Carbonyl Reactivity

1. Explain, using both resonance and frontier molecular orbital (FMO) arguments, why
carbonyls are electrophilic at carbon, but alkenes are not typically electrophilic.

O O From an MO perspective, while both carbonyls

and alkenes have an antibonding * orbital, the
electronegative oxygen of the carbonyl lowers
the energy of the orbital suf f iciently that it can
Carbonyls have a "resonance contribution" act as a much better acceptor, with the larger
that places a positive charge on carbon orbital coef f icient ("lobe") on the carbon atom.
and a negative charge on oxygen, making
the carbon essentially permanently
electrophilic. Alkenes lack this stabilized
resonance structure, because each carbon
could be negatively or positively charged,
but either way it is a very poor resonance
contributor.

2. Using both resonance and frontier molecular orbital (FMO) arguments, rationalize the
reactivity of the following carbonyl compounds towards nucleophilic attack.
Most reactive Least reactive

OH NR2 O NR

OH NR2 O NR

These resonance structures become progressively worse f rom lef t to right -- thus the degree to
which positive charge is localized on carbon is less, and reactivity as an electrophile decreases
accordingly.

From an MO point of view, as the electronegativity of the heteroatom increases (also taking
f ormal charge into account), the energy of the * antibonding orbital is lowered, increasing the
orbital coef f icient on carbon, making it more accessible to attacking nucleophiles and thus more
reactive.
 Carbonyl Additions: Synthesis and Reactivity
1. Provide a complete synthesis of the following desired product starting from benzene. You may use any
inorganic reagents, plus any organic reagents with six or fewer carbons. You do not need to show any
mechanisms.
Starting Material O O

Cl
AlCl3 1. MeMgBr

2. H+ workup

OH

(+/-)

Desired Product

2. In the borohydride reduction of ketones, it is observed that cyclobutanone reacts approximately 17 times
faster than acetone. Explain this observation.
O OH
NaBH4 O NaBH4 OH
is 17x faster than
MeOH MeOH

This is a comparison that has its basis in strain and bond angles. The ideal bond angle f or sp2
carbons (such as in carbonyls) is 120 , compared to that f or sp3 carbons (such as in alcohols),
which is 109.5 . The f our-membered ring (cyclobutanone) is more strained, as it deviates greatly
f rom the ideal bond angle. Thus, relief of strain is a great motivating f actor that helps speed the
reduction -- the ketone f orm possesses approximately 30 of strain, while the alcohol f orm has
only about 20 . Acetone does not exhibit this strain, so it has "nothing to gain" f rom reacting in
this context -- it lacks the same thermodynamic (enthalpic) driving f orce.

3. Explain the selectivity observed in the following hydride reduction:

Ph Ph
Ph Ph
NaBH4
O OH
Try to see the system in
3D, or build a model: it O N MeOH N
Me O Me
will become clear that H
H
only one carbonyl's *
antibonding orbital can trajectory
be attacked; the other accessible H H is blocked!
is sterically blocked both carbonyl
above and below the ring
by the bulky phenyl group! H

O N Ph O
Me
 Arrow-Pushing with O and N
Oxygen and nitrogen are uniquely powerful arrow-pushers, because they have two useful properties:

1. Lone pairs that can act as bases or nucleophiles.

2. High electronegativity, which also makes them good leaving groups under many circumstances.

Let's look at these properties in more detail. Note: in all the structures shown below, the O or N is shown
without any protons attached, since the details of protonation may vary with the conditions. The group "X" is
any potential leaving group, "Nu:" is any nucleophile, and "E+" is any electrophile (such as CH3I).
These illustrations are only schematic; actual molecules might be protonated or deprotonated as appropriate,
and could have multiple bonds (C=O or C=N).

LONE PAIR REACTIONS: the atom prefers to be unprotonated and/or negatively charged.
Protonation Reaction with Electrophile "Lone Pair Push"
+ E +
H
O
O O
H
H H X
X X

H+ E+
N
N N
H
H H X
X X

LEAVING GROUP REACTION: the atom prefers to be protonated and/or positively charged.

Reaction with Nucleophile ("SN 2-like") "Neighboring Proton Pull" ("E2-like")

O
O
H B:
X H
X
Nu:

N
N
H B:
X H
Nu: X

Now describe each of the steps in the following mechanism in terms of the above ideas. Look at ALL the
atoms!
H+ H+
O OH OH OH OH 2

N N
Protonation NH HN H CH3 CH3
H HN
H 3C NH 2 CH3 CH3
CH3 :OH 2
Rxn H 2O: Lone
with Protonation Deprotonation
pair
Nu φ Deprotonation
push
 Carbonyl Addition: Simple Mechanisms
Provide a complete curved-arrow mechanism for each of the following transformations.

O NaBH4, MeOH
Mechanistic OH
reminder: H
Donor: BH H
Acceptor: * CO
H B H
H
H OMe
O

H
H

O 1. EtMgBr OH
Mechanistic
reminder:
H 2. H+ workup
Donor: CMg
Acceptor: * CO
Et MgBr

H
O

H H
O O H3O+ HO OH
H
H H

OH
OH
H
O
H
H :OH2
:OH2
 Carbonyl Addition: More Mechanisms
Provide a complete curved-arrow mechanism for each of the following transformations.
O OH
1. MeLi (1 equiv.)
H
O
H 2. H3O+ workup

O O
organolithium
addition to
H carbonyl H
H O

O Li Me
H
hemiacetal H O
OH f ormation O H

O O

OH
HO CN NaOH, H2O
OH O
H

HO
H O CN O CN
OH OH
H H
reverse of
cyanohydrin
f ormation OH
O O H
O O
H H
H OH
hemiacetal
OH
O
f ormation
O
O
 More Carbonyl Reactivity

1. Explain the ranking of equilibrium constants for the hydration reactions of the substrates
shown below.
O H2O HO OH [hydrate]
Keq =
R R' R R' [carbonyl]

Carbonyl Compound Keq Value Explanation

O
Electron-withdrawing groups (here, the
1 x 106 f luorines) destabilize the carbonyl f orm
F3C CF3 (carbon has a partial positive charge); the
hydrate f orm does not have this resonance
O contributor, and is thus not as destabilized
3 x 104 by the EW Gs.
F3C H

O
2 x 103
H H
Alkyl groups are electron-donating, and
thus stabilize the electron-def icient carbon
O of the carbonyl, so the pref erence f or the
1
hydrate f orm at equilibrium is greatly
H3C H diminished relative to the above species.

O
1 x 10-3
H3C CH3
Resonance with the aromatic ring f urther
O stabilizes the carbonyl, such that the
species would actually be destabilized by
CH3 9 x 10-6 f ormation of the hydrate -- remember,
"when there's a choice, choose
conjugation!"

2. The following compound has two carbonyl groups, but only one will become hydrated under aqueous
conditions. Which one is it? Draw the structure of the hydrate. Can you explain why the value of the equilibrium
constant for the hydration reaction is 0.8?

O HO OH
OCH3 H2O OCH3
H3C H3C
O O
Ketones are more electrophilic than esters (the alkoxy moiety is electron-donating by resonance,
raising the energy of * CO and making it a worse acceptor),so only the ketone will be hydrated.
The equilibrium constant can be explained by the f act that the neighboring ester carbonyl is
inductively withdrawing, slightly stabilizing the hydrate f orm more than f or a regular ketone.
 Oxidation of Alcohols: Mechanisms
There are two main steps in the mechanism of CrO3 oxidations. Let's figure out the mechanisms by making
analogies to other, similar mechanisms you learned in Chem E-2a. Draw the "analogy" mechanism first,
then try to figure out the chromate mechanism:

Analogy Oxidation Mechanism

1. Formation of Sulfonate Ester (E-2a) 1. Formation of Chromate Ester (E-2b)

pyridine pyridine
RCH2–OH + ClSO2R' RCH2–OSO2R' RCH2–OH + CrO3 RCH2–OCrO3H
O O
O
S
R' Cl Cr
O O O

RH2C O Cr O
R' O
O O O
S Cr
O H
O RH2C O
RH2C O
N
H H
N N

2. Elimination (E2) to form C=C (E-2a) 2. "Elimination" to form C=O (E-2b)

H KOtBu H H H
pyridine
O O
H H
t
R OSO2R' BuOH R R CrO3H R

t
BuO:
H N
H
H
H H
R OSO2R' R O
O
H R
R CrO3H

3. Under aqueous conditions, primary alcohols (such as the one above) are further oxidized to carboxylic
acids because the aldehydes become hydrated. Provide a complete curved-arrow mechanism for the acid-
catalyzed hydration of an aldehyde, and show how it can be oxidized to a carboxylic acid. (You can make an
analogy to the acid-catalyzed hydration of an alkene.)
O
H H H
H3O + OH CrO 3
O R OH
OH H2O
R R H2O: H
H OH
H H
H OH OH
OH :OH2 O
H H R
OH OH O OH
OH R O R CrO3H
R
R O Cr O O
H Cr R
:OH2
H2O: O O O O Cr O H
O
 Carbonyl Addition-Elimination: Acetals and Imines
Provide a complete curved-arrow mechanism for each of the following transformations.
Why are these referred to as "addition-elimination" mechanisms?

O OH
H HO
O O
H +
H cat.
H
OH

H
:sol
O O H
HO
OH
H

OH
H OH H+ transfer O O
O
OH
OH2
OH

In borh of these mechanisms, the nucleophile adds to the carbonyl, and a leaving group is eliminated
to re-form the C-O double bond.

H H O NH2 N
O
H H pH 5 H
OH

NH2

:OH2

HO H2O H
H+ transfer N
N H HN H
H2 H
 Imines and Enamines: Challenging Mechanisms
Provide a complete curved-arrow mechanism for the following transformation.

OMe
O
H2N
OMe
H
H+ N

OMe
+
H
OH OMe
O:
NH2
H H
OH
OMe
:

H2N H+ transfer
OMe

H OMe OMe OMe

+
:

OMe H transfer OMe OMe

:NH
N NH

OH2

:solv H+
Me Me
O O :OMe
H

N N N

:solv H OMe
H

N N N
 Carbonyl Reactivity: Hydration
Ninhydrin, shown below, is a triketone that has been used for the detection of amino acids.
In aqueous solution it exists as a monohydrate. Indicate which of the three ketones is
hydrated (draw the hydration product), and briefly justify your answer.

O O
H 2O
O OH
OH
O
O
ninhydrin
ninhydrin monohydrate

The two carbonyls adjacent to the phenyl ring are in conjugation with the aromatic π system and are thereby
stabilized, making them less electrophilic (and thus less likely to react) than the central ketone.

More importantly, the central ketone is strongly destabilized by the presence of two neighboring carbonyl
groups; as this ketone is adjacent to two electron-withdrawing groups, it is very electrophilic and undergoes
hydration relatively rapidly.
 Carbonyl Reactivity: Bisulfite Addition Complexes
1. You first learned about sodium bisulfite, NaHSO3, in the context of dihydroxylation of
alkenes, although you were not shown the mechanism. Aqueous sodium bisulfite also
reacts as a nucleophile with certain highly reactive aldehydes and ketones. The structure of
sodium bisulfite is shown below; draw a complete arrow-pushing mechanism for the
following transformation. (Hint: what is the HOMO of sodium bisulfite?)
Sodium bisulfite, O
NaHSO3: HO SO3Na
NaHSO3
O
H2O
S
HO ONa
O
O H H
S
HO ONa
O O
O O S ONa

2. The compounds shown below, called acetophenone and pinacolone, do not react with
aqueous sodium bisulfite. Provide a brief explanation for why each fails to react. You
would do well to consider the conditions under which the reaction occurs in both cases.
O
NaHSO3
CH3 No reaction!
H2O

acetophenone

O
H3C NaHSO3
CH3 No reaction!
H2O
H3C CH3
pinacolone
In the case of acetophenone, resonance contribution f rom the attached aromatic ring makes the
carbonyl carbon much less reactive as an electrophile, and since there are no protons available in
solution to protonate the carbonyl and activate it towards nucelophilic addition, the reaction does
not proceed.

In the case of pinacolone, it is the steric bulk of the tert-butyl group that prevents reaction. Recall
f rom E-2a that, as we saw in the cases of SN2 reactions and epoxide ring-opening reactions, under
basic conditions reactions tend to be driven by steric considerations rather than electronics, so
too much steric bulk can hinder (or in this case completely prevent) approach of the nucleophile.
 Carbonyl Reactivity: Acetals
A student attempted to prepare the 1,3-dioxolane of p-anisaldehyde according to the
equation shown below:
O
CHO OH
HO O

MeO H+ cat. MeO

Draw a complete curved-arrow mechanism for this transformation as written.

O H sol: H
O
H
O
MeO
MeO
HO
OH
O
H
OH
HO MeO
MeO

OH OH2
+
OH H transfer OH
O O
H
MeO MeO

Unfortunately, the reaction failed and the student isolated only unreacted starting materials.
In fact, all attempts at preparation of an acetal of this aldehyde failed, regardless of the
alcohol chosen to protect it. Explain briefly why this reaction was unsuccessful. Your
explanation must incorporate clearly drawn diagrams/resonance structures to be considered
complete.
As you know, methoxy groups are powerf ul resonance donors into pi-electron systems; carbonyls are
conversely electron-withdrawing. W hen the carbonyl oxygen is protonated it becomes more
electronegative,
drawing more electron density f rom the ring, but the methoxy group helps to compensate f or this ef f ect.
T hus the resonance structure shown below is a signif icant contributor, and the carbonyl carbon f ails to be
suf f iciently electrophilic to react with the alcohol and f orm an acetal!

OH OH
no electrophilic
carbonyl carbon!
H H

MeO MeO
 Carbonyl Reactivity: Acetal Hydrolysis
Rank each series of acetals below in order of decreasing rate of acid-catalyzed hydrolysis (1 = fastest rate of
acetal hydrolysis; 3 = slowest rate of acetal hydrolysis). Explain your answers. (Hint: For part (b), it may be
useful to note that the rate-determining step of acetal hydrolysis is alcohol elimination from the O-protonated
acetal to form the oxonium ion.)

EtO OEt H3C EtO OEt

EtO OEt
H3C H3C
(a)
CH3
H3C H3C CH3 H3C CH3
CH3

1 3 2

Acetal hydrolysis relieves steric crowding; the ketone is less congested. Crowded
acetals exhibit the greatest steric destabilization of the acetal relative to the ketone,
so they hydrolyze more quickly than less crowded acetals. Acetal 1 is the most
crowded, so it hydrolyzes the fastest. Acetal 3 is the least crowded, so it hydrolyzes
the slowest.
EtO OEt EtO OEt
EtO OEt
(b) H H
H3C H
MeO

2 1 3

Since the rate-determining step of acetal hydrolysis is formation of the oxonium ion, we
compare the stability of the three oxonium ions formed:

OEt OEt
OEt
H H
H
:

MeO

OEt OEt

H H

MeO
Oxonium ion stabilized Most stable oxonium ion: Least stable oxonium ion:
by neighboring phenyl stabilized by neighboring no special stabilization by
ring (more resonance phenyl ring and the electron- any neighboring groups
structures are possible) donating methoxy substituent
(shown above)
More stable oxonium ions are formed more quickly, and hence result in a faster rate of acetal
hydrolysis. Acetal 1, with the most stable oxonium ion, hydrolyzes fastest. Acetal 3, with the
least stable oxonium ion, hydrolyzes slowest.
 Aldehydes and Ketones: Multistep Synthesis
1. Propose a synthetic pathway for the following multistep transformation.
Starting Material
1. NaH
NaBH 4
2. EtBr
H
MeOH
HO O
O
Use the methyl substituent 1. O3
as your synthetic "handle"! O H 2. Me 2S

1. PhMgBr O

2. H + workup
OH O

CrO3

O O

Desired Product
2. Propose a synthetic pathway for the following multistep transformation. You may ignore
stereochemistry.
Starting Material

THPO 1. BH 3, THF THPO OH

HO O
2. H 2O 2, NaOH
H + cat.
(must use pyridine!!!
Without it, we're under CrO3, pyridine
acidic conditions and the
THP ether will hydrolyze)

OH MgBr THPO O
HO 1.

2. H 3O+ (workup
and deprotect)

1. BH 3, THF OH
2. H 2O 2, NaOH HO
OH

Product

Desired Product
 The Wittig Alkene Synthesis
1. Provide a complete arrow-pushing mechanism for each step in the following reaction
sequence. What is the final product?.
1. Ph3P
Br
2. nBuLi
3. acetone
Ph3P:

PPh3
PPh3 PPh3
PPh3 O O
H
:Bu O

2. Propose a synthetic pathway for the following multistep transformation. The Wittig
reaction should be a key step in the synthesis.
Starting Material
OH CrO3 O Ph3P CH2

Br2

Br
Br

Desired Product
3. Propose a synthetic pathway for the following multistep transformation. The Wittig
reaction should be a key step in the synthesis.
Starting Material

mCPBA 1. MeMgBr
Ph Ph Ph
+
2. H workup
O OH
CrO3

Ph Ph
Ph3P CH2
O

Desired Product
 Wittig Mechanisms
1. Provide a complete arrow-pushing mechanism for each step in the following reaction
sequence.

1. NaH Ph
Br PPh3 O
2.
Ph
Ph Ph

H
H
H H
PPh3
Br PPh3 Br PPh3

Ph
O
Ph
Ph3P O Ph3P O
Ph Ph PPh3
Ph Ph

O PPh3

Ph

Ph
 More Wittig Mechanisms
1. Provide a complete arrow-pushing mechanism for all steps in the following reaction
sequence. 1. Ph P 3
2. nBuLi
I
3. O
Ph 3P: H

Ph 3
P
O
PPh 3
H

Bu:

PPh 3
O
PPh 3 O
H

2. The following similar multistep transformation was attempted, but was did not work. As it
turns out, the desired ylide forms, but is unreactive. Provide a curved-arrow mechanism for
the formation of the ylide, and analyze its structure to explain why it is so unreactive.
O

1. Ph 3P H
I ylide
2. nBuLi
Not formed!
Ph 3P:

This ylide is a cyclic, fully conjugated system with

PPh 3 4n+2 π electrons -- it is aromatic! Thus it is very
PPh 3 stable, and would be an extremely poor
H nucleophile (donation of its electrons would break
the aromaticity).
Bu:
 Ylide Mechanisms
1. Provide complete curved-arrow mechanisms for each of the following transformations.

O CH 2 O

(a) S
H 3C CH3
+ S(CH3) 2
(This one is hard; start with a list of
bonds you need to make and break, and (+/-)
don't forget the basics of arrow-pushing!)

O O O

CH3
S
CH3
CH 2 S
(+/-) (+/-)
S H 3C CH3
H 3C CH3

1. MeI O
(b) H
CH3 2. KOH
S

O O O

H H
CH3
:

CH3 S
S
:

H 3C :OH CH3
S H
Me I CH3

O:
O CH3
S
CH3
S
H 3C CH3
(+/-)
 Aldehydes and Ketones: Reagents
Each of the following transformations can be carried out in one or two steps. Fill in the reagents required for
each step. If a step is not needed, mark an X for that step.

OEt 1. H3O +

OEt 2. Zn(Hg), HCl

or H2NNH2 , KOH, Δ The Mozingo reduction may also
3. X
be used, though it requires a third
step:
2. H + cat., HS SH
3. Raney Ni

O
1. OsO 4

2. NaHSO3 , H2O O
O
3. , H+ cat.

OMe
OH CrO 3
1. OMe

2. MeOH, H+ cat.

3.

N
1. O 3

2. Me2S

3. NH 2 , pH 5

HO

O H3O +
1.

O 2.
NaBH4, MeOH HO
3.
OH