Enolate chemistry (condensation and conjugate addition) Flashcards
Factors that effect the acidity of alpha carbons of various carbonyl compounds
Inductive effects
resonance localization
increasing electronegativity of the atom
Esters are ___ acidic than aldehydes or ketones
Less
ENolates are most nucleophilic at the
carbon
Nearly all of the negative charge on an enolate is on
the oxygen
overlap first then
deprotonation
enolate formation requires that the C-H bond
align parallel to the carbonyl bond
aligned enolates are
acidic
non aligned enolates are
not acidic
SN2 reactions are
MO controlled
MO controlled
for the reaciton ot proceed there should be good overlap oof the nucleophile and the sigma C-X bond of the electrophilek
keto-enol tautomerization via enolates mechanism
- Break C-H
- Form O-H
-Break C-O - Form C-C
- Form O-H
Deuterium
An isotope of hydrogen with one proton and one neutron in the nucleus having an atomic weight of 2.014
deuterium labelling does no occur on
the beta carbons
deuterium labelling
using deuterium to replace all hydrogens on a structure to label it
racemate
a mixture containing equal amounts of two enantiomers
racemization
the chemical reaction resulting in the conversion of L amino acids to D amino acids for amino acid dating
chiral center
carbon with four different substitutions and a lack a plane of symmetry
one conquesunce of enolates being flat
chiral centers on alpha carbon undergo reacemization
why does racemization occur
due to the ability of things to add to the top or bottom of an enolate
epimerization
the reversible the interconversion of epimers
epimer
diasteromers that differ at only one chiral center
diasteromer
stereoisomers that are NOT mirror images thus they have different physical properties and optical rotations
enolate
intermediate
stabilized by resonance
enol & base— enolate
unsymmetrical ketones can form
two different enolates
kinetic enolate
less substituted enolate
formed quickly
removal of an acidic alpha hydrogen
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kinetic control
a reaction in which the product ration is determined by the rate at which the products are formed
thermodynamic control
a reaction in which the product ratio is determined by the relative stability of the products
thermodynamic enolate
more substituted double bond
higher activation energy
more thermodynamically stable
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lithium di-isopropyl amide
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LDA is
strong bulky base
how to make a kinetic enolate
selectively using a strong bulky base at a low temperature
how to make a thermodynamic enolate
can make selectively by reading with RO-/ ROH and setting up an equilibrium mixture of enolates
less substituted alpha carbon will
be deprotonated faster
which could make deprotonation harder
steric interactions
kinetic vs thermodynamic energy diagram
Image
which enolate is less stable
kinetic enolate
which enolate is more stable
thermodynamic enolate
halogenation of enolates in thermodynamic conditions
substitution at the most substituted carbon
halogenation of enolates in kinetic conditions
additional the least substituted carbon
alkylation of enolates in thermodynamic conditions
addition to the most substituted carbon
alkylation of enolates in kinetic conditions
addition to the least substituted carbon
alkylation is restricted to
primary, allylic, and benzylic electrophiles
aldol
contains both aldehyde and alcohol functional groups
image
thermodynamic aldol formation requires
two steps and heat for the aldol condensation product
what can occur between ketones
aldol condensations
aldol addition mechanism of thermodynamic aldol
1) protonation (annotate formation)
2) elimination
thermodynamic aldol conditions lead to what kind of reaction
E1, because it is a conjugate base mechanism that occurs in multiple parts
an intramolecular aldol reaction is the second step to the
Robinson annulation rection
in a mixture of two aldehydes
a mixture of enolates will form
each enolate will react
with itself and another aldehyde
nonenolizable aldehyde
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nonenolizable aldehyde + symmetric ketone
makes a cross aldol product
kinetic aldol conditions are predictable
high selectivity at low temperature under non-aqueous conditons
reagents for thermodynamic aldol condensation
NaOH & H20, NaOH & H20 & heat
reagents for kinetic aldol condensation
LDA, low temp, aldehyde, acid workup
ester enolate reaction is called
clauses condensation
clasien condensation
enolate ion of one ester acts as nucleophile attacking another ester
clausien condensation product
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transesterfication is competitive with
the claisen
always match he ester group with
the base used
clauses condensation mechanism
1) deprotonation of ester alpha carbon to give an ester enolate
2) attack of enolate on a second equivalent ester
3) elimination of RO(-)
- Acid base reaction of beta-keto ester prodyct
4) mils acid quench
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beta-keto ester
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acid base reaction of beta- keto ester
the enolate is not basic enough to deprotonate starting ester so all the RO- is consumed
quenching of the reaction
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crossed claisen product
joins two different esters
Dieckmann condensation
intramolecular clauses condensation
thermal decarboxylation
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beta-keto carboxylic acid
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most carboxylic acids do not
spontaneously lose CO2
beta keto acid ____ CO2 upon heating
loses
acetic acid, butanoic acid, alpha keto acid, and gamma keto acid all boil without
losing CO2
mechanism of decarboxylation of beta-ketoacids
cyclic concerted transition start that results in the formation of an enol intermediate
aceoacetic ester synthesis
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maolonic ester synthesis
the process by which to convert a Masonic ester to a carboxylic acid
Malonic ester synthesis mechanism
1) CH3O- acts as a base to remove acidic proton and create enolate
2) Enolate acts as a nucleophile to attack alkyl halide in the Sn2 reaction
3) addition of aqueous acids leads to hydrolysis of esters into carboxylic acids
4) decarboxylation occurs to form enol and carbon dioxide
strong acids can cause
racemization
ketones are
chiral
enrols are
achiral
halogenation of ketones are slow withou
acid
halogenation of ketone bond breaking and formation
break C-C, form C-X, Form C-O, break O-H
acid catalyzed aldol condensation bond breaking and formation
Form C-O, Break C-C (pi) & form C-C, break C-O pi, Break O-H
acid catalyzed aldol condensation mechanism
1) keto enol tautomerimsm
2) protonation, form O-H
3) elimination, form C-O
4) deprotonation, break O-H
H20 is a. ____ leaving group than OH-
better
Mannich reaction
compounds capable of forming an enol react with imines from formaldehyde and a primary or secondary amine to yield beta-aminoalkyl carbonyl compounds
mannich reaction mechanism
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mannich reaction reagents
O=CH2, CH3CH2NH2, HCl
conjugation addition
is the addition of a nucleophile to a pi-bond conjugated with electron withdrawing groups such as C=O, CN, or NO2
conjugates addition can also be called a
1,4 addition
Michael reaction gives
1,5 diketones
1,5 diketone
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Michael reaciton mechanism
1) enolate formation
2) conjugate addition
Michael reaction
1,4 nucleophilic addition of enolate anion or enamine to a,b-unsaturated carbonyl (done over EtO- and EtOH)
image
Robinson annulation
A reaction that collectively constituted the following reactions:
—> Michael addition followed by Intramolecular Aldol Condensation followed by Dehydration
Michael reaction reactants
NaOH, Ketone
Robinson annulation reactants
KOH, CH3OH, heat
robinson annulation mechanism
- Michael addition
- aldol reaction
- condensation, E1CB
