alpha carbon in relation to carbonyl group
0
beta carbon in relation to carbonyl group
0
alpha protons
protons attached to an alpha carbon
enol intermediate
0
enolate intermediate
0
tautomers
Isomers that can interconvert by changing the location of a proton
in the presence of _____ a ketone or aldehyde exists in equilibrium with an enol
catalytic acid or base
are a ketone or enol generally favored at equilibrium?
ketone is generally favored
what is unique about 1-3-diketone?
the enol of 1,3-diketone is stabilized by conjugation and intramolecular H-bonding; it is more stable than a typical enol and is favored at equilibrium.
the alpha position in an enol is ______.
nucleophilic through resonance.
why is an enolate much more nucleophilic than an enol?
it carries an overall negative charge
an enolate can undergo what type of attack?
C-attack or O-attackbut it generally undergoes a C-attack
C-Attack
0
O-Attack
0
Two possible enolate C-attacks
0
________ are the only acidic protons on an aldehyde or ketone that can be removed to form an enolate.
Alpha protons
are beta or gamma protons acidic?
no
will deprotonation of beta or gamma protons yield a resonance stabilized intermediate?
no
how to make an enolate
through the deprotonation of a molecule's alpha carbon
what happens when the pKa values of the base and enolate are similar?
both products and reactants are present in significant amounts
LDA
a strong base commonly used to form enolates irreversibly
LDA full name
lithium diisopropylamide
LDA structure
0
how to make LDA?
treating diisopropylamine with n-butyllithium
when LDA is used to form an enolate, the amount of ketone present at equilibrium is _____.
negligible
LDA features
two bulky isopropyl groups, which allows it to be a strong base, but not a good nucleophile
what happens to an alpha proton's acidity if it is alpha to two carbonyl groups?
they are much more acidic
why are protons that are alpha to two carbonyl groups much more acidic?
the increased stability of the resulting enolate
do you ever use NaH or LDA to form the enolate of 1,3-dicarbonyl?
no. they are already acidic enough to be irreversibly deprotonated by an alkoxide so using these would be overkill.
1,3-dicarbonyl
0
what base do you use if you want to form an enolate from a ketone and have both the enolate and ketone present at equilibrium (reversible)?
NaOH or NaOEt
what base do you use if you want to form an enolate from a ketone and have irreversible enolate formation?
NaH or LDA
what base do you use if you want to form an enolate from a 1,3-dicarbonyl compound?
NaOH or NaOEt. Adding LDA would be unnecessary because this is already irreversible
under _____ conditions, ketones/ aldehydes undergo alpha halogenation.
acidic
what halogens can be added via alpha halogenation to a ketone or aldehyde?
Cl2, Br2, I2 (not fluorine)
acidic conditions means an _____ is the reactive intermediate
enol
with alpha halogenation, where does the halogenation occur if the ketone is unsymmetrical?
-halogenation occurs after at the more substituted carbon-the major product results from the more stable (more substituted) enol
Alpha halogenation provides a two-step synthesis for the synthesis of
alpha,beta-unsaturated ketone
alpha, beta-unsaturated ketone
0
bases that can be used to make an alpha, beta-unsaturated ketone via an alpha halogenation
1.pyridine2.t-BuOK3.Li2CO3
Hell-Volhard Zelinski (HVZ) reaction
brominates the alpha carbon of a carboxylic aciduses 1)Br2, PBr3 2)H2O
can alpha halogenation be achieved also under basic conditions?
yes
under basic conditions, _____ is the reactive intermediate
enolate
when doing alpha halogenation under basic conditions, what can often happen?
poly-halogenation (multiple Br's adding)
haloform reaction
under basic conditions, methyl ketones are converted to carboxylic acids using excess halogen and hydroxide1) NaOH, Br2------------->2) H3O+
bromoform
CHBr3
what halogens can be used in a haloform reaction?
Br2, Cl2, I2
what are the best conditions for a haloform reaction?
it works best if the other alpha carbon has no alpha protons (there is a tertbutyl or something as one of the carbon groups)
aldol addition reaction
when an enolate attacks the aldehyde
is aldol addition an equilibrium process?
yes
for simple aldehydes undergoing an aldol addition reaction, what part of equilibrium is favored?
aldol product
for most ketones undergoing an aldol addition reaction, what part of equilibrium is favored? why?
the ketonethe intermediate of this reaction has steric hinderance, therefore making the forward reaction unfavored.
what are some features of the product of aldol addition?
-there will be a hydroxyl (OH) in the beta position-there will be an alcohol and carbonyl group
retro-aldol reaction
The reverse of an aldol condensation reaction, in which a carbon-carbon bond is cleaved with heat and base, yielding two aldehydes, two ketones, or one of each.
when an aldol product is heated under acidic or basic conditions, what forms?
alpha, beta-unsaturated carbonyl(a double bond between the alpha and beta position with loss of OH group in beta position)
aldol condensation
when an aldol product is heated under acidic or basic conditions, yielding a new double bond between the alpha and beta positions
what is the difference between aldol condensation and aldol addition?
aldol addition is simply adding two molecules together due to an enolate attack while aldol condensation drives that process further via heat and an acid or base condition to yield a new double bond between the alpha and beta carbons with the OH on the beta carbon leaving.
what is more favored, Aldol addition or aldol condensation?
aldol condensation, it is often impossible to isolate the aldol addition product
what usually has greater product yield? aldol condensation or aldol addition?
aldol condensation has much greater yield rather than the initial ketone/aldehyde being favored. This is due to the product having much more stability through conjugation
when performing an aldol reaction/condensation under acidic conditions, what product is usually yielded?
condensation product
two different aldehydes in crossed aldol reaction yield how many possible products?
4 possible aldol products
mixed aldol reaction
two different aldehydes/ketones react in a crossed aldol reaction (or a mixed) aldol reaction
how can a crossed Aldol reaction be practical?
if the number of products can be minimized
how can you minimize the amount of product through a crossed aldol reaction?
1. if one of the substrates is relatively unhindered and without alpha protons2. LDA is used as a base
direct aldol addition
-using LDA as a strong base in a crossed aldol reaction in order to minimize the amount of product.-this works because one compound is completely converted to enolate with LDA and the other carbonyl compound is then slowly added to the enolate
intramolecular aldol reaction product
-cyclic compounds-only 5 and 6 membered rings can form well in this way-this happens through one of the groups forming an enolate and attacks the other group
Claisen condensation
esters undergo reversible condensation reactions-nucleophile= enolate of an ester-electrophile= ester
what type of reaction is a claisen condensation reaction?
nucleophilic aryl substitution reaction
what is the preferred enolate that you should draw on an exam?
have the negative on the O because this is the major product
what are the three limitations to clause condensation?
1. the starting ester has to have 2 alpha protons because the removal of the second proton by the alkoxide ion is what drives the equilibrium forward2. hydroxide (-OH) cannot be used as a base to promote Claisen condensation; otherwise ester hydrolysis occurs.3. an alkoxide that matches the -OR group of the ester is needed or else mixture of esters occurs (transesterification).
transesterification
mixture of esters
crossed claisen condensations are only useful if one of the following criteria is met:
1. one ester has no alpha protons2. perform directed Claisen condensation with LDA as the base
Dieckmann cyclization
intramolecular claisen condensations
what type of rings can form through Dieckmann cyclization?
5 or 6 membered rings
what type of reaction is the alkylation of the alpha position?
the enolate attacks the alkyl halide via an SN2 reaction
alkylation of the alpha position limitations
-1' alkyl halides are favored. if a 2' of a 3' alkyl halide is used, E2 elimination predominates-the aldol reaction also completes with the desired alkylation, so a strong base like LDA must be used-regioselectivity is an issue with unsymmetrical ketones (two different enolates can form)
kinetic enolate of alkylation of the alpha position
0
thermodynamic enolate of alkylation of the alpha position
0
the kinetic enolate is favored by _____ conditions so you use ____ at ____ temperature(s).
irreversibleLDAlow
the thermodynamic enolate is favored by _____ conditions so you use ____ at ____ temperature(s).
reversibleNaHroom
masonic ester synthesis
alkyl halide is converted into a carboxylic acid with 2 additional carbons-starting material diethyl malonate reacts with a base to make the corresponding enolate which then reacts with the alkyl halide
diethyl malonate
0
1,3-dicarboxylic acids undergo decarboxylation in a ____ process.
pericyclic
decarboxylation
The complete loss of a carboxyl group as carbon dioxide
aldol condensation products (a,B-unsaturated carbonyls) have how many resonance structures?
3
aldol condensation products (a,B-unsaturated carbonyls) what carbon can be attacked?
either the carbonyl one or the one on the double bond farther from the carbonyl depending on the nucleophile used
gilman reagents
R2CuLi
Grignard reagents generally attack the ______ position of a,B-unsaturated carbonylsthis is called _____ addition
carbonyl1,2 addition
Gilman reagents generally attack the ______ position of a,B-unsaturated carbonylsthis is called _____ addition
beta1,4 addition or conjugate addition
tautomerization
The rearrangement of bonds within a compound, usually by moving a hydrogen and forming a double bond
conjugate addition
Addition of a nucleophile to the beta carbon of an alpha, beta unsaturated carbonyl compound.
stronger nucleophiles tend towards ____ addition; less reactive nucleophiles tend to ____ addition
1,2conjugate
stabilized enolates give ___ addition exclusively
1,4
Michael reaction
conjugate (1,4) addition
Michael donor
nucleophile that does conjugate addition
Michael acceptor
the a,B-unsaturated carbonyl
Michael donors that give exclusively 1,4-addition with an unsaturated carbonyl compound
0
Common Michael acceptors
0
how do enamines behave like enolate?
they are nucleophiles through resonance so they behave like enolate ions
enamine characteristics (nucleophilic, Michael)
it is less nucleophilic than an enolate ion and is a Michael donor
Stork Enamine Synthesis
(1) formation of an enamine, (2) a Michael addition, and (3) hydrolysis
stork enamine synthesis product
1,5-dicarbonyl compounds
aldol and claisen product
1,3-difunctional compounds
what type of enolate does LDA form?
it will make the double bond on the less substituted carbon