Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 1

Weak Nucleophile/Base (and strong acid) Conditions (H2O and ROH) with Carbonyl Compounds and
Epoxide Compounds

Weak nucleophiles (water, H2O and alcohols, ROH in our course) react with secondary and tertiary RX
compounds (SN1 > E1 reactions). Also, methyl and primary alcohols react under strong HX acid conditions via
SN2, while secondary, and tertiary alcohols react under strong HX acid conditions via SN1 (HX = HCl, HBr, HI).
All alcohols react via E1 reactions with H2SO4/. Rearrangements are always a possibility in carbocation
chemistry.
Weakly electrophilic carbonyl, nitrile and epoxide compounds also become strongly electrophilic in strong acid
and protic solvents. We will only use limited examples (H2O, ROH and amines) to introduce these reactions. In
weak base/nucleophile reactions (strong acid) the order of events is usually 1. Add a proton, 2. add weak
nucleophile and 3. lose extra proton). Because the acidic conditions are usually strong protic acid, the solvents
used are typically protic (H2O/H2SO4 = H3O+/H2O or ROH/TsOH = RO+H2/ROH).
Carbonyl reactions with water and alcohols often have products and reactants in equilibrium with one another,
while with epoxide reactions are irreversible, due to the release of large ring strain. Writing mechanisms in acid is
often longer (than base) because there is an initial protonation step, sometimes intermediate resonance structures,
and a final deprotonation step required.
One final point is that water is often used to shift the equilibrium, in acid, to one side or the other by adding
water (hydration) or removing water (dehydration). The acid we will use when water is the solvent will be sulfuric
acid (H2SO4) and the acid we will use when an alcohol is the solvent (nonaqueous) will be toluenesulfonic acid
(TsOH). You can think of TsOH as ‘organic’ sulfuric acid. Other acids are possible, but not discussed here.
Very strong acids used in our course.
H OTs H OSO3H
O O H
H O Ts H O SO3H
H O S = H O S O
pKa -1
=
pKa -3
O O
used in nonaqueous conditions used in aqueous conditions
toluenesulfonic acid = TsOH (it's like "organic" sulfuric acid) sulfuric acid = H2SO4

Generic Carbonyl Addition Reactions of Aldehydes and Ketones in Aqueous Acid (= hydration)
Write a step-by-step mechanism for O
H H
the addition of water to an aldehyde H H H2SO4 O O
or ketone = carbonyl hydrates. This C O
is a reversible reaction that favors C
R R'
the C=O side of the equilibrium. R R'

Possible mechanism without details (you add those)

H O SO3H O SO3H H3O

H H
H H O O
O O O
R C R' R C R'
C C resonance C
R R' H H H H
R R' R R' O O
O O
H H H

Possible mechanism with details.

H O SO3H O SO3H H3O
H H
H H O proton O
O O O add nucleophile
to carbocation transfer
R C R' R C R'
C proton C resonance C
R R' H H H H
R R' transfer R R' O O O
carbonyl O
H H H
compound carbonyl
equilibrium reaction, usually favors carbonyl compounds, except when R = R' = H hydrate
Write a mechanism for the reverse reaction = dehydration of carbonyl hydrate to carbonyl and water.
Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 2

Write a step-by-step mechanism H H O

O O H2SO4
for the elimination of water from H H
a carbonyl hydrate. C C O
R R' R R'

Possible mechanism without details (you add those).

H H OH2
H H
H O H OH2
O O H
O O O
R C R' R C R'
C resonance C C
O O R R' R R' R R'
H H OH2
H H
equilibrium reaction, usually favors carbonyl compounds, except when R = R' = H
Possible mechanism with details.
H OH2
H H H H
O O H H OH2
O O
O O
R C R' R C R' C
C resonance C R R'
O O R R' R R'
H OH2
H H H

Carbonyl Addition Reaction in Alcoholic Acid (forms a hemi-acetal/ketal), followed by an SN1 reaction (forms
an acetal/ketal). To form the acetal/ketal requires the removal of water to shift the equilibrium to the right. If water
is added the equilibrium will shift to the left, reforming the carbonyl group and 2 x ROH. This is an equilibrium
reaction that can be pushed in either direction. That turns out to be a very valuable feature of this reaction, called
protection/deprotection that we will study more later.
Write a step-by-step mechanism for the addition of an
alcohol to an aldehyde (or ketone) = hemi-acetal O TsOH H3C CH3
(hemi-ketal). Removal of water forces and additional (-H2O) O O
SN1 step with a second methanol molecule leading to H3C H
C 2 C
an acetal (or ketal). Addition of water forces the O
R R' H2SO4 R R'
equilibrium back to the aldehyde or ketone. H2O
Possible mechanism without details (you add these). O Ts Ts O H
H H
H O Ts H H O O
O O O
R C H R C H
C C C
R H H3C H H CH3
R H R H O O
O O
carbonyl = A H3 C H H3 C
compound hemi-acetal = B
equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left
CH3 H3C H
H3C H3C H O H H
O O H H
O R H O
R H O
R C H H C C
R C H
R C H
O O O
O H3C
H3C H3C remove H2O O
H3C
add H2O H3C
acetal = C acetal hemi-acetal = SN1 reaction
Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 3

possible mechanism with details

Ts O H
H O Ts O Ts H
H
H H add nucleophile O proton O
O O O to carbocation transfer
R C H R C H
C C resonance C
proton R H H3C H H CH3
R H R H O
transfer O O
O
carbonyl = A H3 C H H3C
compound hemi-acetal = B
equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left
proton
CH3 H3 C H transfer
H3C H H
H3C H O
O O O
O H H
R H R H water is a good O
R C H H C C leaving group
R C H
proton resonance R C H
O O O
transfer O
H3C H3C H3C
H3C remove H2O O
acetal = C acetal hemi-acetal = SN1 reaction add H2O H3C

Similar mechanisms with a diol = ethylene glycol (protection of a C=O, aldehydes and ketones)

O
H2 TsOH
Write a similar mechanism when O C H (-H2O) O H H
both alcohols are in the same C O
R R' H C O C O
molecule (= ethylene glycol). H2
R R'

Possible mechanism without details (you add these).

Ts O H H
toluenesulfonic H
H O
acid H O
O O O
H O Ts resonance
O
O H
H
aldehyde H H O
O O hemi-acetal
or ketone O H O Ts hemi-ketal
ethylene glycol

H H (remove) H H
O O
O Ts Ts O

O H resonance
O O
O O O
O H H
H
O O O
acetal or ketal
equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left
Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 4

possible mechanism with details

O Ts H
toluenesulfonic H
H Ts O H O
acid H O
O O O
H O Ts resonance
O
O H
H
aldehyde H H O
O O hemi-acetal
or ketone O H hemi-ketal
O Ts
ethylene glycol

O Ts H H (remove) H H
O O
Ts O

O resonance
O H
O
O O O
O H H
H
O O O
acetal or ketal

Write a mechanism for the reverse reaction (deprotection of a carbonyl).

O
Write a mechanism for O H2SO4 H2
O H H O C H
the reverse reaction using O C
C H C O
H2SO4 / H2O. R R' H2
R R'
Possible mechanism without details (you add these). H H
O
H H O
H OH2 O
H H
O resonance
O H
O
O O
O H O
H H
O O O
acetal or ketal

equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left
H
H O
O H H
O
O O
resonance
O
H
aldehyde O
H O H O
or ketone H
O H O hemi-acetal H2 O H
ethylene glycol hemi-ketal
Possible mechanism with details O H H
H H O
H OH2 O
resonance H H
O H
O O
O O
O H O
H H
O O O
acetal or ketal
equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left H
H O
O H OH2 H
O
O O
resonance
O
H
aldehyde O
H O H O
or ketone H
O H O H2O H
ethylene glycol hemi-acetal
hemi-ketal
Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 5

SN1 reaction
addition reaction
A The equilibrium is controlled
B C here. Removing water pushes
carbonyl compound acid hemi-acetal or ketal acid the reaction toward the acetal or
+ acetal or ketal
catalyzed + catalyzed + ketal, and adding water pushes
alcohol alcohol the reaction toward the
water
carbonyl and alcohols
elimination reaction SN1 reaction

Carbonyl groups are very susceptible Acetal/ketal groups are very inert to attack
to attack by strong nucleophile/bases by strong nucleophile/bases such as the
such as the n-butyl carbanion or LDA. n-butyl carbanion or LDA. The diol is also
Also, alcohols are weakly acidic. The protected. This protects the organic compounds
acetal/ketal takes care of both problems. from either point of view.

Formation of a THP protected alcohol. DHP is an enol ether, which a condensation of an aldehyde and a single
alcohol. When a second alcohol is added to DHP in the presence of an acid catalyst (TsOH) and acetal forms,
which protects the alcohol (instead of the carbonyl group). A similar strategy is used, but protects a different
functionality (the alcohol).
overall mechanism for protection of an alcohols as a THP ether (tetrahydropyran, using DHP = dihydropyran and TsOH)
H
O
H R O Ts
R THP
O H
O O sometimes
O written this way
alcohol acetal R
DHP = dihydropyran
(enol ether)
possible mechanism without the details
H H H
H H
H
H OTs alcohol O
resonance H R
H O
O H H R O R
O THP protected alcohol
O H O H O O
DHP = R as an acetal
dihydropyran H
H R
(enol ether)
O

possible mechanism with the details

H H H
H H
H
H OTs alcohol O
resonance H R
H O
O H H R O R
O THP protected alcohol
O H O H O O
DHP = R as an acetal
dihydropyran H
H R
(enol ether)
O

H
Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 6

Deprotection of a THP protected alcohol

overall mechanism for protection of an alcohols as a THP ether (tetrahydropyran, using DHP = dihydropyran and TsOH)

O
H H O
R
H H
O H OH2 HO O H
O alcohol alcohol + aldehyde
R
acetal (discard)

possible mechanism without the details

O resonance H H
H H O
H
O H H
H H H O
O O O
O O O
R O O
acetal R R
H H H
H H alcohol

H2O H H H O
O H H
H
resonance H
O H
HO O H O
O H H
H O O
alcohol + aldehyde H H O O
(discard) O O
H
H H H

possible mechanism with the details

O resonance H H
H H O
H
O H H
H H H O
O O O
O O O
R O O
acetal R R
H H H
H H alcohol

H H O
H2O H
O H H

H
resonance H H
O H
HO O H O H
O O
H O O O
alcohol + aldehyde H H O O
(discard)
H H H H
Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 7

Fischer Ester Synthesis Reaction - In a closely related series of steps it turns out that carboxylic acids and
alcohols can form esters and water (which is removed) using catalytic toluene sulfonic acid. Using aqueous
sulfuric acid and lots of water will hydrolyze the ester back to the carboxylic acid and the alcohol. This is again an
equilibrium controlled by the removal or addition of water. If you can write a mechanism from the overall reaction.
If you need help, use the reactions mechanism written without the details. If you need more help, study the
proposed mechanism and then try the other approaches.
overall mechanism for Fischer esterification
O O
TsOH
H3C H (-H2O)
C H C CH3 O
O
R O R O H H
carboxylic = A alcohol ester = C water
acid
possible mechanism without the details
H O Ts H
H H H O
O O resonance O resonance O H
R C O
C H C H C H C H H3 C H
R O R O R O R O O O
carboxylic H3C H
acid
proton O Ts
equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left transfer

O Ts Ts O H
H H H
H
O O resonance H H
resonance O O
O
H
C CH3 C CH3 H
C CH3 R C O
R O R O R C O
R O
O
O
H3C
H3 C
T.I.
O H H
O
C CH3
R O
water can be distilled out and
removed from the equilibrium
ester
Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 8

possible mechanism with the details

H O Ts H
H H H add nucleophile O
O O resonance O resonance O to carbocation H
R C O
C H C H C H C H H3 C H
proton R O R O
R O R O O O
transfer
carboxylic = A H3C H
acid
proton O Ts
equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left transfer

O Ts Ts O H
H H H water is a good H
O
resonance
O resonance O leaving group, and H H
O
O
a good carbocation H
C CH3 H
C CH3 C CH3 forms R C O
R O R O R C O
R O
O
proton O
H3C
transfer H3C
water can be T.I. = B
O H H
distilled out
and removed O
C CH3
R O from the equilibrium
ester = C

Propose a mechanism for the reverse reaction: acid hydrolysis of an ester.

overall mechanism for hydrolysis of an ester to an alcohols and carboxylic acid
O O
TsOH
H3C H
(-H2O) C H
C CH3 O O
R O R O
H H
ester water carboxylic acid alcohol
possible mechanism without the details
O H OH2 H H
H H H
O
O O resonance O
C CH3 H
resonance
R O R C O
C CH3 C CH3 C CH3
ester R O R O R O
H H O
O H3C

equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left
H H
O H H H O O
O O O H H
C H resonance resonance R C O R C O
R O C H C H C H
R O R O R O O O T.I.
carboxylic acid
O H3C H H3C
H3 C H H2 O H
Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 9

possible mechanism with the details H

H H H H H O
O H OH2 O O O
O
resonance
resonance H
CH3 O
CH3
O O O O
O H
ester O CH3 H3C
CH3
H H
water
O
H H H
H H
O H3C O H H H
H O H
alcohol O O
O H H H
O H H
O O
resonance resonance O O
H H O O
O H H H
O H3C H H3C
O O
carboxylic
acid H O

There are many examples of carbonyl groups reacting with primary RNH2 The following reaction shows
the formation of simple imines with carbonyl groups. Reaction with hydrazine (H2NNH2) is similar.
Write a mechanism for imine
H R
formation usingTsOH (-H2O). O
Neutral nitrogen is a good enough N R H OTs N O
nucleophile to attack without H H
protonating the carbonyl group. H (remove)

possible mechanism without the details

H
H H H H
H O
O TsO H O O (remove)
O H

N R
N N N
H H N
R R R
R NH2 H H H R
H
equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left
resonance
Imines can be made into amines using sodium 1. NaH3BCN
cyanoborohydride (NaH3BCN),followed by workup. H 2. workup
HN
Reaction with hydrazine, followed by strong base R
and heat can reduce the C=O to a CH2. This R'ONa /  N
N R
reaction is called the Wolff-Kishner reduction. C when R = NH2
R R NH2 H
H2

possible mechanism with the details

H
H H H H
H O
O TsO H O O (remove)
O H

N R
N N N
H H N
R R R
R NH2 H H H R
H
equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left
resonance

R NH3 N
N R
R R NH2 H
Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 10

When carbonyl groups react with secondary amines, R2NH, enamines form. Enamines are nucleophilic
on the second carbon of the C=C double bond. They are neutral versions of enolate chemistry in
reactions with common electrophiles, and very similar to biochemical examples in nature. The following
reaction shows the formation of simple enamines with carbonyl groups. After reaction with an
electrophile they can be hydrolyzed back to a carbonyl group.
Write a mechanism for enamine H
formation using 2o amines and TsOH O
(-H2O). Neutral nitrogen is a good N H OTs O
N H H
enough nucleophile to attack without
(remove)
protonating the carbonyl group.
possible mechanism without the details H
H
H H H O
O H (remove)
O TsO H O
O H

N
N N N N
H
R2NH

equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left
resonance

Br
H3C
CH3 H
H3C H2O N N
N
O can react
hydrolyze
back to C=O with good R NH2
electrophiles
enamine

possible mechanism with the details H

H H H H
H O
O TsO H O O
O H (remove)

N
N N N
H N
R2NH

equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left
resonance

Br
H3C H
H2O CH3
H3C N N
N
hydrolyze
O can react
back to C=O R NH2
mechanism with good
not shown electrophiles enamine
Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 11

Nitriles can be hydrolyzed in milder acid (HCl/H2O) to primary amides and in stronger acid (H2SO4/H2O/) to
carboxylic acids.
Write a mechanism for an acid O
hydrolysis of a nitrile group to O
H OH2 H OH2
a primary amide in HCl/H2O N H
or a carboxylic acid in C O N H
H2SO4/H2O/ (harsher conditions). H H
O
HCl/H2O H H2SO4/H2O/
possible mechanism without the details H H2O H H
H N
N N
H OH2 N
C O
C H H
H H O O
nitrile OH2
H

O
H H H H H H
H N N N
N resonance resonance
H H H
amide H O O O

possible mechanism with the details

H H2O H H
H N
N N
H OH2 N
C O
C H H
H H O O
nitrile OH2
H

O
H H H H H H
OH2
H N N N
N resonance resonance
H H H
amide H O O O

possible mechanism without the details

O H H H
O O O
H OH2
H
H resonance resonance
N H H
N N N
amide H
H H H

O
H H
H H H H H
N O
O O O
H
H H
H H H
N N
O H N
O O
H H H H2O O
H H H
resonance
H

H H
O O OH2 O
resonance
H H H
O O O
Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 12

possible mechanism with the details

O H H H
O O O
H OH2
H
H resonance resonance
N H H
N N N
amide H
H H H

H O
H H H H
H N H OH2 H
O O
O H O
H
H H
H N H
O N N
H
O O
H H H O
H H H
resonance H2O
H

H H
O O OH2 O
resonance
H H H
O O O

Epoxides in Acid Solution

As was the case with carbonyl compounds in acid, epoxides first add a proton. The positive charge in the
intermediate is distributed over the oxygen and both carbon atoms (Ca and Cb, below). The weak nucleophile is
attracted to the backside of the more substituted carbon because it carries a larger partial positive charge than the
less substituted carbon (just like carbocations). This is the opposite epoxide carbon to what was attacked in strong
base (but still backside attack because of the bridging oxygen atom). If the more substituted carbon is chiral, we
should see a change in the absolute configuration (from R to S or S to R).
overall mechanism for epoxides in aqueous acid (H2SO4 / H2O = hydration conditions)
H
O O
H
Cb Ca H OH2 CH3
H H H H Cb Ca
H
H CH3 O H diol compound
O
epoxide compound R absolute configuration
S absolute configuration H

possible mechanism without the details

H O SO3H
H H
H O O
H proton H
O O
CH3 transfer CH3
Cb Ca Cb Ca
Cb Ca H H H H
Cb Ca H H H H
H H O H H O
H CH3 O H
H CH3 O
H H
Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 13

possible mechanism with the details

H O SO3H
H H
H O O
H proton H
O O
CH3 transfer CH3
Cb Ca Cb Ca
Cb Ca H H H H
Cb Ca
H H proton H H O H
O H
H H H
O
H CH transfer
3
H CH3 O
H H
epoxide compound inversion of diol compound
S absolute configuration configuration R absolute configuration
Ca has greater partial positive charge than Cb because it is more substituted, so the weak nucleophile attacks it faster. Notice
that a different carbon of the unsymmetrical epoxide was attacked than was the case in strong nucleophile/base conditions.
Because that carbon is chiral in this example, we can see the inversion of configuration (from S to R), even though there is
an "OH" on both carbon atoms.

overall mechanism for epoxides in alcoholic acid (TsOH / ROH)

H
O O
H
Cb Ca H3 C OH2 CH3
H H H3 C H Cb Ca
H
H CH3 O H hydroxy ether compound
O
epoxide compound R absolute configuration
S absolute configuration H3C

possible mechanism without the details

H O Ts O Ts
H H
H O O
H proton H
O O
CH3 transfer CH3
Cb Ca Cb Ca
Cb Ca H CH3 H H
Cb Ca H H H H
H H O H H O
H CH3 O H
H CH3 O
H3 C H3 C

possible mechanism with the details

H O Ts O Ts
H H
H O O
H proton H
O O
CH3 transfer CH3
Cb Ca Cb Ca
Cb Ca H CH3 H H
Cb Ca
H H proton H H O H
O H
H CH3 H
O
H CH transfer
3
H CH3 O
H3C H3C
epoxide compound inversion of
S absolute configuration hydroxy ether compound
configuration R absolute configuration
Ca has greater partial positive charge than Cb because it is more substituted, so the weak nucleophile attacks it faster. Notice
that a different carbon of the unsymmetrical epoxide was attacked than was the case in strong nucleophile/base conditions.
This is easy to see in this example because "methoxy = -OCH3" (from the attacking weak nucleophile) is different than
"hydroxy = -OH" (from the epoxide oxygen).