both for alkylation and for protonation. E.g.:
• α-alkylation of dienolates:
R
γ
1
O
β
Br
R1
R2
α
α
γ
Br
OLi
β
β
R1
α
O
R2
γ
R2
actual product
• α-protonation of dienolates: formation of deconjugated carbonyl compounds:
R1
γ
O
β
α
H3O+
R2
OLi
β
R1
γ
α
R2
H3O+
β
R1
γ
α
O
R2
actual product
Molecular orbital based rationale for selective α-carbon reactivity of dienolates: greater
electronic density at the α-carbon relative to the γ-carbon, and consequent greater αnucleophilicity relative to γ- nucleophilicity
Principle of least motion: a reaction that could theoretically lead to multiple products tends to
form preferentially the product that requires the least amount of internal motion due to the
repositioning / displacement of atoms during rehybridization.
lecture of Oct 16
p. 3
Invoking the principle of least motion to rationalize the selective α-carbon reactivity of
dienolates:
C, C remain
doubly bonded:
≈ no relative motion
C, C remain singly bonded:
≈ no relative motion
smaller extent
of internal motion
favored
OLi
β
R1
γ
E+
R2
α
γ
C, O go from singly bonded
to doubly bonded: they move
closer to each other
O
β
R1
α
R2
E
C, C go from doubly bonded
to singly bonded: they move
farther from each other
α
C, C go from singly bonded
to doubly bonded: they move
closer to each other
γ
R1
greater extent
of internal motion
disfavored
γ
O
β
C, O go from singly bonded
to doubly bonded: they move
closer to each other
R2
α
E
C, C go from doubly bonded
to singly bonded: they move
farther from each other
Deprotonation of α,β-unsaturated ketones (= enones), e.g., cyclohexenone: potential formation
of two regioisomeric dienolates:
O
O
α'
deprotonation
of the α' position
O
α
deprotonation
β
γ
cyclohexenone:
a typical enone
thermordynamically disfavored:
resonance disperses charge
only over the α' carbon
of the γ position
thermordynamically favored:
resonance disperses charge
over the α and γ carbons
Deprotonation of, e.g., cyclohexenone under kinetic (non-equilibrating) conditions (slight excess
of LDA, THF, –78 °C): deprotonation occurs selectively at the α' position:
• proper representation of the half-chair conformation of cyclohexene and of cyclohexenone:
H
H H
H
H
H
H
H H
H
H
H
H H
H
H
O
H
H
H H
H
H
H H
H
H
H
H
H
H
H
H
O
H H
H
H
lecture of Oct 16
p. 4
• formation and fate of the enone-LDA complex:
LDA
N
••
O
only this H
is properly
aligned for
deprotonation
(excess)
H
H
H
H
O
kinetic enone
dienolate. The
(–) charge is
delocalized over
one C=C bond
Li
H
HH
OLi
O
H
Normal O- and C-reactivity of kinetic dienolates of enones
O–TMS
O-reactive E+
O
OLi
e.g., TMS-Cl
LDA
O
(excess)
C-reactive
kinetic enone
enolate
E+
Me
e.g. CH3–I
Deprotonation of enones under thermodynamic (equilibrating) conditions: deprotonation occurs
selectively at the γ position:
O
appropriate
conds. (e.g.,
slight defect
OLi
of LDA (notes
of Oct 14)
thermodynamic
enone dienolate:
The (–) charge is
delocalized over
two C=C bonds
O
Selective α-alkylation and protonation of thermodynamic enone dienolates:
O
α
γ
O
OLi
Br
Br
α
α
β
β
β
γ
γ
actual product
O
α
H3O+
OLi
α
β
γ
O
β
γ
H3O+
α
β
γ
actual product
O
lecture of Oct 16
p. 5
Soft enolization of enones such as cyclohexenone leading directly to regiochemically defined
silyl enol ethers
TMS-OTf
O
O–TMS
N
Et
kinetic silyl enol ether
faster-forming, but
thermodynamically
disfavored isomer
non-equilibrating conds.
O
TMS-OTf
Me3Si–NH–SiMe3
equilibrating conds.
O–TMS
thermodynamically
favored isomer