2012 chem3115lecture3.pdf
TRANSCRIPT
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Lecture 19 Carbonyl Chemistry. Reducing reagents: Chemo and diatseteroselectivity;
Introduction to Felkin-Anh model.
Lecture 20 Carbonyl Chemistry. Organometallics: formation and reactivity; 1,2 vs 1,4
addition; Felkin-Anh vs Chelation control
Lecture 21 Carbonyl Chemistry. Enolates: formation, regioselectivity; silylenol ethers:
thermodynamic vs kinetic control; enolate geometry with LDA
Lecture 22 Carbonyl Chemistry. Enolates: Aldol reactions; diastereoselectivity via
Zimmerman Traxler transition states. Auxillary approach to enantioselectivity.
Lecture 23 Chemistry of other sp2 centres. Alkenes: synthesis via Wittig, Julia and
Metathesis (RCM and cross metathesis).
Lecture 24 Chemistry of other sp2 centres. Palladium in Contemporary Synthesis:
general mechanism, Suzuki, Stille, Negeshi, Sonogashira and Heck reactions.
Lecture 25 Workshop problems; Recap and review.
Lecture outline
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Enolates: introduction
We have seen examples of hydride and organometallic reagents as nucleophiles.
Another set of nucleophiles are enolates.
Reminder:
Hydrogen atoms a to a carbonyl are acidic.
pKa ~ 20 pKa ~ 25 pKa ~ 32
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Enolates: regioselectivity
Enolates can react at carbon or oxygen, i.e. they are ambident nucleophiles
So can we predict which site they will react at, i.e. regioselectivity ?
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Enolates: regioselectivity
Almost all electrophiles react at carbon atom Silyl reagents are hard electrophiles.
Hard nucleophiles react fastest with hard electrophiles.
Silyl reagents react at oxygen atom.
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Enolates: reactions
Enolates react with a large range of electrophiles, e.g.:
alkylations
acylation
Claisen ester
condensation
Aldol reaction
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Enolates: reactions
Remember, silyl reagents are
hard reagents; they react at
oxygen.
Note: this is not an SN2 reaction.
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Enolates: formation
The three commonly used ways to form enolates are:
•Deprotonation.
•Metallation of silyl enol ethers.
•Addition to a,b-unsaturated carbonyls
Deprotonation:
As we have already seen, hydrogen atoms a to a carbonyl are
acidic and can be removed with a base.
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Enolates: formation
Deprotonation of cyclohexanones:
Axial protons are more acidic and therefore
are deprotonated first.
During deprotonation, the developing p
orbital is parallel with the C=O bond and
can therefore form the enolate
It is the conjugation of the p orbital
with the pi bond of the carbonyl that
provides the resonance stabilisation
of the enolate
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Enolates: formation
Thermodynamic vs kinetic enolate formation.
Thermodynamic product Kinetic product
tetra-substituted alkene;
thermodynamically more
stable product
No methyl group; less crowded
therefore less steric hinderance;
likely to be deprotonated first.
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Enolates: formation
If reaction is reversible, then difference in energy of the products determines product ratio.
If reaction is irreversible, then difference in activation energies determines product ratio.
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Thermodynamic reactions
Reactions are reversible and reach an equilibrium state
Difference in free energy between the products dictates selectivity
ΔG = -RT lnK (K is the equilibrium constant, or ratio of two products)
Note activation energy does not control the position of the equilibrium, but does control the rate
at which equilibrium is reached
lowest energy (most stable) product is the major product
Enolates: formation
Kinetic reactions
are irreversible (reverse reaction is very slow)
major product is not necessarily the most stable (although it can be)
activation energy of competing reactions is the controlling factor
lowest energy pathway leads to major product
- ratio of products = k major/k minor = eΔEact/RT
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Enolates: formation
Thermodynamic vs kinetic enolate formation.
To generate this enolate, we need thermodynamic control.
Reversible reaction, i.e. set up an equilibrium.
Use an alkoxide base, e.g. KOt-Bu or NaOt-Bu.
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Thermodynamic vs kinetic enolate formation.
To generate this enolate, we need kinetic control.
Irreversible reaction
Use a strong, irreversible base, e.g. n-BuLi, LDA, NaH
Enolates: formation
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An even better way to ensure that this enolate
is formed is to make the silyl enol ether and
then perform a silicon metal exchange.
TMSCl acts as a Lewis acid and
activates the ketone.
This allows for a very bulky
base to be used which
enhances kinetic control.
Enolates: formation
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How could we make this enolate?
Direct deprotonation will lead to a mixture as there is little difference between the enolate
But which organometallic reagent
adds to the alkene of an enone?
Enolates: formation
organocuprates
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Enolates: diastereoselectivity
Alkylations of enolates, enamines and silyl enol ethers of cyclohexanone prefer axial attack.
Attack from the apparently more hindered bottom face makes the trigonal carbon atom turn
tetrahedral by forming a vertical bond to the electrophile downwards. The ring goes directly to a
chair conformation with the electrophile in the axial position. This is the least energy pathway
(kinetic control).
The transition state leading to the higher energy twist boat conformation is of higher
energy than the transition state leading to the chair conformation.
Cyclohexanones
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Axial attack also dominates in conjugate addition to 6-membered rings.
Enolates: diastereoselectivity
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Norzoanthamine
(anti-osteoporotic)
Masaaki Miyahita (2004 and 2009)
Enolates: diastereoselectivity
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Diastereoselectivity on smaller ring systems.
Essentially one diastereoisomer is formed. The alkylation is irreversible and as such is under ‘kinetic
control’.
Note we are not concerned with enantiomers here. The i-Pr group is the only group out of the plane of
the 4-membred ring enolate. We have arbitrarily drawn it ‘down’ in the diagram to show the
electrophile approaches from the opposite side to this sterically bulky group.
The product is racemic, but essentially one diastereoisomer.
Enolates: diastereoselectivity
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When there are 2 or 3 trigonal carbons in the ring, the ring is flatter and diastereoselective reactions on
the whole obey simple steric control.
Eg. Conjugate addition.
The newly formed stereocentre can dictate the reaction of electrophiles with the
enolate intermediate….
Enolates: diastereoselectivity
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Enolates: formation acyclic systems
The discussion to this point has dealt with cyclic systems….what about acyclic systems?
The outcome of enolate forming reactions on acyclic substrates can be predicted with good
accuracy if the reaction proceeds via a cyclic transition state.
NB cis or trans in this
case refers to the O-metal
group e.g.
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LDA deprotonation of acyclic substrates can proceed via a cyclic transition state
Enolates: diastereoselectivity
normally this severe 1,3-diaxial
interaction between one of the iso-propyl
ligands on N and R dictates the formation
of a trans enolate
If X is very large this 1,2
interaction dominates the
reactive conformation and
gives the cis enolate
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Enolates: diastereoselectivity
Large steric clash
between
t-butyl group and
ethyl group
Lesser steric clash
between
isopropyl group on LDA
and ethyl group
Favoured
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Summary
Enolates:
•Mostly react at carbon atom (except for silicon reagents)
•Can be formed by deprotonation, silicon-metal exchange, 1,4-addition to enones
•On six membered rings:
•Electrophiles approach from the axial direction
•(conjugate addition also takes place from the axial direction)
•On smaller rings
•Electrophiles approach from the least hindered face
•(conjugate addition also takes place from the least hindered face).
•For acyclic systems, enolate geometry can be predicted if a cyclic transition state is involved
e.g. LDA deprotonations
•Discussed the differences between thermodynamic and kinetic control
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Next time
Aldol reactions