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Chem 330 Topics Discussed On Oct 5: O O Meli Sime Li + Me Si

The document summarizes topics discussed in a CHEM 330 lecture on October 5. It discusses the conversion of silyl enol ethers to lithium enolates and C-alkylation of carbonyl enolates. It also discusses the preparation of enolates from esters, nitriles, and tertiary amides using LDA, but notes primary and secondary amides cannot form enolates. Ivanov enolates of carboxylic acids are discussed. Difficulties in preparing aldehyde enolates and temporary conversion of aldehydes to imines or hydrazones to suppress aldol reactions are covered. The document also discusses deprotonation of ketones and regioselectivity issues,

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Subhabrata Mabhai
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49 views5 pages

Chem 330 Topics Discussed On Oct 5: O O Meli Sime Li + Me Si

The document summarizes topics discussed in a CHEM 330 lecture on October 5. It discusses the conversion of silyl enol ethers to lithium enolates and C-alkylation of carbonyl enolates. It also discusses the preparation of enolates from esters, nitriles, and tertiary amides using LDA, but notes primary and secondary amides cannot form enolates. Ivanov enolates of carboxylic acids are discussed. Difficulties in preparing aldehyde enolates and temporary conversion of aldehydes to imines or hydrazones to suppress aldol reactions are covered. The document also discusses deprotonation of ketones and regioselectivity issues,

Uploaded by

Subhabrata Mabhai
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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CHEM 330

Topics Discussed on Oct 5


Conversion of silyl enol ethers to Li enolates by reaction with MeLi, e.g.:
O SiMe3

O Li
MeLi

(likewise for ester-derived


silyl enol ethers)

+ Me4Si

C-Alkylation of carbonyl enolates as a fundamental C-C bond forming process in modern


synthetic organic chemistry
Preparation and C-alkylation of enolates of the major classes of carbonyl and carbonyl-like
compounds
Preparation of enolates of esters, nitriles, and tertiary amides with LDA and their C-alkylation
Inability of primary and secondary amides to form enolates due to initial deprotonation of the N
H group (pKa 15) and formation of a fairly energetic anion which resists further deprotonation:
O
R

base

N
H pKa 15

O
N

R = H: primary amide
R = alkyl: secondary amide

fairly energetic:
resists further
deprotonation

Ivanov enolates of carboxylic acids:


Br
O
O
pKa 5

LDA

LDA
O

low-enegy anion:
undergoes further
deprotonation

COOH
O

Ivanov enolate

(1 equiv.)
then aq.
workup

Difficulties encountered in the preparation of aldehyde enolates by deprotonation of aldehydes


with LDA:
rate of deprotonation rate of aldol addition of the enolate to an intact aldehyde
and consequent polymerization of the aldeyde under basic conditions
Imines (=Schiff bases): nitrogen analogs of carbonyls, e.g.:

lecture of Oct 3

p. 2

H
a carbonyl
compound

H
an imine

Temporary conversion of aldehydes to imine-type derivatives as way to suppress aldol-type


reactions during deprotonation:
H2NZ

R
H

NZ

R
H

H2O

any enolizable
aldehyde

Z = alkyl; e.g. tert-Bu: an imine


Z = NMe2: a dimethylhydrazone

imine-type derivative

cannot be converted cleanly


to an enolate with, e.g., LDA

easily and cleanly converted


to an enolate with, e.g., LDA

Formation, deprotonation, and alkylation of tert-butylimine and N,N-dimethylhydrazones


derivatives of aldehydes, e.g.:
H2N
MgSO4

1. LDA

(e.g.) Br

2.

H2N N

1. LDA
NMe2

2.

NMe2

(e.g.) Br

Hydrolysis of imines and hydrazones as a method to retrieve the corresponing aldehyde:


aq. H+
N

R
H

( + H2NG; G = tert-Bu, NMe2)

the overall result is equivalent to the alkylation of the enolate of the starting aldehyde

Retrieval of aldehydes from N,N-dimethylhydrazones through ozonolysis (applicable so long as


no interfering functionality, such as olefins, are present in the molecule)
The -alkylation of aldehydes by the above methodology as a process of considerably lesser
significance than the -alkylation of other carbonyl compounds
"Enormous complexity" of the mechanism(s) of deprotonation of ketones

lecture of Oct 3

p. 3

Deprotonation of ketones: the issue of regioselectivity with unsymmetrical substrates:


O

base

likewise:

& / or

base

& / or

Olefin-like nature of enolates:


O

more significant
resonance struct.

O
less significant
resonance struct.

Principle: just as in the case of an olefin, the thermodynamic stability of an enolate increases
with increasing substitution around the C=C bond, e.g.:
O

O
more stable than:
3 substituents
around C=C

and
2 substituents
around C=C

O
more stable than:

4 substituents
around C=C

3 substituents
around C=C

Principle: treatment of an usymmetrical ketone of the type shown above with a weaker base that
deprotonates the substrate slowly and reversibly (e.g., an alkoxide such as tert-BuOK) leads
preferentially to the more substituted, more thermodynamically favorable enolate:
O

tBuOK

OK

OK
+ small amounts of

tBuOK

OK

OK
+ small amounts of

Mechanistic rationale for formation of the more thermodynamically favorable enolate upon
deprotonation of, e.g., 2-methylcyclohexanone with tBuOK (or with NaH/cat EtOH):

tBuO (pKa 19) is insufficiently basic to deprotonate the ketone (pKa 20) completely
and irreversibly. Enolate formation will occur under conditions of reversibility, permitting
the accumulation of the more thermodynamically favorable enolate, T, at the expense of
its isomer K:

lecture of Oct 3

p. 4

O
slow and

slow and
ROH +

+ RO

reversible
C

K - less stable:
minor enolate at equilibrium

+ ROH

reversible

T - more stable:
major enolate at equilibrium

In such a reversible reaction, the product ratio is determined solely by the energy
difference between products T and K. In the present case, the majority of the molecular
population of starting ketone will be channeled through the reaction pathway leading to
enolate T, which becomes the major product.

energy
O Mt

O Mt
K

E prods.
T

A reaction that proceeds under these conditions is said to be thermodynamically


controlled. Enolate T may be described as the thermodynamic product of the
deprotonation reaction (= thermodynamic enolate).

Principle: treatment of an unsymmetrical ketone of the type shown above with a strong (pKa >
30), hindered base that deprotonates the substrate rapidly and irreversibly (e.g. LDA and
related agents) and that contains a Lewis acidic, oxophilic metallic counterion leads
preferentially to the less substituted, less thermodynamically favorable enolate:
O

LDA

OLi

OLi
+ small amounts of

Mechanistic model (NOT "mechanism") for the deprotonation of ketones with, e.g., LDA (78
C, THF), resulting in formation of the thermodynamically less favorable enolate
Lewis acidic, oxophilic character of Li+
Probable first interaction of LDA with the substrate, e.g., 2-methylcyclohexanone: complex
formation:

lecture of Oct 3

p. 5

Li

+ Li N

note: the formal (+) on the O atom enhances the acidity of adjacent protons by making the O more
electron-attarcting. Moreover, the formal () on the Li atom enhances the basicity
of the N atom
by increasing the extent of NLi bond polarization, thereby augmenting the electronic density on the N
atom. Therefore, this activated complex is primed for proton transfer from C to N

Preferred conformation of the complex:


H

H
O

Li

Me

cyclohexane in a chair conformation


Me group (A-value = 1.8) equatorial:

Principle: The C-H orbital of the proton that is removed by the base must be aligned with the
large lobe of the *C=O orbital to permit maximum electron delocalization during proton transfer
dihedral
angle = 0

only this H is
properly aligned
for deprotonation

*C=O
H

C-H
H

R
H

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