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3a) …If X is a leaving group, then you kick out the leaving
group and the result is a SUBSTITUTION REACTION.
Carbonyls
Have X as a Leaving Group Don’t have X as a Leaving Group
Carboxylic Acid (RCO2H) Aldehyde (RCHO)
Ester (RCO2R’)
Amide (RCONR’2)
First, let us look at a generic mechanism for the formation of an acetal or ketal. Here, we start with the
ketone, so we will be forming a hemiketal, and then a ketal.
• In step 1) the oxygen is protonated. This makes the carbonyl carbon more electrophilic by
giving it a greater partial positive charge
• Then the first equivalent of alcohol attacks the electrophile in step 2)
• Then, the tetrahedral intermediate is formed, when this is deprotonated by the :B, the hemiketal
is formed as seen inside the orange box
• The mechanism doesn’t stop here… the remaining alcohol group on the molecule is protonated
by H—B+, to form H2O as a leaving group, with this, a double bond is formed.
• Then, the second equivalent of alcohol attacks the electrophilic carbonyl carbon
• Another tetrahedral
intermediate is formed.
• The HOCH3+ is
deprotonated by the :B
1) and ultimately, the ketal
2) is formed, as shown in the
pink box.
Now let’s look at an example of an intramolecular formation of hemiacetal as seen in the assembly of
cyclic glucopyranose from acyclic glucose.
by
• Mechanism: * remember that this whole process is reversible.
1) 2) 3) 4)
• In step 1) the alcohol attacks the carbonyl carbon, forming the tetrahedral intermediate found in
step 2).
• The H2O here serves as a catalyst The OH is underlined in bold yellow; it serves as a proton
bus in the reaction by shuttling the proton around. For instance in the second step, it
protonates the negatively charged oxygen in the second step. In the third step, it deprotonates
the alcohol. Why should we protonate the O- before deprotonating the +OH? In this case, it
doesn’t really matter what the sequence of the proton transfer is.
• The final product is formed and water is regenerated in step 4).
Is the following a valid mechanism step? NO!! This is not valid because 4 member ring
intermediate has ring strain!
• There is a 1,3 H- shift
• This does not happen because of the nature of
the orbitals
• This process if forbidden
How to speed up the reaction:
Why are hemiacetal/acetal and hemiketal/ketal formation faster in the presence of an acid?
• Because alcohol is a poor nucleophile , it usually helps to have an acid catalyst. Protonating
the alkoxide (RO-) of the tetrahedral intermediate shifts the equilibrium towards the product
side.
• Additionally, acid can protonate the carbonyl oxygen, this increases the electrophilicity of the
carbonyl group.
Why are hemiacetal/acetal and hemiketal/ketal formation faster in the presence of a base?
• Deprotonating the tetrahedral intermediate’s oxonium ion (R2OH+) makes the deprotonated
atom a poorer leaving group.
• The deprotonation also converts the weakly nucleophilic alcohol into a stronger alkoxide
nucleophile.
• The reaction can also proceed in an E2 like fashion that was see in 5b, with the elimination of
water occurring at the same time another water deprotonates the nitrogen so it can form a new
N=C bond, forming the imine.
• The mechanism step shown below CANNOT REALLY HAPPEN in a lab. It can only really
happen in an enzyme where the substrate is held tightly. Why can’t it happen? Because it is a
TRIMOLECULAR COLLISION, which is unlikely.
If we react
Ph Ph
O=< + CH3OH O=<
OH OCH3
You might be thinking that perhaps carboxylic acid is not a good enough electrophile
Ph
O=< it’s lone pairs give it resonance therefore it is resistant to nucleophilic
OH
You might want to deprotonate CH3OH to make it CH3O- but this doesn’t work because it would
rather grab the acidic proton from the carboxylic acid instead of attacking the carbonyl carbon. In
other words, instead of following the black arrow, it would rather follow the pink arrow
Ph Ph
O=< + CH3O- O=< NO REACTION
OH OCH3
In that case, you might want to change the leaving group from an OH to a halogen such as Cl (i.e. react
with an acyl halide instead of a carboxylic acid), however since halogens like Chlorine are reactive, we
realize that we want to start with a carboxylic acid
Ph Ph
-
O=< + CH3O O=<
Cl OCH3
• The reason that there is some delta+ on the carbonyl carbon is because the more electronegative
oxygen is taking some electron density away from the carbon, in a carboxylic acid.
Ph
O== δ+ this δ+ is not very big because of electron donation from resonance
OH
So how do we make the carbonyl carbon more electrophilic? We can protonate the carbonyl oxygen,
this would make the oxygen more electron deficient and make the δ+ bigger
Ph Ph
O== δ+ vs. HO ==+
δ+ protonating the carbonyl oxygen
OH OH makes it more electrophilic
What can we use to protonate the carbonyl oxygen? We can use a strong acid like H2SO4 which does
nothing but protonate!
Ph CH3OH Ph
O== δ+ O==
OH H2SO4 OCH3
This reaction is called a Fischer esterification where we convert the carboxylic acid into an ester
using a small alcohol and a strong acid.
CH3OH H—OSO3H CH3O+H2 ~ first we protonate the alcohol using strong acid
A) the proton goes on the carbonyl oxygen This is better! The oxygen atoms
are more stable because of
resonance!
B) The proton goes on the ‘alcohol’ of the carboxylic acid Doesn’t increase resonance… but
due to subtle inductive effects,
alcohol is more basic
After protonating the carbonyl oxygen, we move on to the step with a yellow star near it. This is the
attack of the alcohol on the carbonyl carbon.
Then, we see in step 3 that the alcohol grabs the hydrogen from the positively charge oxygen in the
HOCH3 group in the tetrahedral intermediate. Then, in step 4, one of the alcohol groups gets
protonated so that it can leave as water in step 5. The carbocation intermediate in step 6 has a
resonance form where oxygen takes the positive charge that was formerly on the carbon, when the
oxygen of this resonance structure is deprotonated by the alcohol in step 7, the end product is an ester
and a protonated alcohol.
4
5
6 7
Tetrahedral intermediates that are the same are underlined in light blue to show that the different
mechanisms arrive at the same products. For the E2 mechanism, a bimolecular interaction occurs
where dehydration occurs simultaneously with the oxygen reforming a double bond with the carbon
while an alcohol deprotonates it.
In the above reaction, the carbonyl is protonated after methanol because methanol is a stronger base.
In real life:
There isn’t much stability difference between a carboxylic Acid and an ester
To drive the reaction towards the ester, we can use Le Chatelier’s Principle
• To go towards the ester, use a large amount of alcohol or remove the water as it is formed
• To go towards the alcohol, add a lot of water
• Note that adding a lot of acid does not influence the position of the equilibrium, you just have
to make sure that the acid is strong (sufficiently acidic) to protonate the carbonyl or alcohol.
In the reaction where:
“H+”
PhCO2H + CH3OH PhCO2CH3 + H2O
In the case of an aldehyde or a ketone, it’s easier for the alcohol to attack the carbonyl carbon, however
the alcohol has more difficulty attacking the ester because of the resonance involved
OH OR’
R OR R’OH
O== R’OH R—C—R in the case of an ester O== R—C—OR”
R R
ketone OH OH
First, the nitrogen of the NH3 attacks the carbonyl carbon, forming a tetrahedral intermediate.
Afterwards, the OCH3 leaves and the new C—N bond is formed
GRIGNARD REACTIONS
In order for carbon (C) to be nucleophilic enough to attack the electrophilic carbonyl carbon, it must
have a sufficiently negative charge.
i.e R3C- : functions as the nucleophile H3C- : this is the carbon anion or “carbanion”
In these reactions we want to form a new C—C bond
Can we use methyl?
H3C—H base H3C- this doesn’t happen because pka ~ 50 for the hydrogens attached
to the carbon in the methyl, therefore it is hard to take away the
proton
But in reality, we don’t need the full negative charge in the Carbon for it to be sufficiently
nucleophilic.
To give Carbon a δ- then it has to be attached to something that is less electronegative than it
• Carbon is more electronegative than any metal
• Metals generally have low electronegativity
δ- δ+
H3C—M electronegativity: less than 2.5 make a C—Metal bond
Electronegativity: 2.5
Usually M = a metal. This metal is usually Magnesium (Mg)
Hence, Grignard reactants are organometallic, this means that they have a Carbon—Metal bond
Why Magnesium?
Mg prefers to be in a 2+ oxidation state base
Do esters and ketones undergo substitution ? Yes, but the net reaction is an addition reaction
δ- δ+ O-
OCH3 1) >—MgBr * the reaction does not end here! It keeps going!
O== δ+ Ph—C— CH2CH3CH3
Ph 2) H3O+
There is more Grignard in
the solution, so the new No leaving group to
Eject leaving carbonyl reacts with more eject so addition occurs
Nucleophile attacks group Grignard reactant
carbonyl carbon
The ester and amide undergo substitution, but when it changes into a ketone, it undergoes an addition
process and converts into the alcohol
~ these reactions are a method of adding more than one carbon at a time, wheareas the Grignard
reactions were for one or more carbons.
CH3 CH3
~this reaction is rather different in that it can make all kinds of different alkyne anions
~the alcohol still has the C==C bond
~ biggest drawback: if you wanted to onl one add carbon, it is dificult because it’s hard to separate the
C==C bond so that only one carbon attaches.
With the Grignard reactants we have created new C—C bonds, what happens when you want to make
a new C—H bond?
• We use metals with a hydrogen attached to it
• Why?
• We want a hydride ion -H: that has a negative charge large enough to attack the carbonyl
carbon
o We need to use a metal that is less electronegative than hydrogen
o 2 are really useful for this process
NaBH4 a borohydride
H
it isn’t very polar but it has a negative charge that it
-
H—B —H would like to get rid of
*the blue bond or any bond for that matter, can be seen essentially
H as “H-“
LiAlH4
Net addition
occurs because
none of the
substituents are a
leaving group
• we could have used NaBH4 as a proton source but it’s concentration is low compared to the
solvent, so we use CH3OH instead
Although NaBH4 is a good source of creating a new C—H bond, it does not react with anything that is
less reactive than an aldehyde or a ketone
O O OH O
NaBH4
alcohol
OCH3 OCH3
• NaBH4 is chemoselective in the above reaction, this means that it operates on one functional
group and leaves the other alone
If we want to react with less reactive carbonyls we have to fine something stronger thanNaBH4.
H—BH3 BH3 in order for it to be more reactive, you have to make B less willing to have a
a negative charge
~looking down at the same row as Boron, we find that we can use Aluminum (Al) which is further
down than Boron
• This is less electronegative so it is more inclined to dump the hydrogen
• More reactive source of hydride
• Good enough to attack esters, anhydrides, amides, etc.
• HOWEVER YOU CANNOT USE A PROTIC SOLVENT due to it’s high reactivity
So our new reactant is:
Li+ H — AlH3
• It reacts just like NaBH4 except that since there’s a leaving group, substitution occurs before
net addition is achieved.
• LiAlH4 can also react with amides to form terminal amines by getting rid of the carbonyl
O
1) LiAlH4 R—CH2NR2
R NR2 2) H3O+
• LiAlH4 is so strong that it can even react with a carboxylate ion
O O H OH
1) LiAlH4
R O- 2) H3O+ R H Ph H
the pink line indicates where the bond is broken when the base attacks the carbonyl carbon
• Hydrolysis is faster with OH- than without it
o Without OH- the nucleophile would be H2O
H3O+
the reaction is slower without H3O+ because the protonation of the carbonyl oxygen increases the
electrophilicity of the carbonyl carbon, making it easier for the water to attack it
Tetrahedral intermediate
fragments
So Chymotrypsin
1) enhances electrophile
2) enhances nucleophile
3) makes new C—C bonds