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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.:

(likewise for ester-derived silyl enol ethers)

O O

MeLi

SiMe3 Li

+ 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-likecompounds

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

NR

H

R = H: primary amide

R = alkyl: secondary amide

base

pKa ! 15

O

NR

fairly energetic:resists further

deprotonation

O

NR

Ivanov enolates of carboxylic acids:

O

OH

LDA

pKa ! 5

O

O

low-enegy anion:undergoes furtherdeprotonation

O

O

LDA

Ivanov enolate

Br

(1 equiv.)then aq.workup

COOH

Difficulties encountered in the preparation of aldehyde enolates by deprotonation of aldehydeswith 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.:

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lecture of Oct 3 p. 2

O

H

a carbonylcompound

N

H

an imine

R

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

reactions during deprotonation:

RO

H

any enolizable aldehyde

RN–Z

H

imine-type derivative

H2N–Z

cannot be converted cleanlyto an enolate with, e.g., LDA

easily and cleanly convertedto an enolate with, e.g., LDA

– H2O

Z = alkyl; e.g. tert -Bu: an imineZ = NMe2: a dimethylhydrazone

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

derivatives of aldehydes, e.g.:

R

H

O

H2N

MgSO4

H2N N

R N

NMe2

R N 1. LDA

2.

Br(e.g.)

1. LDA

2.Br(e.g.)

R N

NMe2

R N

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

RN

G

aq. H+

RO

H H

( + H2N–G; 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

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

OObase

likewise:

O

& / or

O O

base

O

& / or

Olefin-like nature of enolates:

O Omore significantresonance struct.

less significantresonance struct.

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

O

more stable than:

OO O

more stable than:and

3 substituents

around C=C

2 substituents

around C=C 3 substituents

around C=C

4 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

O tBuOKO–K

tBuOKO–K

+ small amounts of

+ small amounts of

O–K

O–K

Mechanistic rationale for formation of the more thermodynamically favorable enolate upondeprotonation 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, permittingthe accumulation of the more thermodynamically favorable enolate, T, at the expense ofits isomer K:

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OO

slow and

reversible

O

slow and

reversible+

T - more stable:major enolate at equilibrium

K - less stable:minor enolate at equilibrium

+ ROHROH + RO

C

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

!E prods.K

T

O

O

Mt

Mt

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:

OLDA

O–Li

+ small amounts of

O–Li

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: complexformation:

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O

+ Li N

O Li

N

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

Preferred conformation of the complex:

LiO

H

MeH

cyclohexane in a chair conformationMe group (A-value = 1.8) equatorial:

H N

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

ORH

HH

dihedralangle = 0only this H is

properly alignedfor deprotonation

! C-H

" *C=O

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