导图社区 Crbonyl Reactions
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Crbonyl Reactions
Crbonyl Reactions思维导图，包括：Nucleophilic addition/1,2-addition、Conjugate addition/1,4-addition、nucleophilic acyl substitution、Carbonyl condensation。
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Crbonyl Reactions
Nucleophilic addition/1,2-addition
Targets
Ketones & aldehydes
why not neucleophilic acyl substitution?
H and R are not good leaving groups
so they stay at the tetrahedral state
only sometimes eliminate the water
exeption
cannizzaro reaction
nucleophilic addition OH- to an aldehyde
expels hydride ion as a leaving group
Ex. H:- on NADH
the aldehyde is oxidized into acid, and another carbonyl group is reduced to alcohol
common in biological system
-Br, -Cl, -OR, -NR2 are good leaving groups.
so they substitution, because they can't stay at tetrahedral state, and eliminate those groups
generally all carbonyl groups with its electrophilic carbon
Carboxylic acids, nitriles, carboxylic acid derivatives
but some of them followed by leaving group leaves, so result in substitution
reactivity
The electrophile(carbonyl carbone)
ketones are generally less reactive than aldehydes
like 99.9% ketone in its hydration equilibrium, but 0.01 aldehyde in its hydration equilibrium
Alkyl groups inductive effect
weaken partial positive carbon
Steric hindarance effect
aromatic ring most reduce its reactivity
electron donating
The nucleophile
H-Y/Y-
The addiltion is less favored when the electronegative atom group Y = -OCH3,-OH,-Br,-Cl,HSO4-.
the reverse reaction is favored
Y are good leaving groups
So when Y is poor leaving groups like C-, the reaction is irreversiable.
Elimination of water?/ followed by protonation?
The nucleophile
negatively charged
OH-, H-, R3C-, RO-, cyanide ion
directly yield tetrahydral alkoxide intermediate
following by protonation
neutral
usually carries a hydrogen atom
elimination of water can happen on amines
generate C=Nu bond
HOH, ROH, H3N, RNH2
4 important aspects
alcohol formation
hydration(form germdiols)
Catalysis
Acid catalysis mechanism
protonation of Carbonyl oxygen makes the carbonyl carbon more electrophilic
Water deprotonates the protonated diol intermediate then regenerates acid catalyst
Base catalysis mechanism
hydroxide ion is more nucleophilic than water
water protonates alkoxide ion then regenerates hydroxide ion
highly reversible
form germdiols
grignard addition
1. acid complexation of MgX+ to the carbonyl oxygen, make the carbonyl carbon more electrophilic
similar with acid catalyze mechanism
2. after nucleophilic attack of R-, the tetrahedral megnesium alkoxide intermediate is hydrolsed, get rid of MgX to give alcohol
The reaction is irreverible
carboanion is a very poor leaving group
Actually can produce carboxylic acid
grignard addition on CO2..
called carboxylation of grignard reagent
on C=O of Carbondioxide
followed by protonation of aqueous HCl
hydride addition(reduction)
H:- usually comes from LiAlH4 and NaBH4.
requires acid/water to protonate the alkoxide intermediate/ion
Imine and Enamine formation
Imine R2C=NR
neucleophile is primary amines
ex. Schiff base in our body
can produced by Alanine react with PLP
a common way of its metabolism
nitriles can added by grignard reagent to yield Iminium ion, then it adds a water to yield a ketone, by a machanism that is exact reverse of immine formation
p626
enamine R2N-CR=CR2
analogous: enol----double bond carbon connects a hydroxyl group, but here connects 2' amino group
neucleophile is secondary amines
also through iminium ion!
Reductive amination
Imine and enamine can directly reduced to corresponding amine in presence of reducing agents NaBH4
special case
convert C=O into CH2
treat ketone/ aldehyde with NH2=NH2
first nucleophilic addition
Then intemediate iminium ion eliminates as an N2
mechanism
catalyzed by acid
But optimum PH is 4-5
When PH<4, acid protonates most basic amine nucleophile, and inhibits the first step to let it become rate limiting
1. neucleophilic attack
2. proton transfer with in
Dipolar Tetrahydral intermediate
3. acids protonates -OH on
neutral carbinolamine
Make -OH2+ a better leaving group, and it leaves as water: dehydration
common Rate limiting step
4. finally yield Iminium ion
5. deprotoation by water act as base, regenerate acid catalyst
different
deprotonates the proton on nitrogen yield imine
deprotonates the hydrogen on α carbon yield enamine
no hydrogen on the iminium ion, because we use secondary amine
All steps are reversible: hydrolysis of immine and enamine
ex. stock reaction
nitrile's grignard addition
Acetal formation
Acetal, R2C(OR')2
We call it Ketal if we get it from ketone
unreactive to bases, hydride reducing agents, and catalytic hydrogenation
peotecting groups
excess aqeous acid cleaves it reversely to keton / aldehyde
Add 2 equivalent of alcohols on aldehydes and ketones
1. Initially yields hemiacetal/ hydroxylester
reversible
more favor carbonyl compound
3 steps
specific acid catalyst protonate carbonyl oxygen
neucleophilic attack by alcohol's oxygen
remove the proton on OR, regenerate acid catalyst
2. in presence of acid, protonates -OH, make it leaves, produce an intermediate oxonium ion R2C=O:+ -R
3. second neucleophilic addition of the alcohol to the carbonyl carbon to yield acetal
Catalyzed by acid
same mechanism with hydration acid catalyst
control equilibrium
we distill water to drive actetal formatoion
and treat acetal to a large excess of aquous acid to drive equilibrium to the left
alkene formation
neucleophilic addition of phosphorus ylides RxC- --P+(C6H5)3
produced by SN2 reaction of primary alkyl halide with triphenyl phosphine
followed by treatment with base
mechanism
yildes attack carbonyl carbon
produce a dipolar, alkoxide ion intermediate
it form alkene spontaneously by forming intermolecular O-P bond and produce a 4-membered ring
also produce a second product
(Ph)3P=O
yilides addition can produce all number of alkene substitution but not tetrasubstituted alkenes
steric hindered effect
Real value of it is to generate only 1 E/Z configuration
Nitrile can be view as an aldehyde
hydrolysis to give amides
Acid or base catalyst
first hydrolysis to amides, then to amine
first yield imine, than tautomerize into amide
Reduction to give amines
LiAlH4+H2O
first imine, then adds water to amines
special
grignard addition to give ketones
1. R'MgX, ether
2. H3O+
produce imine ion first, then adds water
reverse of imine formation
production of nitriles
SN2 of alkyl halides
NaCN attack primary nucleohilide
Dehydration of amides
amides+SOCl2
also yields SO2 and 2HCl
E2 like with imine intermediate
Conjugate addition/1,4-addition
happended only on an α-β unsaturated aldehyde/ketone
The β carbon act as a electrophile
because carbonyl group withdraw its electrons through ressonance make it nucleophilic
mechanism
neucleophile attacks β carbon
produce a resonance stablized enoalte ion
resonance make α carbon very nucleophilic
protonation on the α carbon, produce saturated aldehyde/ketone
net affect
neucleophile adds on β carbon, proton adds on α carbon, no changes on carbonyl group
but carbonyl group is essential to catalyst this reaction
Neucleophiles could be Amines, water, alkylgroups
alkylation
no grignard reagent, that'll only gave 1,2-addition
Only uses LiR2Cu
R could be 1', 2', 3', aryl, alkenyl groups
nucleophilic acyl substitution
targets
carboxylic acid derivatives
acyl group is bonded to an electronegative atom or substituent
so this group act as a leaving group
ex.
only in laboratory
acid hylide
acid anhydrides
in both laboratory and biological
ester
amides
primarily in biological
thioester
acyl phosphate
general mechanism
Step1: first nucleophilile attack the carbonyl carbon
produce a tetrahedral intermediate
Step 2: one oxygen electron pair displace Y group, regenerate C=O, resulting a new carbonyl compond as a product
The Y group leaves as a stable anion
2 steps
different from SN2 1 step(second order kinetics because no rate limiting step)
Reactivity
kinetic
most nucleophilic acyl substitution's first step (addition) is rate limiting
steric factor
unhindered, more accessible carbonyl group is make the nucleophilic attack easier
also depends on nucleophile's stereohiderance!
case: acid chloride's alcoholysis / ester production
electronic factor
stongly polarized acyl compounds react more readily than less polar ones
generally increase with electronegatinity
inductive effect
different substituents effect polarization similar with they effect reactivity of aromatic ring toward electrophilic substitution
inductive donating/activating
inductive withdrawing/decativating
reactivity
carboxylate anion<amides<carboxylic acid≈Ester<Acyl phosphate <Thioester<Acid anhydride<Acid chloride
subsequent elimination step is rarely rate limiting
but also important.
you should compare 2 group's pKa to know whether the reaction can happen, or to what equilibira
more electronegative one is a better leaving group, because it stabalize a negative charge better
equilibria
It's usually possible to convert a more reactive acid derivative into a less reactive one.
The reactivity order is therefore a way to keep track of a large number of reactions.
so why acid chloride and acid anhydide never exist in biological system
they are too reactive
specific
carboxylic acids
acyl substitution products.
acid hilides
acid chlorides
treat acid with thionyl chloride; SOCl2
in CHCl3
strategy:
replace -OH into -O-S=O-Cl, a much better leaving group, and use Cl- as a nucleophile to nucleophilic acyl substitute it.
acid bromides
treat acid with phosphophorus tribromide(PBr3)
in ether
acid anhydrides
800℃ heat
only can link 2 Acetic acid by remove 1 equivalent of water
You usually can't link higher acids use this method
esters/ cyclic ester: called lactone
SN2
carboxylate ion+ R'X(primary alkyl hilide)
Nucleophilic acyl substitution
R'OH(alcohol) in strong acid catalyst
also called Fischer esterification reaction
limitation: require an excess of a liquid alcohol as solvent
Only synthesis methyl, ethyl, propyl, and butyl esters.
because Keq close to 1
all steps are reversible
to move the equilibrium to product
amides
treat with amine RNH2
DCC activates the carboxylate group first
DCC first replace carboxylate's -O- to a better & nonacidic leaving group(by carboxylate O- adding to a C=N bond of DCC), than it's substituted by amines
essential for laboratory short peptides synthesis
normally amine is a base to deprotonate carboxylic acid into unreactive carboxylate anions
primary alcohols
LiAlH4
first nucleophilic acyl substitution by H:-
produce aldehyde
not isolatable because aldehyde is much more reactive
second nucleophilic addition by H:-
protonation by acids
hydride ion is a base as well as nucleophile, the actual nucleophilic acyl substitution step takes place on the carboxylate ion rather than on the free carboxylic acid and gives a high-energy dianion intermediate. In this intermediate, the 2 oxygens are undoubtedly complexed to a lewis acidic aluminum species. Thus, the reaction is relatively difficult, and acid reductions require higher temperatures and extented reaction time.
Strong acid catalyst
require strong acid catalyst
acid can catalyst both 2 steps of nucleophylic acyl substitution
Step1: protonates carbonyl oxygen to make the carbon more electrophilic
more common since steps 1 are most cases ratelimiting
Step2: protonates -OH into -OH2+: a good leaving group
or activated by producing much better leaving groups
except biological system
a carboxylic acid is activated by reaction with ATP to give an acyl adenylate
an analogous nucleophilic acyl substitution on phosphorus
ATP is activated by coordination to maganesium ion, and nucleophilic addition of a fatty acid carboxylate to phosphorus P=O double bond, giving a pentacoordinate intermediate
then expels diphosphate ion(PPi) as leaving group
which undergoes nucleophilic acyl substitution with the -SH group on coenzyme A.
The -SH group of coenzyme A adds to the acyl adenosyl phosphate, giving a tetrahedral alkoxide intermediate
then expels AMP as leaving group and yields the fatty acyl CoA
loss of the acidic proton
yield carboxylate ion
acidity because it's stabalize by resonance
better nucleophilic O- but not good leaving group for substitution
used by SN2 with alkyl halide to synthesis ester。。
acidity
elctron donating group: reduce acidity
elctron withdrawing group: increase acidity
substitution of α carbon
α-bromination of carboxylic acid（HVZ reaction)
treatment
1. Br, PBr3
2. H2O
mechanism
carboxylic acid + Br ---acidbromide + HBr
HBr catalyze enolization of acidbromide, yield acid bromide enol
Acid bromide enol reacts with Br2 yields α-bromo acid bromide
α-substitution
addition of water hydrolyzes the acid bromide
nucleophilic acyl substitution
finally yields α-bromo carboxylic acid
Decarboxylation
treatment
heating
result
the carboxylic acid group loses as a carbon dioxide
requirement
it is unique to compounds that have a second carbonyl group 2 atoms away from the -CO2H
happended on a diacid
converts into an acid enol and tautomerize to carboxylic acid
or on a β-ketoacid
converts into an enol and tautomerize to ketone
mechanism
Cyclic
require second carbonyl group appropriate possitioned
initially form enol
Production
hydrolysis of nitriles
oxidation of primary alcohols or aldehydes
reaction of Grignard reagents with CO2 (carboxylation)
oxidation of alkyl benzenes
Acyl chlorides
can convert into
acids
hydrolysis(react with water)
direct add H2O, with out catalyst, so does below
we usually use bases such as pyridine or NaOH to neutralie generated HCl
anhydrides
react with an carboxylate ion
produce all forms of anhydrides
esters
Alcoholysis(react with alcohol)
most common laboratory ester synthesis method
synthesis all possible esters
we usually use bases such as pyridine or NaOH to neutralie generated HCl
strongly steric hinderance by each partners bulky groups
it's possible to esterify a diol only on the less hindered -OH
Amides
Aminolysis(react with ammonia/amines)
most common laboratory amides synthesis method
synthesis all possible amides
only happends on monosubstituted, and disubstituted amines
2 equivalent ammines must be used
requir 1 extra equivalent to neutralize generated HCl
but 1 use equivalent of a nonexpensive base is also OK
Reduction
Alcohols
reduction by LiAlH4 yields primary alcohol
less common, because direct reduce acids is usually more cheap
Grignard reagents
generates 2 same substituted tertiary alcohol
ketones
react with Lithium diorganocopper (R' 2 CuLi)
in Ether
Just like grignard reaction, but isolatable ketone intermediate
follewed by loss of R'Cl to form ketone
diorganocopper only reacts with Acyl chlorides
production
acid hilides
acid chlorides
treat acid with thionyl chloride; SOCl2
in CHCl3
strategy:
replace -OH into -O-S=O-Cl, a much better leaving group, and use Cl- as a nucleophile to nucleophilic acyl substitute it.
acid bromides
treat acid with phosphophorus tribromide(PBr3)
in ether
Acid anhydrides
can convert into
2 acids
hydrolysis
presence of NaOH and H2O
esters
alcoholysis
presence of NaOH and H2O
usually commertially prepare acetate esters form acetic anhydrides(most cheap)
amides
Aminolysis
presence of NaOH and H2O
-NH2 is more nucleophilic so can competes with alcoholysis
Reduction
LiAlH4: Alcohols
only half of the molecule used
low efficiency so less commonly used than acyl chlorides for introducing acyl substituents
production
Acyl chlorides react with carboxylates RCO2-
produce both symmetrical/ unsymmetrical
800℃ heats acetic acid
only can link 2 Acetic acid by remove 1 equivalent of water
You usually can't link higher acids use this method
esters/Lactones
can convert into
less reactive
lactones
means both linear and cyclic esters
Hydrolysis: acids
Hydrolysis base catalyst
in base called sponification
yildes alkoxide ion and carboxylic acid
but alkoxide ions immediately deprotonate carboxylic acid
so may treat with aqueous acid if you want carboxylic acids
isotope labbling prove the nucleophilic acyl substitution mechanism
hydrolysis with acid catalyst
Usual mechanism: reverse of ficher esterification
acids first activated for nucleophilic attack by protonation of acid's carbonyl oxygen
then alcohol attacks the carbonyl carbon
The scond internal proton transfer transfer -OH2+'s proton to -OR oxygen make it a better leaving group
Enzyme mechanism: 2 sequential neucleophilic attacks
1. transesterification to give a acyl enzyme
with tetrahedral intermediate
2. hydrolysis to give an acid and free enzyme
with tetrahedral intermediate
both step requires general acid catalysts to make leaving group leave
reduction
Primary alcohols
1. LiAlH4 in ether solution
2. H3O+ protonation
full reduction
tertiary alcohols
1. 2 RMgX(Grignard reagent) in ether solution
give 2 identical substitution
with a can't isolatable ketone intermediate
2. H3O+ protonation
aldehyde
1. DIBAH, toluene
-78℃
2. H3O+ protonation
Partial reduction
transesterification through alcoholysis
Alcoholysis of an ester yields another ester
amides
treat with
ammonia and amines in ether
less commonly used than acid chloride
production
SN2 of primary alkyl halides/ ficher esterification of acids
SN2
carboxylate ion+ R'X(primary alkyl hilide)
only adds primary partner..
ficher esterirication :Nucleophilic acyl substitution
Acid+R'OH(alcohol) in strong/mineral acid catalyst
limitation: require an excess of a liquid alcohol as solvent
Only synthesis methyl, ethyl, propyl, and butyl esters.
because Keq close to 1
all steps are reversible
to move the equilibrium to product
Amides
can be converted into
it's the least reactive acyl derivative
so abundence in biological system
hydrolysis: acids +ammine
similar(basically same) with ester acid/base catalyzed hydrolysis
base catalyst is hard because it can't protonates -NH2 to make a better leaving group
reversible
equilibria shifts by base deprotonates acids product
acid catalyst also followed by internal proton transfer
reversible
equilibria shifts by catalyst protonates NH3 product
but both requires heating in aqueous acid/ aqueous base
Biological enzyme (proteases) catalysts cleavage
identical with ester cleavage with acyl enzyme intermediate
Reduction
amines
Reduction by LiAlH4 in ether solution, followed by H3O+ protonation
converts C=O into CH2
with not ketone intermediate but iminium ion intermediate
common in production of cyclic amines from cyclic amides---lactams
preparation
mostly through acid chloride
+ammonia
+monosubstituted ammine
+disubstituted ammine
Biological
they are not very reactive, relatively stable
Thioesters: RCOSR'
ex. Acyl coA such as acetyl coA
transfer acetyl group to amines
ester + ammine , amide formation
Acyl phosphates: RCO2PO32-/RCO2PO3R'-
summurize
Nucleopiles
H2O
Hydrolysis
yields carboxylic acid
Alcohol
Alcoholysis
also called transesterification when alcoholysis esters
generally catalyst by bases by converting into more neuocleophilic alcolate ion
yields ester
Ammonia/ammine
Aminolysis
yields amide
Hydride H:-
Reduction
yields aldehyde/primary alcohol
Grignard reagent
Grignard reaction
yields tertiary alcohol
thiol
more nucleophilic than alcohol
carboxylate ion
in biological reactions it's called esterification?
Carbonyl condensation
genral
targets
2 carbonyl partners
first partner nucleophilic donor
second partner electrophilic acceptor
they could be identical
symmetrical adol reactions
or different
mixed adol reactions
mixture of product in laboratory
selective product in living system by enzyme
mechanism
1. convert first partner into an enolate-ion nucleophile
by base catalyst
2. add the enolate-ion nucleophilic α carbon to the electrophilic carbonyl carbon of the second partner
The first partner undergo α-substitution
the second partner undergo
nucleophilic 1,2- addition for the adol reaction
nucleophilic acyl substitution for the claisen condensation reaction
nucleophilic 1,4-addition for the micheal reaction
conjugate acid protonates tetrahedral alkoxide ion intermediate
regenerate base catalyst
connect all domains
Adol reaction
Adol?
means aldehyde+alcohol
common result of adol reactions
Targets
Aldehydes and ketones with an α hydrogen atom
mechanism
catalyst by base
ex.NaOH
exactly same as general
reversible
factors affect equilibrium
Reaction condition
Substrate structure
Favors condensation product
aldehydes with no α-substituent
Favors reactant
di α-substituted aldehyde
any steric hinder near the reaction site
the mechanism for reverse reaction is reversed
1. base abstracts the -OH hydrogen from the aldol to yield a β-keto alkoxide ion
2. β-keto alkoxide ion undergo selfcleavage to give one moleclue of enolate ion and one molecule of neutral carbonyl compound
3. conjugate acid protonates enolate ion to regenerate base catalyst
Treatment (compete with normal α-substitution)
they are both base catalyzed/ use enolate ion intermediate
exact experiment conditions different
α-substitution
require a full/1 equivalent of strong base
statergy: ensure every thing happed rapidly
complete convert them into enolate ion
need very low temperature
stop carbonyl condensation
add the 1 equivalent electrophile immediately
reduce the amount of carbonyl condensation
carbonyl condensation
require only a catalytic amount/0.05 equivalent of relatively weak base
small amount of enolate ion are generated
base catalyst are continously regenerated
So, unreacted carbonyl compound still present
then we can warm the mixture
dehydration
between β-hydroxyl group and α-hydrogen
generate conjugated enones or α，β-unsaturated products
they have sharing pi electrons system/ holistic pi MO
more stable than nonconjugated enones
just like conjugated diene
condition
basic
E1cB
through enolate ion
Acidic
E1/E2
through enol
temperature
a bit higher than idol formation
hard to isolate adol, usually the product of carbonyl condensation
Value
move the idol formation equilibrium to product
removal of water
even though the initial equilibrium is unfavored
intramolecular
in dicarbonyl compounds
form cyclic componds
e.x. diketones
mixture of products?
yes, depends on which of the 2 enolate ions is formed
but because the steps are reversible, so when equilibrium reached, only the most stable cyclopentenone product----less starin one----is formed thermaldynamically
Claisen condensation reaction
Targets
between 2 ester molecules
treatment
1 equivalent of a base
e.x. sodium ethoxide
Na+EtO-
mechanism
1. EtO- abstracts an acidic alpha hydrogen atom from an ester molecule, yielding an ester enolate ion.
2. The enolate ion adds in a nucleophilic addition reaction to a second ester molecule, giving a tetrahedral alkoxide intermediates
3. The tetrahedral intermdiate expels alkoxide ion to yield a new carbonyl compound, ethyl acetoacetate
This is different from aldo reaction
it doesn't expel the leaving group
here because alkoxide ion is good leaving group
So it's actually together a nucleophylic acyl substitution
4. But ethoxide ion is strong enough base to deprotonate ethyl acetoacetate, shifting the equilibrium and driving the overall reaction to completion
It requires a full equivalent of base！
drive reaction to completion
increase yield
Pronation of the enolate ion by addition of aqueous acid in a seperate step yields the final β-keto ester product
The product
highly acidic
because it has "doubly activiated" hydrogen atom
but require the starting ester have more than 1 α hydrogen, or the product will not have hydrogen atom beween 2 carbnonly groups
Intramolecular
diesters
1,6-diester
produce five membered cyclic β-keto ester
1,7-diester
produce six membered cyclic β-keto ester
They can be further alkylated and decarboxylated
just like acetoacetic ester synthesis
prepare 2-substituted cyclohexanones and cyclopentanones
called Diekmen cyclization
The Micheal reaction
conjugate carbonyl additions
nucleophilic enolate ion reacts with an α,β-unsaturated carbonyl compound
by nucleophilic 1,4-addition
best example
enlate ion derived from
β-keto ester or other 1,3-dicarbonyl compound
conjugate carbonyl compound
unhindered α，β-unsaturated ketone
actually there are far more choices
p 729
Stork reaction
The nucleophile is an enamine
as we saw it's produced by adding 2' amine to carbonyl group, usually ketone
:NR2-CR=CR2
which has similar resonance with enolate ion
with nucleophilic alpha carbon
p 731
it adds to an α，β-unsaturated carbonyl acceptor in a micheal-like process.
3 general steps
1. enamine formation from a ketone
2. Micheal addition to an α，β-unsaturated carbonyl compounde
3. enamine hydrolysis back to a ketone
net effect
Just equal to Micheal addition of a ketone to an α，β-unsaturated carbonyl compond
it advantage to direct micheal addition
enamines are neutral, easily prepared, handled than enolate ion
enamine can introduce monoketones
but enolate ion can only form from β-dicarbonyl componds
common in biological system
Carbonyl α-substitution
Keto-enol tautomerism
normal enol less than 0.0001%
But very reactive
contribute to a lot of chemistry
exist in all carbonyl compound with α hydrogen
ketone
aldehyde
carboxylic acids
ester
other carboxylic acid derivatives
ester, acids, amides are ever smaller enolized
so they do not udergo common acid catalyst α substitution
but they can be converted by LDA into enolate ions
Catalysis
acid
1. protonation of carbonyl oxygen
2. conjugate base deprotonate the intermediate cation's α cation
regenerate the acid
like E1
base
1. deprotonation of 1 α-hydrogen
2.conjugate acid(water) protonates the enolate ion
usually neglected when strong base is applied
directly produce enolate ion
This indicate another imortant fact
α-hydrogens are acidic!
increase 10^40 times than alkane
acidity is further increased if we flank the hydrogen atom by 2 carbonyl group
negative charge delocolizes over both carbonyl group
orbitally, enolate ion formes when C-H bond is roughly parallel to the carbonyl groups' p orbital
practically, strong base like LDA is used to completely converte carbonyl compoud into enolate ion
LDA is also steric hindered
Both intermediates
1.intermediate cation
stabalized relative less
bad resonance structure
positive charge on oxygen
2.enolate ion
stabalize more
two forms
form 1: negative charge on carbonyl oxygen
electrophile react on oxygen
yield enol derivative
form 2: negative charge on α carbon
electrophile react on carbon
yield α-substituted carbonyl compound
ex. halogenation, alkylation
good resonance structure
more common reaction intermediate than enol
better nucleophiles: 1 negative charge
easy to be isolated/prepared
are stabalized by 2 resonance forms
and can be converted forward or back
other reactivity fact
enol tautomer's α carbon is most electron rich/nucleophilic
electron contributes by enol's resonance
by oxygen
So
attack site of electrophile
α-substitution
2 possible enol/ enolate ions in ketones some times both exist(left/ right)
enol cases are effected by intermediate carbocation stabilization
more substituted C+ more favor
enolate ions further reactivity should consider steric hinder effect
less hindered more favor
SN2
α-substitution
mechanism
Acid catalysis
1. acid protonates carbonyl oxygen
2. an enol is produced through tautomerism, and acid catalyst regenerated
PS: the real reaction is happened on enol, but not the cation intermediate
not like the base reaction happened on enolate ion intermediate
2. electrophile attack the double bonds yields resonance stabalized cation intermediate
electrons come from oxygen
yieled cation intermediate
2 resonace structures
more stable c+ is favored if 2 sides can choose in ketone cases
3. base deprotonates hydrogen on oxygen
evidence
use D3O+
rate of deuterium exchange
means D exchange α hydrogen
rate limiting
equal to rate of halogenation
Base catalysis
SN2 between enolate ions and alkyl halide
Real example
halogenation of ketone& aldehyde (common acid catalysis α substitution)
halogens in acidic solution
favor more substituted α position
Because its enol with more double bond stabilizaton
also more stable c+ is favored
E2 elimination can followed
treat by pyridine or other steric hindered bases
generate double bonds
α-bromination of carboxylic acid (HVZ reaction)
treatment
1. Br, PBr3
2. H2O
mechanism
carboxylic acid + Br ---acidbromide + HBr
HBr catalyze enolization of acidbromide, yield acid bromide enol
Acid bromide enol reacts with Br2 yields α-bromo acid bromide
α-substitution
addition of water hydrolyzes the acid bromide
nucleophilic acyl substitution
finally yields α-bromo carboxylic acid
alkylation
Happens only on enolate ions
base catalysis
treatment
alkyl halide or tosylate
reactivity
-X
Tosylate>-I>-Br>-Cl
R-
H3C->RCH2->Allylic>benzylic
mechanism
SN2
nucleophile
enolate ions' negatively charged α carbon
It is more favored when the negative charge is in less steric hindered carbon
determine main product in ketones
electrophile
carbon on alkyl halide
examples
malonic ester synthesis
R-X -----> RCH2CO2H(acid)
elongate 2 carbons
routes
p708
produce enolate ion
2 alkylation steps, second one is intramolecular
followed by hydrolysis/ decarboxylation
Acetoacetic ester synthesis
R-X -----> RCH2COCH3(ketone)
elongate 3 carbons
routes
p 711
enolate ion formation
1/2 alkylations
decarboxylation followed
direct alkylation of ketones, esters, and nitriles
mono carbonyl compound
their enolate ion are harder to form
LDA is needed to generate enolate ion
Compete with nucleo philic addition
eventhough another compete reaction is dominant
carbonyl condensation reaction between enolate ions
nonpolar solvent THF
Both involve dicarbonyl compounds
easy to generate enolate ion