Exercises in organic chemistry and their solutions

Tarek H. Musslimani
Haifa University, Haifa
Israel

Introduction
This booklet is written for undergraduate students majoring in chemistry and life
sciences. During my undergraduate study in chemistry I was looking for such a text
but could not find it. Therefor I decided to create such a text for other people that
may need it during their study of organic chemistry. The text is divided into two parts:
1) physical organic chemistry and 2) synthetic organic chemistry. The first part
includes around 50 questions about structure and reactivity of organic compounds and
the second part is about questions in the area of synthetic organic chemistry, dealing
with strategies and methods of synthesis and transformations of organic molecules.
There is analogous work to this text in the literature. However to my opinion it is not
satisfactory although it is more comprehensive. The advantages of this text are its
simplicity and the extensive details given in the explanation of the answers of the
questions. I would appreciate any comment or feedback you may have on this work.
Please use the following e-mail address for this purpose:" tarekm40@yahoo.com".

Section 1: physical organic chemistry

1.1) Explain the order of stability of the carbocations that are generated from
the following compounds?
Cl
Cl
2
3

Ph
Cl
Cl
4
Answer:
The degree of stability of the generated carbocations depends on the amount of
delocalization of the positive charge by adjacent double bonds. Structure 4 seems to
be the carbocation most delocalized by double bonds, because it is adjacent to two
phenyl rings. Structure 1 and 3 are similar to structure 4 in that they are both benzylic
carbocations. However, structure 3 is further delocalized by an additional double
bond. So it is more stable than structure 1. Structure 2 is still stable, but the least
among all four compounds. It is still relatively stable because it is a tertiary
carbocation and adjacent to a double bond.
1.2) Explain the difference in the rate of the following solvolysis reaction of the
following two compounds?

Cl
Cl
1

Rate:

100000

Answer:
Structure 1 is a secondary carbocation and structure 2 is as well a secondary
carbocation. However, structure 2 is much more stabilized than structure 1 by
additional hyperconjugation of 6 methyl groups. This extra stabilization of structure 2
does not happen with structure 1. This in turn explain the difference in reactivity
between the two compounds.
1.3) Suggest a mechanism to the following reaction?

O
O
R

O
O

O
H

CO2

O
H
NH

OH
O

C(O)H2

O
R

Buffer
O

O
R

Answer:
The first step of the mechanism is the decarboxylation of the -ketoacid. -keto acids
eliminate carbon dioxide easily. The end product of the decarboxylation tautomerizes
to the more stable keto form. The second step of the mechanism is the deprotonation
of the hydrogen to the ketone group. This hydrogen is acidic enough to be
deprotonated by the strong base diethylamine. The third step is the attack of the
generated anion on the formaldehyde, and the protonation of the oxygen of the formed
product to give -hydroxy ketone. This compound undergoes elimination of water
under basic conditions to give a double bond. Under the reaction conditions the
buffer provides the conditions to eliminate the water molecule and give ,
unsaturated ketone.
1.4) Which of the following carbocations is the most stable?

1) Methyl carbocation
4

2) Tert-butylcarbocation

3) Cyclopentadienyl cation 4) Benzyl carbocation

5) Tropylium carbocation.
Answer:
The most stable carbocation of the forgoing compounds is the tropylium carbocation
because it is aromatic. The benzylic cation comes next in stability because of the
delocalization of the positive charge by the aromatic ring. Cyclopentadienyl
carbocation comes next in stability. It is less stable than the tropylium and benzylic
carbocations because it is anti-aromatic, but it is still more stable than the tert-butyl
carbocation and methyl carbocation because of the delocalization of the positive
charge of cyclopentadienyl cation by the two double bonds in the ring. Tert-butyl
carbocation is more stable than methyl cation due to extra stabilization by
hyperconjugation that is present in tert-butyl cation and absent in the case of methyl
cation. Methyl carbocation is the least stable among all four compounds in this
question.
1.5) Nitration of which of the following compounds is faster?

vs

(1)

NO2
(2)

NO2
vs

Answer:
Nitration is an example of electrophilic aromatic substitution which depends on
the substituent on the benzene ring. Electron donating groups (EDG) activate
the benzene ring more than the unsubstitued ring for electrophilic aromatic
substitution and direct the attachment of the electrophile to the benzene ring to
the ortho and para positions, while electron withdrawing groups (EWG) direct
the attachment of the electrophile to the ring to the meta position only. As an
example lets take the two following two compounds: cyanobenzene, and
fluorobenzene.

F
Cl2

F
Cl

FeCl3

Cl
+

F
Cl

+
CN

CN
Cl2
FeCl3

CN
+
Cl

Cl

CN
+
Cl
CN is an electron withdrawing group and therefor directs the attachment of the
electrophile to the ring to the meta position. One would ask however, why the EWG
directs meta and EDG directs ortho-para? The answer to this question is that
substitution ortho/para in the case of EDG puts positive charge on the ring next to the
EDG. This is a good thig since this would stabilize the intermediate so formed. In
the case of EWG substitution ortho/para would put positive charge next to an EWG
which needs electron density to stabilize the intermediate. However a positive charge
next to EWG is not a good thing energetically. Substitution in the meta position
avoids putting a positive charge next to an EWG. In the case of the chlorination of
fluorobenzene we see that ortho substitution puts positive charge next to the fluoride
atom which can delocalize its lone pair to the empty p orbital on the ring.
Substitution para is analogous to the substitution in the ortho position in that it puts
positive charge next to the fluoride atom, which then is stabilized by the lone pair of
the fluorine atom. In the case of cyanobenzene which is deactivated by the EWG
substitution in the meta position never puts positive charge next to the electron
6

withdrawing group and this is a good thing because it can stabilize the intermediate.
Now back to our question. Methyl is an EDG by hyperconjugation and therefore
activates the ring in comparison to benzene itself. Therefor we expect that toluene or
methylbenzene would react faster than benzene in electrophilic aromatic substitution.
In the case of nitrobenzene and meta-methyl-nitrobenzene, so we already know that
nitro group is EWG and therefore it is deactivating and it does not nitrate readily.
Substitution by a methyl group activates relatively the ring because methyl group is
electron donating group by hyperconjugation so we can say that methylnitrobenzene
nitrate more readily than nitrobenzene itself.
1.6) Suggest a mechanism to the following reaction?
NH2

Ph
Ph

Ph

HNO2

CH

Ph

OH CH3

CO

CH
CH3

Answer:

N
NH2

Ph
Ph

Ph

HNO2

N +
C

CH

Ph

OH CH3

OH

CH
CH3

Ph
C
Ph

OH

+
CH
CH3

1,2 shift
Ph
Ph

CO

CH
CH3

Ph
+ H+

Ph

+
C

CH

OH

CH3

The first step of the mechanism is the conversion of the primary amine to the
diazonium salt by the action of nitrous acid on the primary amine. This is a well
known procedure to convert a primary amine into a good leaving group. A
nitrogen molecule is easily expelled from the diazonium salt to give a secondary
carbocation. Note that there are two phenyl groups and a hydroxyl group next to
the positive charge. It is well known in organic chemistry and in particular in
carbocation chemistry to observe 1,2 migrations of functional groups to give the
more stable carbocation. In our case there is a phenyl group 1,2 migration to
give the more stable carbocation adjacent to a hydroxyl group. We had a

secondary carbocation and finished with a carbocation next to a hydroxyl group

which can stabilize the charge by its lone pair. From here and after putting the
lone pair of the oxygen on the positive charge we get a ketone group. This leads
to the product.
1.7) Explain which of the following compounds react faster?
Cl

Cl

Answer:
Structure 1 gives an allylic carbocation which is stabilized by conjugation with
the adjacent double bond, while in structure 2 there is no such stabilization.
This stabilization lowers the activation barrier to the reaction, and therefor
makes it go faster than the reaction without the assistance of the double bond.
1.8) Explain which substituent in the para position would give the faster
elimination reaction?
Answer:
Cl
+

O-

Y
Y
Y= CH3 , NH2- , CN, NO2

The elimination process takes place through an attack of the ethoxide ion on the
benzylic proton. During this process a partial negative charge develops on the
benzylic carbon. This partial negative charge is stabilized by electron
withdrawing groups and destabilized by electron donating groups. Therefor we
expect that electron withdrawing groups would stabilize the transition state of
the reaction and hence lower the activation barrier to the reaction, while electron
donating groups would destabilize the transition state of the reaction, and
therefor raise the energy barrier to the reaction. Methyl and amine groups are
electron donating groups while cyanide and nitro are electron withdrawing
groups.
1.9) Suggest a mechanism to the following reaction?

) Al
3

N
OTs

Answer:
) Al
3

OTs

This reaction is a typical Beckmann rearrangement in which an oxime

undergoes rearrangement. In this case we have a protected hydroxyl group by a
tosyl group and the acid is not a usual bronsted acid ( a proton) but rather a
Lewis acid. The first step of the reaction is the binding of the Lewis acid to the
oxygen of the tosylate group, which makes it a good leaving group. After that
there is a migration of the alkyl group which is trans to the tosylate group
concomitant with the leaving of the tosyl group. A six membered ring
carbocation is generated after which a propyl anion of the lewis acid attacks the
carbocation to form the desired product.
1.10) Explain the relative rates of solvolysis of the following compounds?

Cl

Cl

Cl

Cl

Answer:
All of the compounds mentioned above involve benzylic active site. They differ
in that they have cyclopropyl group in the para position with different number of
methyl groups. Structure 1 has the highest rate, because cyclopropyl behaves
like a double bond and there is no adjacent methyl groups to disturb it.
Structure 2 is second in rate, and the reason why its rate is lower than structure 1
is that there is a methyl group which disturbs the effective action of the
cyclopropyl group by pushing it out of the optimal geometry required for good
conjugation. In structure 3 the overlap of the cyclopropyl through conjugation is
further diminished and disturbed by the pushing of the cyclopropyl out of its
preferred orientation for overlap with the ring. This disturbance occurs by the
two methyl groups adjacent to it. Structure 4 does not have cyclopropyl group
in the para position so its reactivity is the slowest.
1.11) Explain the difference in the rate of reaction between the following two
compounds?
Cl

Cl

Rate:

3.7

Answer:
The difference in rate between these two compounds is obviously ascribed to the
anchimeric assistance (neighboring group participation) that the double bond
makes on the reacting center. This effect does not exist in structure 2. This
explanation accounts for the difference in reactivity of these two compounds.
1.12) Predict the order of reactivity in solvolysis of the following compounds?
OPNB

OPNB

OPNB

OPNB

Answer:
Structure 1 is the least reactive of the four compounds, because there
is no double bond which can assist in enhancing the reactivity
10

through anchimeric assistance of the double bond. All other three

compounds share the effect of neighboring group participation of the
double bond. Structure 4 is the highest in reactivity due to the
existence of the two methyl groups on the double bond. This makes
the double bond more rich in electron density than the other
structures. Structure 3 is next in reactivity, because it has only one
methyl group on the double bond. Structure 2 has no methyl groups
so it is less reactive than the structures that have methyl groups on
the double bond. Structure 2 is still more reactive than structure 1
because the latter does not have a double bond for anchimeric
assistance.
1.13) Suggest a mechanism to the following chemical conversion?

NH2

OH

Answer:

NH2

+
N

+
- N2

HNO2

OH

OH-

This is a general method to convert a primary amine to an alcohol. The first step is
the conversion of the primary amine to the diazonium salt which is an excellent
leaving group by the action of the nitrous acid. A cyclopropyl cation is generated as a
result. This carbocation is strained and therefore it rearranges by expansion to give
the less strained cyclobutyl carbocation which then adds a hydroxyl group to form
cyclobutanol.
1.14) Which of the following compounds react faster with KI in acetone and
explain why?

11

Br

1)

+ KI

Br

2)

Acetone

+ KI

Acetone

Answer:
Reaction 2 reacts faster because we have a benzylic active site ( a positively
charged carbocation) which is stabilized by delocalization of the positive charge
into the benzene ring which stabilizes the transition state and hence lower the
energy barrier of the reaction. Reaction 1 proceeds in a lower rate, because first
we don't have a benzylic carobocation which can be stabilized by the ring, and
secondly the carbocation generated in reaction 1 is further deactivated by the
adjacent ketone electron withdrawing group, which contributes to destabilizing the
transition state and hence raising the energy barrier of the reaction.
1.15) Predict the rate of solvolysis in methanol of the following compounds ?

Cl

Cl

Cl

Cl

NO2

Answer:
Structures 2, 3 and 4 are similar in that they all carry benzylic carbocations.
Structure 3 is however the most reactive among all four compounds, and this is
because the para position is occupied by a methyl group which exerts extra
stabilization of the carbocation that is generated in solvolysis. This stabilization is
due to the electron donating ability of the methyl group through hyperconjugation.
12

Structure 4 has a nitro group in the para position, which is a deactivating group
by electron withdrawing of electron clouds from the ring and hence destabilizing
the carbocation generated. For this reason structure 4 is less reactive than
structure 3. Structure 2 is more reactive than structure 4, because it is not
substituted at all on the ring. So it is more reactive than structure 4 but less
reactive than structure 3 due to the existence of the methyl group in the para
position. Structure 1 is the least reactive among all four compounds, and this is
because it is not a benzylic carbocation to be stabilized by a ring.
1.16) Explain which compound will react faster in solvolysis of the following
compounds?
Cl
Cl

CH

Cl

Answer:
Cyclopropyl ring behaves like a double bond, because it has a p-orbital adjacent
to the positive center in which it can stabilize. The two cyclopropyl rings exert
effect like two double bonds. Therefor structure 3 reacts faster than the other
two compounds. This is due to the extra stabilization of the transition state of
the reaction by the two cyclopropyl rings, which in turn lowers the activation
barrier of the reaction. Structure 1 has only one cyclopropyl ring so it exerts
effect like a single double bond. This makes it second in reactivity to structure
3. Structure 2 is The least reactive among all three compounds because it is
secondary and has no cyclopropyl rings.
1.17) What is the chemical meaning of early and late transition states?
Answer:
An early transition state in the Hammond postulate suggests an exothermic
reaction with low energy barrier. A late transition state in the Hammond postulate
suggests an endothermic reaction with high energy barrier.
1.18) What is a primary and secondary isotope effect?
A primary isotope effect happens when hydrogen is replaced by deuterium in a
given reaction and there is a direct involvement of breaking or the formation of
the bond to the hydrogen or deuterium. An example of a primary isotope effect is
the elimination reaction of a proton in E2 type reactions.
Secondary isotope effect happens when the hydrogen or deuterium is not
involved directly in the reaction but exerts effect by changing the rate of the

13

reaction by replacing hydrogen with deuterium. An example of secondary isotope

effect happens in the Diels-Alder reaction as is shown by the following reaction:
1.19) Explain why the methylene group in the following compound is acidic and
is easily removed by a base?

Answer:
The methylene group in this compound is acidic, because the conjugate base
generated as a result of the deprotonation is aromatic. So this is an exothermic
reaction, because we get a much more stabilized compound than the starting
material.
1.20) Explain why the equilibrium of the addition reaction of water to
acetone lies far to the left the product is not favored?
O

O
H2O

+ OH2

Answer:
The reason why the product is not favored is that there is a separation of
charge in the transition state which makes the reaction barrier high. This
reaction is also entropically disfavored because we start with two compounds
and end up with one compound, so there is an increase in order and a decrease
in disorder.
1.21) Give a mechanism to the following nucleophilic aromatic substitution
reaction?
NO2

NO2
+

Br

Answer:

14

II

NO2

I-

Br

NO2
Br

NO2
I

The first step of the mechanism is the nucleophilic addition of iodide ion to the ring.
By this step we break the aromaticity of the ring. This is a high energy intermediate,
and it follows by an elimination of the bromide to give the product.
1.22) Explain if nitration of toluene is easier, or more difficult benzene?

Toluene

Benzene

Answer:
Toluene is an activated aromatic ring due to the attachment of the methyl group,
therefore its nitration will be easier than benzene itself because it is not activated.
1.23) When a rapid equilibrium is expected for a given reaction?
Answer:
A rapid equilibrium is obtained in a given reaction when the enthalpy of that reaction
approaches zero and the activation barrier to that reaction is very low.
1.24) What is meant in the Diels-Alder reaction by normal electron demand reaction
and inverse electron demand reaction?

15

Answer:
Diels-Alder reaction is a reaction between a diene and a dienophile.
Normally the diene is electron rich and the dienophile is electron poor.
When this happens we say that the reaction is under normal electron
demand. The reaction under these conditions is accelerated by electron
donating groups on the diene and electron withdrawing groups on the
dienophile. Diels-Alder reaction under inverse electron demand occurs
when the diene is electron poor and the dienophile is electron rich. This
kind of reactions is enhanced by electron donating groups on the dienophile
and electron withdrawing groups on the diene. The frontier orbitals
involved in the reaction under normal electron demand are the HOMO
(highest occupied molecular orbital) of the diene and the LUMO
(lowest unoccupied molecular orbital) of the dienophile. The frontier
orbitals that govern the reaction in the inverse electron demand reaction are
the HOMO of the dienophile and the LUMO of the diene.
1.25) What is the difference between an amine and an enamine?
R1

En-amine

R2

NH

Imine

Answer:
An enamine is the tautomer form of an imine. It is obtained by the reaction
of a secondary amine with a ketone. An imine is obtained when a primary
amine reacts with a ketone.
1.25) Explain the trend in selectivity in the following reactions?

16

ICl

I
100%
O-

Cl

90%

10%

NH2Cl
100%

Answer:
In all cases we have a primary alkylchloride. Substitution is
more likely when the nucleophile is not basic, and
elimination takes place predominantly when the nucleophile
is very basic such as what happens with the amide ion. In the
first reaction there is 100% substitution, and this happens
because iodide ion is not basic at all. (Basic means affinity
for protons). In the second reaction there is 90% elimination
and 10% substitution. This trend happens because methoxide
is basic and not nucleophilic. It is less basic than amide ion
in which case we get 100% elimination.
1.26) which if the following compounds is chiral?
F

Cl
Cl

CH2Cl2

H
C

C
H

Cl

1
F

H
N

T
C

Cl
2

SF2

Cl
4

Answer:
Chirality means no plane of symmetry exists for a molecule. Methylchloride is not
chiral, because it has 3 identical hydrogens and in addition it has a plane of symmetry
therefore it is not chiral. Methylenechloride is not chiral, because it has two identical
hydrogens and a plane of symmetry. This makes the molecule achiral. Structure 1 is
17

chiral because it has no plane of symmetry. Structure 2 is chiral because all

substituents on the carbon are different, so there is no plane of symmetry and this
molecule can rotate the plane polarized light. Structure 3 is not chiral because it has a
plane of symmetry in the plane of the molecule. Structure 4 is not chiral although it
has no plane of symmetry, because the energy barrier for the umbrella flipping is so
low that the molecule exists in two conformations. This makes it achiral.
Difluorosulfide is achiral because it has more than one plane of symmetry.
1.27) Given the following reactions. In reaction 1 and 2 indicate which compound is
more reactive towards electrophilic aromatic substitution the product, or the starting
material?
SO3H
1)

H2SO4

Cl
2)

Cl2\ FeCl3

Answer:
In the case of the first reaction, the product is substituted with electron withdrawing
group which is deactivating. So the electrophilic aromatic substitution in the case of
reaction 1 is more difficult in the product. The starting material is not deactivated so
it is more reactive towards electrophilic aromatic substitution than the product. In the
case of the second reaction, the chlorine atom is activating because it has lone pair
which can be delocalized into the ring. It is therefore more activating than the starting
material. Chlorobenzene is activating through resonance while it is deactivating
through the inductive effect or the -bond.
1.28) Give a name to the following compound?

Answer:
In order to understand how we name this bicyclic compounds we look at the shortest
bridge of the central carbon atoms. In this case it is bridge a. The number of carbons
in this bridge not including the terminal carbons is zero. Then we look at the four
membered ring and see how many carbons are bridging. This time also not including
the terminals. Therefor there are 2 atoms bridging. Then we look at the five
18

membered ring, and analogously we see there is 3 carbons that are bridging. The
naming is therefore:
3,2,0 bicyclic heptane
1.29) Explain which compound is the most basic and why?
H
N
NH2-

NH3
3

N
4

Answer:
Structure 1 is the most basic of the four compounds, because it is a negatively charged
amine. After that comes triethylamine, which is more basic than ammonia due to the
existence of the ethyl groups. Ammonia comes next which is less basic than
triethylamine but more basic than pyrrole. Pyrrole is the least basic because this
compound is aromatic, and its lone pair is shared by the ring to form the aromaticity.

1.30) Given the following three compounds. Decide which one is the most acidic?
CH4

CH2

CH2

HC

CH

Answer:
The acidity of the CH bond depends on the hybridization manner of the orbitals on the
carbon atom attached to the hydrogen. In the case of methane the hybridization
around the carbon atom is Sp3. In ethylene the hybridization around the carbon atom
attached to the hydrogen is Sp3. In the case of acetylene, the hybridization is Sp. The
more s orbital character there is in the bond the more acidic in that bond. In Sp3
hybridization there is 25% of s orbital character. In Sp2 hybridization, there is 33.3%
of s orbital character in the bond. In Sp hybridization, there is 50% of s orbital
character. As is mentioned the acidity increases with the amount of s orbital character
in the bond between the carbon and the hydrogen. From this we conclude that
hydrogens of acetylene are the most acidic followed by the hydrogens of ethylene and
finally the hydrogens of methane are the least acidic.
1.31) Which of the following compounds is aromatic?

19

Answer:
Aromaticity of any organic compound depends on the rule 4n+2. Thiophene is
aromatic because of the sharing of the lone pair on the sulfur by the ring. The count
of electrons in the case of thiophene is 6. This is including the lone pair on the
sulfur. This number then follows the aromatic rule of 4n+2 with n=1.
Cyclobutadiene is anti-aromatic because it has only 4 electrons (2 double bonds).
Benzene is an aromatic compound because it has 6 electrons (3 double bonds)
which obeys the 4n+2 rule with n=1. Structure 4 is anti-aromatic because it has 8
electrons which does not obey the 4n+2 rule.
1.32) Which of the following compounds is the strongest acid?

OH

OH

OH

OH

NO2
NO2

Answer:
Phenol, meta-nitrophenol and para-nitrophenol all involve a phenol, while structure 2
is a benzylic alcohol. Benzylic alcohol is the least acidic because the conjugate base
is not delocalized through the aromatic ring. Para-nitrophenol is the most acidic
because the negatively charged conjugate base is stabilized through resonance by the
para substituted nitro group and the aromatic ring. The meta substituted nitro group
exerts similar effect to the para substituted nitro group to different degrees. Para
substitution being effective through resonance, while meta substitution being effective
through induction (Induction means effect through the bond). Phenol itself is less
acidic than the nitro substituted phenols but more acidic than the benzylic alcohol
because the latter does not have resonance structures that can stabilize its conjugate
base.
1.33) Explain the difference in reaction rates of the following two reactions?

20

Cl

Cl

OTs

(1)

OTs

(2)
N
H

Answer:
Structure 1 reacts faster than structure 2 because the sulfur atom exerts a neighboring
group participation which facilitates the leaving group departure. Analogously
structure 3 reacts faster than structure 4 because of neighboring group participation of
the nitrogen atom which facilitates the leaving group departure.
1.34) Give a mechanism to the following reaction?
O

HBr

Br

Answer:
O

+
O

HBr

H+

Br

Br -

Br

If we draw resonance structure of 1 we find that the negative charge resides on the position to the oxygen. Therefore when we add HBr to the compound we get
protonation to the oxygen atom. As a result a carbocation stabilized by the oxygen

21

is generated to the oxygen. Bromine ion then attacks the carbocation to form the
product.
1.35) Calculate the double bond equivalence of the following compounds?
C5H 5N and C4H4S
Answer:
Double bond equivalence (DBE) means the number of double bonds in a compound.
A ring in compound counts as a double bond. The formula to calculate DBE is as
follows:
(2C+2-#H)/2
The formula states that DBE is equal to the number of carbons multiplied by 2, and
then add to the product the number 2. To the result subtract the number of hydrogens
in the compound and the whole result divide by 2 to get the DBE. For halogens in the
molecule subtract 1 for each halogen and add one to each nitrogen in the molecule.
In the compound C5H5N:
The number of carbons is 5. Multiplied by two gives 10. Add 2 gives 12. From the
result subtract the number of hydrogens (5 hydrogens). This gives 7 then add 1 for
the nitrogen. This gives 8. Then divide by 2 to get 4 double bonds. The molecule is
pyridine.
In the compound C4H4S:
The number of carbons is 4. Multiplied by 2 gives 8. add 2 gives 10. From the result
subtract the number of hydrogens (4 hydrogens). This gives 6. Then divide by 2 to
get 3 double bonds. The structure is thiophene.
1.36) Which of the following groups has a peak around 2200 cm-1 in the IR.
OH, Methyl, CN, or carbonyl group.
Answer:
OH group has a peak in the range of 3500cm-1. Ethyl group has a peak around
3000cm-1. carbonyl group has a peak around 1700cm-1. CN group has a peak around
2200cm-1. So the answer to this question is the cyano group.

22

1.37) Explain why pyrrole does not add a proton to its nitrogen, but instead it adds it
to its double bond, while pyridine adds a proton to its nitrogen and not to its double
bond?
Answer:
Addition of a proton to the nitrogen in pyrrole makes it anti-aromatic. Besides, there
are no resonance structures to the double bonds when we have the proton on the
nitrogen. In the case of pyridine the lone pair of the nitrogen is not shared by the ring
for aromaticity so they are available for protonation.
1.38) Explain why indole adds an electrophile to its position and not to its
position?

Beta
+

HN

HN

E
+

+
E+
Alpha
HN
+

HN
E

HN
E

Answer:
Addition to the nitrogen makes the delocalization of the charge destroy the
aromaticity of the benzene ring. Substitution to the nitrogen does not make this
problem.
1.39) What can you say about the mechanism of a reaction SN1 or SN2 if it is
accelerated by polar solvents and slowed down by nonpolar solvents?
Answer:

23

It is well know that SN1 reactions develop a positive charge intermediate, therefore it
is expected that this type of reactions would be enhanced by polar solvents. This
would stabilize the intermediate and makes the reaction goes faster. On the contrary,
SN2 reactions develop little positive or negative charge in the transition state.
Therefor it is expected that polar solvents would destabilize the transition states of
such reactions, and nonpolar solvents would stabilize the transition state of these
reactions.
1.40) Why the protons of the methylene group of cyclopentadiene are acidic?
Answer:
The protons of the methylene group in cyclopentadiene are acidic, because the
conjugate base that is generated by deprotonation is very stable due to its
aromaticity, and we know that aromatic structures are very stable.
1.41) Suggest a mechanism to the following reaction?

Conrotatory

Answer:
This is an example of an electrocyclic reaction. It proceeds by a thermal closure of
the ring. The manner of closure depends on the end lobes of the HOMO of the
starting material. If they are of different signs then the closure would be corotatory
and if they are of the same sign then the closure is disrotatory ( opposite ways). In
this case the HOMO of butadiene is of different signs on its end lobes therefor the
closure in this case is conrotatory (the same way).
1.42) Explain how the product of the following reaction is obtained?

24

OCH3
CH3OH

HBr

Br
Answer:
- Br +
Br
1,2 shift
CH3OH
OCH3

The first step of the reaction is the formation of carbocation 1. This is a primary
carbocation which undergoes a migration of a methyl group to form the more stable
tertiary carbocation 2, which then adds the bromide ion to form the product.
1.43) Why allyl carbocation is more stable than ethyl carbocation?

Answer:
Positive charge on carbon atom adjacent to a double bond is especially stable due to
the delocalization of the positive charge by the double bond as is shown above.
Therefor allylic protons are acidic and are easily deprotonated. For the same reason,
allyl anion are also stable due to resonance structures of the negative charge by the
double bond.
1.44) Which of the following compounds has no dipole moment?
O
NH3
Answer:

25

H2O

Of all four compounds ethylene is the only compound that has no dipole moment
because it is a symmetrical molecule.
1.45) Explain why Diels-Alder reaction is thermodynamically favored while
entropically disfavored?
Answer:
As an example of a Diels-Alder reaction lets take the reaction between ethylene and
butadiene.

The reaction is thermodynamically favored because in the reaction we replace two

-bonds by the more stable -bonds. Therefor the reaction is exothermic
(release energy). The reaction is entropically disfavored because we start with a
two compounds and end up with single compound. So the order is increased and
the disorder is decreased and the entropy ( the disorder) is decreased.
1.46) Explain why cyclopropenyl anion is less stable than cyclopropenyl cation?

Answer:
The reason that cyclopropyl cation is more stable than cyclopropyl anion is that the
cyclopropyl cation is aromatic with 2-electrons while cyclopropyl anion has 4 electrons which is anti-aromatic and hence less stable than the aromatic cyclopropyl
cation.
1.47) Explain why protons 1 are more acidic than protons 2 and protons 3 in the
following structure?

Answer:
Protons 1 are more acidic than protons 2 and 3 because protons 1 exist on a carbon
that is adjacent to two carbonyl groups. The anion formed by deprotonation of proton

26

1 is stabilized by the two electron withdrawing carbonyl groups, and it is delocalized

by the CO double bonds. In case of protons 2 and 3, they are adjacent to only one
electron withdrawing group, the carbonyl group. The delocalization of the anion is
stabilized by only one carbonyl group.
1.48) Explain which bond is weaker Si-O or C-O bond and why?
Answer:
C-O bond is -type orbital and is formed by Sp3 hybridized orbital on the carbon
atom. Si-O bond is also formed by a -orbital which is formed by Sp3 hybridized
orbital. The only difference between the two structures is the Si-O bond is stronger
and this is because Si has a low lying d-orbital which can accept the lone pair on the
oxygen giving the bond a double bond character. This extra stability of the Si-O bond
does not occur in the C-O single bond.
1.49) Explain why chlorobenzene adds nitro group in electrophilic aromatic
substitution predominantly to the para position, although it can direct ortho as well?
Cl

Cl
NO2+

NO2

Answer:
The answer to this question is as follows: Chlorine is a big atom, and it exerts a steric
effect on the direction of the substitution. The ortho position is sterically hindered for
the nitro group to approach it. The only remaining position for the nitro is the para
position which is sterically not hindered. It is also important to notice that ortho/para
direction happens here because chlorine atom is ortho/para director and not meta
director.
1.50) Predict the site of protonation of the following compound?

HN

Answer:

27

NH

+
H2N
NH -

In order to find the site of protonation of this compound we draw the resonance
structures, and see where the negative charge resides.
We see from the resonance structure that the negative charge resides on the imine, and
not on the primary amine.
1.51) Why hydrogen peroxide and hydrazine are not stable compounds?

HO

OH

H2N

NH2

Answer:
The reason why hydrogen peroxide and hydrazine are not stable is that both nitrogen
and oxygen atoms have lone pair on it, and therefore there is electron-electron
repulsion between adjacent oxygen atoms and between adjacent nitrogen atoms. This
explanation can account for the relatively long bond in N-N single bond and in O-O
single bond. This explanation can account also for the fact that we don't find neither
in nature nor synthetically polymers of oxygen nor for nitrogen.
1.52) Mono nitration of phenol gives a mixture of ortho and para substitution. How
these two compounds are separated.
Answer:
A usual technique for separation is flash column chromatography. However this
technique is good for purification for the purpose of identification of the compound.
It is not good for large quantities. Another method for separation is distillation which
is used in order to purify the two compounds in this question. Para-nitro-phenol has
strong hydrogen bonds between its molecules through the O-H bonds. Therefor it has
a high boiling point. Ortho-nitro-phenol has intra-molecular hydrogen bond between
the O-H group and the nitro group. It does not have the intermolecular hydrogen
bonds available for para-nitro-phenol. Therefore the boiling point of ortho-nitrophenol is lower than that of para-nitro-phenol for the reasons mentioned above.
1.53) Which is more reactive lithium-aluminium-hydride or sodium-boro-hydride?
Answer:
Both Lithium-aluminium-hydride and sodium-boro-hydride are reducing agents and
are sources of hydride ions. Lithium-aluminium-hydride is more reactive than
sodiumborohydride, and therefor it is less selective than sodium-boro-hydride.

Section 2
Synthetic organic chemistry

28

2.1) How to synthesize the following compound?

O

Answer:
O

O
+ LDA

Br

There are two methods to synthesize this compound. The first is di-cyclohexyl-Li-Cu
addition to , unsaturated ketone and this is a one step reaction. The cuprate reagent
is synthesized from cyclohexyl-lithium reacting with CuI which forms the cuprate
reagent. Cyclohexyl-lithium is synthesized from cyclohexane which is activated by
the light induced bromination followed by transmetallation with BuLi to give the
cyclohexyl-lithium. The second method uses 1-bromo-1-cyclohexylmethane with
acetone. The first step is the generation of the anion from acetone by the action of
LDA( lithium-disopropyl-amide) then there is a nucleophilic substitution to form the
desired product.
2.2) Suggest a method how to synthesize the following compound?

29

Answer:
Br
Br2\ FeBr3

MgBr
Mg

Br

We start from benzene and activate it by bromination using Lewis acid and bromine
molecule. We convert the brominated benzene to the Gringard reagent by treating the
bromobenzene with magnesium in ether. After we prepare the gringard reagent which
is a nucleophilic reagent we do nucleophilic substitution using propyl bromide to
generate the desired product.
2.3) How to synthesize the following compound?

OH
O

Answer:

30

MgBr

Br

Mg
ether
O

OCH3

Cl

OH

OCH3
KOH

We start from 1-bromo-1-phenylethane, and prepare the Gringard reagent by the

action of magnesium in ether on the bromine substituted ethylbenzene. After we
prepare the Grinard reagent we treat it with methylchlorate to form the desired
product. Methyl chlorate reacts by giving the chloride as the leaving group and not
the methoxide which is a bad leaving group.
2.4) How to synthesize the following compound starting from cyclohexane?

Answer:

Br
Br2

KOH

light

NBS

KOH

Br

The first step of the reaction is the activation of cyclohaxane by the light induced
bromination of cyclohexane. This is followed by the formation of a double bond by
the elimination reaction accomplished by KOH. The next step is the selective
allylic bromination of cyclohexene using N-bromo-succinimide (NBS). After that

31

we do elimination reaction using KOH as a base to get the conjugtated

cyclohexadiene.
2.5) How to prepare cyclopentadiene from cyclopentane?

Answer:
Br

Br2

KOH

NBS

Light

Br

KOH
Br

This synthesis is analogous to the synthesis of cyclohexadiene. First we activate the

cyclopentane ring by the light induced bromination. We then get the cyclopentene
by the elimination reaction carried out by the action of KOH as a base. We then
selectively brominates the allylic position using NBS. Followed by the elimination
reaction using KOH to obtain the conjugated diene.
2.6) How to synthesize the following compound?

Answer:
Br
NBS
+

Br
KOH

32

The first step is the Diels-Alder cycloaddition between 2,3 dimethyl-butadiene and
ethylene to form the ring. We then selectively brominate the allylic position
followed by elimination of the bromine to get the conjugated double bonds and the
desired product.
2.7) How to synthesize the following compound?

Answer:
O

Mg
Br
OH

MgBr

OH

H+

In this structure we have a double bond which is a strategic disconnection in retrosynthesis. We start the synthesis with isopentylbromide which is available
commercially and then convert it to the Gringard reagent by the action of
magnesium in ether solution. After preparing the Gringard reagent we react it with
isopentanal which is prepared by the Gringard reagent prepared from tert-butylbromide. The product of the reaction of isopentanal with the Gringard reagent we
get an alcohol, which dehydrates water upon employing an acid to give the desired
product. The cis conformation is extremely unstable and if formed isomerizes
quickly to the trans isomer.
2.8) Suggest a synthesis to the following compound?

33

Answer:

P(Ph3)CH-

There is a double bond in our product. The synthesis of double bond can be
accomplished by the Wittig reaction using tri-phenyl-phosphine. We start the
synthesis by the action of triphenylphosphine which is a good nucleophile on
methyl bromide. After that we deprotonate the methyl group using a base (LDA) to
form the ylide. We then react this ylide with a ketone to form the double bond. The
appropriate ketone for our case is 2-butanone which after reaction with the ylide
gives the olefine.
2.9) Suggest a way how to synthesize the following compound?
O
O

Answer:

O
O

Cl

MCPBA

(1)
FeCl3

34

O-

OH
(2)

Base

Cl

We suggest two methods how to synthesize this compound. The first method starts
with benzene and we do Friedel-Kraft acylation using a Lewis acid to substitute the
electron withdrawing group acetate ion. After that we do Bayer-Villiger oxidation
using meta-chloro-per-benzoicacid ( MCPBA). Finally we do electrophilic
aromatic substitution to insert chlorine atom in the para position and get the desired
product. The second method starts with phenol and after that we deprotonate it
using a base to form the phenylate ion which is a good nucleophile. It reacts with
chloroacetate and after that electrophilic aromatic substitution of chlorine using
Lewis acid gets the desired product.
2.10) Suggest a method how to synthesize Styrene?

Answer:

Br

CH3O -

OH
H+

CH3MgBr

O
-

CH2(P(Ph)3+

We will suggesr four methods in which how to synthesize Styrene. The first method
uses1-bromo-2-phenylethane reacting with methoxide ion to form styrene in an
elimination reaction. The second method uses bezaldehyde and methyl-magnesiumbromide to form the alcohol which upon treatment with an acid gives the double
bond. Methyl-magnesium-bromide is synthesized from methyl bromide and
magnesium in ether. The third method is a Wittig reaction of benzaldehyde with
methyl ylide to form styrene. The ylide is synthesized from methyl-bromide and triphenyl-phosphine followed by the action of a base (LDA). The fourth method uses
Benzylmagnesiumbromide which reacts with formaldehyde to give the alcohol.
Followed by dehydration using an acid to give the desired product.
2.11) How to synthesize the following compound?

35

OH
Answer:

O
LiAlH4

+
O

OH

H2\Pd
OH

OH

The first step of the synthsis is the Diels-Alder reaction of the , unsaturated
cyclopentanone with butadiene. This is followed by the reduction of the keto group to
the acohol and then the catalytic hydrogenation of the double bond to give the desired
product.
2.12) How to synthesize the following compound?

Answer:

MgBr
+

H+
OH

36

We start with benzaldehyde and react it with the Gringard reagent derived from
benzylbromide. The generated alcohol is then treated with an acid to give the desired
product. The Gringard reagent is prepared by the treatment of benzylbromide with
magnesium in ether. The trans form of this compound is the predominant form.
2.13) How to prepare mono-deuterated-cyclohexane from cyclohexene?
Answer:

Br
OH

H2O/ H+

PBr3

Br
MgBr

Mg

D2O

The first step is the addition of water across the double bond to form the alcohol from
the double bond. After that we convert the alcohol to a bromine by the action of PBr3.
We than prepare the Gringard reagent from bromocyclohexane to make the
cyclohexane nucleophilic after which we quench the Gringard reagent with D2O to
obtain the deuterated form of cyclohexane. The synthesis of deuterated cyclohexane
from cycohexane itself is somewhat similar. Starting with cyclohexane we activate
the ring by the light induced bromination and from there we proceed the same way as
previously mentioned.
2.14) How to realize the following conversion?

Answer:

LiCu
2
O

37

NH2

NH2 / KOH

The main reaction in the synthesis is the dialkyllithiumcuprate addition to the ,

unsaturated ketone. Followed by the elimination of the ketone group by the action of
basic hydrazine. The cuprate reagent is prepared from bromoethylene which reacts
with BuLi in a transmetallation reaction to form the lithiated ethylene which upon
treatment with CuI gives the cuprate reagent required for the reaction. The
,unsaturated ketone is generated from -bromo ketone reacting with a base (LDA)
to give the ,-unsaturated ketone.
2.15) How to make the following reaction conversion?

O
NH2

Answer:

NH

NH3

NH2

H2 / Pd

O
Br

Cl

Reacting the ketone with ammonia gives the imine which upon catalytic
hydrogenation gives the desired amine. The ketone itself is prepared by the reaction
of bromo-cyclohexyl-methane with the respective chloroketone as is shown above to
give the desired ketone.
2.16) How to convert an internal double bond in cyclohexene to an exocyclic double
bond?
Answer:
O
H2O / H

38

OH

PCC

+
(Ph)3P

CH -

The first step of the reaction is the conversion of the double bond to an alcohol by the
addition of water across the double bond. Oxidation of the alcohol to the ketone using
polychlorochromate (PCC) gives the ketone. After that we do a Wittig reaction
between a methyl ylide and the ketone to give the desired exocyclic double bond. The
ylide is prepared from methylbrmide and triphenylphosphine, treating the product
with a base (LDA) to give the ylide.
2.17) How to realize the following conversion?
OH

Answer:

MgBr

Br

OH

Cl

Mg

PBr3

We start with cyclohexanol, and then activate the ring by the light induced
bromination. We then convert this compound into its Gringard derivative by the
reaction of cyclohexylbromide with magnesium in ether. This reagent is then treated
with chloro-cyclohexyl-methane to give the desired product.
2.18) How to make the following conversion?

OH
NH2

Answer:
We have a primary alcohol and we need to convert it into a secondary amine. We
treat the primary alcohol with an acid and convert it to a double bond. Treating it
with acidic water generates the secondary alcohol which upon treatment with PCC

39

which is an oxidizing agent we get the ketone. Treating the ketone with ammonia we
get the imine which upon catalytic hydrogenation we get the secondary amine.

H+

OH

H2O / H +

OH
O
PCC

NH3
NH

OH
H2 / Pd
NH

NH2

2.19) How to make the following conversion?

OH
OH

Answer:

MgBr

Br
OH

PBr3

Mg

OH

MgBr

Starting with benzylalcohol which is not reactive towards nucleophilic substitution

because OH group is not a good leaving group, we convert the alcohol group to the
better leaving group Br by the action of tribromophosphine on benzylic alcohol.
Benzylic bromide can be easily substituted or converted to Gringard reagent by its
treatment with magnesium in ether. This process converts the benzylbromide to the
potential Gringard nucleophile which upon reaction with formaldehyde gives the
desired product. Overall we have extended benzylalcohol by one additional
methylene group to give 1 hydroxy, 2 phenyl ethane.
2.20) How to convert pentane-3-one to pentane-2-one?

40

O
O

Answer:
OH

LiAlH4

H+

O
OH

H2O / H +

PCC
+
OH

O
+
O

The first step of the conversion is the reduction of the ketone to the alcohol by the
action of LiAlH4 followed by the dehydration reaction using a strong acid to get the
double bond. After that we treat this compound by aquous acid to add hydroxyl group
across the double bond. The addition of the water to the double bond is not selective
but a mixure of two compounds is obtained. One is the 2-hydroxy pentane which
upon oxidation gives the desired product. The other product is 3-hydroxy pentane
which upon oxidation regenerates the starting material, which can start the reaction
once again. The two hydroxyl compounds, 2-hydroxy pentane and 3-hydroxy pentane
can be separated either by distillation or by flash column chromatography.
2.21) Suggest two methods how to synthesize methoxide ion?
Answer:

Na +

BuLi +

CH3OH

CH3OH

CH3O - + H2 (g)
+

CH3O -

The first method to generate methoxide ion is by treatment of methanol with Sodium
metal. The product is the methoxide ion and hydrogen molecule. A good sign that
the reaction is proceeding is to notice the development of gas in the reaction which is
hydrogen gas. The second method how to synthesize a methoxide ion which is used
as a base to deprotonate hydrogens is by the action of BuLi ( butyllithium) on
41

methanol. BuLi is a powerful base and is stronger than methoxide in deprotonation.

Butane gas is generated as a byproduct in this reaction in addition to the desired
methoxide ion.
2.22) How to prepare the following compound from phenol. Why the benzylic
methylene group in this compound does not have acidic protons like normal benzylic
protons?

OH
O

Answer:
OH

O-

Br

KOH

We start the synthesis with phenol which has an acidic proton, which can be
deptotonated using an appropriate base to get the phenylate ion which is a good
nucleophile. In order to get the desired product we treat the phenylate ion with
benzylbromide which is an electrophile to get the product. As to the second part of
the question: why the benzylic protons of this compound are not acidic. The answer
is that the methylene group in this compound is adjacent to an oxygen atom which has
lone pair on it. Deprotonation of the methylene group puts a negative charge on the
methylene group adjacent to a pair of electrons. This situation is not favorable
because of the repulsion of the two negative charges, which is a high energy
intermediate.
2.23) How to accomplish the following conversion?

Answer:
The first step of this synthesis is to convert the cyclohexanone to the alcohol by
the reduction reaction of the ketone using LiAlH4 ( Lithiumaluminiumhydride).
We then convert the hydroxyl group to the bromide using PBr3. From the
cyclohexylbromide we can generate the Gringard reagent which reacts with the
aldehyde to give the desired product.
42

2.24) how to generate monodeuterium on benzene from benzene?

Answer:
Br

MgBr

Br2

D2O

Mg

FeBr3

We start the synthesis with non-deuterated benzene. We activate the benzene ring by
bromination reaction using a Lewis acid and bromine molecule. After that we
generate a nucleophile by converting the bromobenzene to the Gringard reagent by
the treatment of bromobenzene with magnesium in ether. Grignard reagents react
violently with water so if we treat our Gringard reagent with D2O we can deuterate
benzene.
2.25) Suggest a method how to accomplish the following conversion?

O
O
O

Answer:
O

OH
LiAlH4

H+

KMnO4

O
OH

O
OH
OH

43

OH

O
H+

O
O

We start with a ketone and end up with an anhydride. A possible way to

accomplish this conversion is to convert the ketone to the alcohol by the
reduction reaction using LiAlH4. We dehydrate the alcohol then using strong
acid to get the double bond, which can be oxidized by KMnO4 ( potassium
permanganate) to give the diacid. This di-acid then can cyclize to form the
anhydride under acidic condition or the treatment with an acid. Another way to
get the diacid from the double bond is to ozonize the double bond to get the
dialdehyde and then to oxidize to get the di-acid which upon treatment with an
acid ( a proton) can cyclize to form the anhydride.
2.26) Suggest two methods to synthesize cyclohexanone?
O

Answer:

O
O

+
Br
Br2

KOH

H2O/ H+

OH

Light
O

OH
PCC

One method to synthesize cyclohexanone is to treat butadiene with a ketene under

thermal conditions or heat. The second method starts the synthesis with cyclohexane.
By activation of the cyclohexane by the light induced bromination of the ring we
form cyclohexylbromide, which can eliminate HBr upon treatment with KOH. We
then add water across the double bond to form the alcohol. We then oxidize the
alcohol to the ketone using PCC to get the desired product.
2.27) Explain a method how to synthesize the following compound?

44

Answer:

H2/Pd

O
+

P (Ph)3

H2/Pd

For the synthesis of this compound we can use to methods: The Diels-Alder reaction
and the Wittig reaction. Using the Diels-Alder method we treat butadiene which is a
diene with a dienophile as mentioned above. The diene is commercially available and
the dienophile is prepared using Gringard reagent prepared from isobutyl bromide and
magnesium in ether solution which then reacts with formaldehyde to give the alcohol
which upon treatment with an acid gives the double bond and the desired dienophile.
The second method utilizes the wittig reaction. We start with cyclohexanone and
react it with an ylide to form the double bond which upon catalytic hydrogenation
gives the desired molecule. The ylide is prepared from triphenylphsphine and 2bromopropane which upon treatment with a base gives the ylide, which reacts with
the ketone to give the olefine, which upon hydrogenation gives the desired product.
2.28) How to synthesize the following four membered ring?

COOH

COOH

Answer:
This four membered ring can easily be synthesized in two steps from A 2+2
cycloaddition of an en-amine which is electron rich with an electron deficient
dienophile. We synthesize the enamine by the reaction of a secondary amine with the
aldehyde and then treat it with the dicarboxylate substituted ethylene.

45

H
N

+
N
COOH
+

COOH

COOH

COOH

2.29) How to synthesize the following compound?

Answer:
O
O

O
+

LDA

O
KOH

HO

O
NH2

NH2

KOH

We use an aldol reaction of cyclopropanone. We treat cyclopropanone with LDA and

then condenses it with another molecule of cyclopropanone to form the -hydroxy
ketone which upon treatment with a base gives the , unsaturated ketone. We then
do a Diels-Alder reaction of this compound with butadiene. Note that the ,
unsaturated ketone is electron deficient due to the existence of the keto group. Finally
we take off the keto group using basic hydrazine solution.
2.30) How to synthesize hexabromo benzene from benzene?
Answer:

46

Br
6 moles

Br2

FeBr3

Br

Br

Br

Br
Br

We treat benzene with an excess of Br2 and a Lewis acid. The first Br atom to enter
the ring dircts ortho/para and the subsequent atoms direct ortho substitution.
2.31) How to synthesize the following compound?

Answer:
O
O

O
-

LDA

OH
O

KOH
(CH3)LiCu

OH
O
NH2

NH2

KOH

We start the synthesis from cyclohaxanone, which is commercially available. We

then do an aldol condensation by treating cyclohexanone with LDA and the condenses
it with another cyclohexanone ring. This forms hydroxyl ketone which upon
treatment with a base dehydrate ( eliminates OH) and gives the , unsaturated
ketone. After that we have 1,4 addition of the dimethyllithiumcuprate to the
unsaturated ketone. The keto group is finally removed by the action of hydrazine and
KOH.

47

2.32) Suggest a method how to synthesize the following compound from

cyclobutane?

Answer:
O
MgBr

Br

Br2

Mg

OH

light
H+

H2/Pd

OH

The first step is the activation of the cyclobutane ring by the light induced
bromination which is accomplished by light and molecules of bromine. The second
step is the preparation of the Gringard reagent from cuclobutylbromide by its
treatment with magnesium in ether. The Gringard reagent is then treated with
cyclopropanone which is commercially available to obtain the -hydroxy ketone.
This compound eliminates OH to give the double bond upon treatment with an acid (
a proton). The product then can be obtained by the catalytic hydrogentation of the
double bond using H2/Pd.
2.33) How to synthesize the following compound?

Answer:
We use the Wittig reaction to form the exocyclic double bond. In order to prepare the
ylide we treat propylbromide with triphenylphosphine and then with BuLi. We then
react the ylide with cyclopentanone. After that we do Diels-Alder reaction of the
exocyclic compound with cyclohexadiene. The product is catalytically hydrogenated
using H2/Pd to give the desired product.

48

Br

BuLi
+
P(Ph)3

P(Ph)3

_
+
P(Ph)3

+
P(Ph)3
O
H2/Pd

2.34) Suggest a method how to accomplish the following conversion?

OH

OH
Answer:
OH

Br
PBr3

KOH

Br

NBS

O
Br

Mg

MgBr

OH

We start from cyclohexylalcohol which can be synthesized easily from cyclohexane

by three steps. The first is the activation of thecyclohaxane ring by the light induced
bromination followed by elimination reaction using KOH to give the double bond
then addition of water across the double bond to give the cyclohexylalcohol. We treat
cyclohexylalcohol with PBr3 to convert the alcohol group to the bromide which upon
treatment with KOH eliminates HBr and gives the bouble bond. The same product is
obtained from cyclohexylalcohol when treated with a strong acid. After obtaining the
cyclohexene we selectively brominate the allylic position using N-bromosuccinimide. After that we convert the bromide to the Grigard reagent by reacting the
bromide with magnesium in ether. We then react the Gringard reagent with
cyclohaxanone to give the desired product.
49

2.35) Suggest a method how to synthesize the following compound?

OCH3

Answer:

O
LDA

O
OCH3

Cl

OCH3
O

MgBr
Br2

Br

Mg

Cl

Light
We start the synthesis by reacting methyl-cyclohexyl ketone with LDA to form the
enolate which reacts with methylchlorate to form the desired product. We synthesize
methylcyclohexylketone from cyclohexane as follows: we activate the cyclohexane
ring by the light induced bromination. We then convert the bromide to its Gringard
reagent which reacts with chloro methyl ketone to give methylcyclohexylketone.
2.36) Suggest a method how to synthesize the following compound?

Answer:
We start the synthesis with isopropanol and convert the hydroxyl group to the
bromide so that we can later prepare the Gringard reagent which can react with
cyclohaxanone to form the alcohol. Upon treatment of the alcohol with the acid the
double bond is generated. Isopropanol is converted to the bromide by its treatment
with PBr3. The Gringard reagent is prepared from the bromide by its treatment with
magnesium in ether. The reaction of the Gringard with cyclohaxanone gives the
alcohol which dehydrates upon treatment with an acid to give the double bond.

50

O
PBr3

Mg
Br

OH

MgBr

OH
H+

2.37) Write the products of the following reactions?

1) Mg
2) CO2
Br

3) H2SO4/ water

Answer:
Mg
MgBr

Br

O-

CO2

H+

OH
O

We have as a starting material ethylbromide which upon treatment with magnesium

we obtain its Gringard reagent which is nucleophilic. It then reacts with carbon
dioxide to form the carboxylate ion which when treated with sulfuric acid gives the
acid.
2.38) Write the product of the following reaction?
1) Zn
Br

2) Acetone
OCH3

3) H+

This reaction is called the reformatsky reaction and it is analogous to Gringard

reaction in which zinc plays the role of magnesium in this reaction. We have an bromo ester which upon reaction with Zn becomes nucleophilic as Gringard reagent.
It can then react with an electrophile which is in this case acetone to form the hydroxy ester.

51

O
Br

ZnBr O

Zn

OCH3

OCH3
O
O-

H+
OCH3

OH

OCH3

2.39) Given to you ceclohexene. How to synthesize cis and trans diols?
Answer:

OH
cold, dilute

OH

KMnO4

MCPBA

OH
H2O/ H+

OH

Cis diols are synthesized from cyclohexene by the action of cold and diluted
potassiumpermanganate (KMnO4) in water. Trans diol are synthesized in two steps
from cyclohexene. The first step is the oxidation of the double bond using MCPBA
(meta-chloro-perbenzoic-acid) followed by the addition of acidic water.
2.40) How to synthesize cyclohexane and 4,4,0- bicyclooctane?
Answer:
Cyclohexane is prepared by the Diels-Alder reaction of butadiene and ethylene
followed by catalytic hydrogenation of the formed double bond. The bicyclic
compound is synthesized also by Diels-Alder condensation of cyclohexene with
butadiene followed by catalytic hydrogenation of the formed double bond. DielsAlder reaction usually requires heat to be accomplished.

52

H2/Pd

H2/Pd

2.41) Suggest a synthesis to the following compound?

Answer:

O
(CH3)LiCu

O
_

CH3Br

The synthesis of this compound can be accomplished from , unsaturated

cyclohexanone by 1,4 addition of dimethyllithiumcuprate followed by the reaction of
the enolate with methylbromide. The synthesis of dimethyllithiumcuprate starts with
methylbromide which upon transmetallation with BuLi is converted to methyllithium.
Treatment of methyllithium with CuI gives the dimethyllithiumcuprate.
2.42) Suggest a way to convert cyclohexane to methyl-cyclohexane?
Answer:
We first activate the cyclohexane ring by the light induced bromination. After we
accomplish this, we prepare the Gringard reagent of this bromide by treating it with
magnesium metal in ether. The Gringard reagent reacts then with methylbromide to
give the desired product.

53

Br
Br2

MgBr
Mg

CH3Br

Light

2.43) How to make the following conversion?

OH
O
OH

Answer:

OH

O
LiAlH4

O
H2SO4

MCPBA

OH
H2O/

H+
OH

Treating cyclohexanone with a reducing agent like LiAlH4 reduces it to the alcohol.
Treating the alcohol with Sulfuric acid generates the cyclohexene. Cyclohexene then
is oxidized using MCPBA to give the epoxide which opens to give the trans diol when
treated with acidic water
2.44) Suggest a method to synthesize 4,4,0-bicyclic-octane?
Answer:
We mentioned in a previous answer to this question that Diels-Alder reaction is a
possible way to synthesize this compound. This time we do Diels-Alder reaction.
However, this time we choose , unsaturated cyclohexanone as our starting material.
This compound is a very good dienophile because its double bond is electron
deficient. We react this compound with butadiene to obtain the bicyclic compound

54

however the product has a ketone which can eliminated with hydrazine and KOH. The
double bond is removed with catalytic hydrogenation.
O

O
NH2

NH2

KOH

H2/Pd

2.45) Suggest a method how to synthesize benzoic acid from benzene?

Answer:
Br

MgBr
Mg

Br2

CO2

FeBr3
COOH

The first step of the synthesis is the activation of the benzene ring by its bromination
using a Lewis acid and molecular bromine. We then convert this compound to its
Gringard reagent to make it nucleophilic. We then treat the Gringard reagent with
carbon-dioxide to prepare the benzoic acid. Another method to prepare the benzoic
acid is to oxidize the commercially available benzaldehyde.
2.46) Suggest a way how to make the following conversion?

Answer:
This reaction is called the Bayliss-Hilman reaction in which an , unsaturated ketone
reacts in a nucleophilc way on its carbon. The first steap of the reaction is the 1,4
addition of the imidazole ring across the conjugated , unsaturated ketone. As a
55

N
O

N
+

CH3Br

O
O
N
+

result an enolate is formed which reacts with an electrophile. In this case it is methyl
iodide. The regeneration of the ,-unsaturated happens by abstracting a hydrogen by
the imidazole ring from the to the carbonyl carbon.
2.47) Suggest a method how to synthesize the following compound?

Answer:
Br
MgBr

Br
Br2

Mg

FeBr3

The main reaction to form the product is between the Gringard reagent formed from
bromobenzene and benzylbromide to give the desired product. Starting with benzene
we brominate the ring using Lewis acid and molecular bromine in electrophilic
aromatic substitution. We then convert this bromide to its Gringard reagent to make it
nucleophilic. The Gringard reagent then reacts with benzylbromide to give the
desired product.

56

2.48) Suggest two ways to eliminate a ketone from cyclohexanone?

Answer:

O
H2N

NH2

KOH
O

OH
H2 / Pd

H+

LiAlH4

The first method to remove a ketone is by treating the ketone with hydrazine and
KOH. An indirect way in three steps is to convert the ketone to the alcohol by the
action of a reducing agent (LiAlH4) followed by dehydration to obtain the double
bond. This step is accomplished by an acid. After that catalytic hydrogenation of the
double bond removes the ketone
2.49) Suggest a method how to make the following conversion?

Answer:

OH
+

P(Ph)3

CH2-

B2H6 / THF

PCC

H2O2 / OHO

We start with cyclohexanone and the product has one extra carbon so we need to
install an additional carbon. We use for this purpose the wittig reaction with an ylide
that contains only one carbon. The ylide is prepared from triphenylphosphine and
methylbromide followed by the action of BuLi to deprotonate the carbon and generate
the ylide. After the reaction of the ylide with cyclohaxenone we get an exocyclic
double bond and we need an OH group on it. We can use Diborane to insert an

57

alcohol. We use B2H6 in THF with hydrogen peroxide and KOH to obtain the
product.
2.50) How to convert cyclohexanone to cyclohexene?
Answer:

Br
H2N

NH2

KOH

Br2

KOH

light

If we remove the ketone then brominates the ring and then use KOH to obtain the
double it will take three steps to obtain the double bond or cyclohexene. The first step
is to remove the ketone with hydrazine and KOH. The second step is to brominate the
cyclohexane using molecular bromine and light. The third step is to do elimination
reaction to make the double bond.
2.51) Suggest a method how to make the following conversion?

O
OH

OH

Answer:
We have in the targeted compound a ketone and a hydroxyl group. We would like to
extend the alkyl chain by two carbons and yet conserve the primary alcohol. The first
step of the synthesis is to convert the alcohol to the Gringard reagent in order to make
it nucleophilic. However we have also a ketone group which can react as well.
Therefor we must prevent the ketone from reacting by protecting it. We do so by
reacting the ketone with a protecting group that is 1,2 dihydroxyethane. After this
reaction is completed, we convert the alcohol to the bromide by the action of PBr3.
We then from this compound prepare the Gringard reagent by treating the
alkylbromide with magnesium in ether. After preparing the Gringard we treat it with
ethylene epoxide which opens to give the primary alcohol extended by two carbon
atoms. The starting material is prepared by the reaction between cyclohexanone and
LDA which forms the nucleophilic enolate that reacts with 1-chloro-3-hydroxy-ethane
to form the starting material. Finally we remove the protecting group.

58

O
OH

OH

OH

PBr3

OH

OH

Br

Mg

Br

MgBr

O
MgBr

OH

H2O
OH

O
OH

2.52) Suggest a method how to synthesize the following compound?

O

Answer:
In order to synthesize this compound we start with 3-pentanone which upon treatment
with LDA makes the nucleophilic enolate which reacts with 2-bromo-propane to give
the desired product. 2-bromo-propane is prepared from isopropanol by treating it
with PBr3.

59

Br
LDA
O

O
OH

Br

PBr3

2.53) Explain how we can deuterate pentane on its second carbon position?
D

Answer:
OH

MgBr

Br

PBr3

MgBr
Mg

D2O

The first step is to use 2-hydroxy-pentane which is commercially available. This

compound is converted to the more reactive alkylbromide by treating it with PBr3.
This compound is electrophilic and we can convert it to the nucleophilic Gringard
reagent by treating the alkylbromide with magnesium in ether. This Gringard reagent
then can react with D2O to form the deuterated pentane.
2.54) Suggest a method how to convert cyclohexanone to its , unsaturated
compound?

Answer:
We start the synthesis with cyclohexanone which adds bromine atom to it by the
action of acid and molecular bromine (Br2). This reaction probably involves the
enolate as a nuncleophile which attacks the bromine molecule. After that we use
BuLi to eliminate the hydrogen and get the , unsaturated compound.

60

O
Br

Br2 / H+

BuLi

2.55) Suggest a method how to deuterate the hydroxyl group in cyclopentanol?

Answer:
_
OH

OD

O
Na or BuLi

D2O

We can start with nondeuterated cyclopentanol and then treat this compound with
BuLi or with metallic Na. The result is the deprotonation of the hydroxyl group to
form the extremely basic negatively charged oxygen atom. This intermediate can
then react with deuterated water (D2O) to give the desired product.
2.56) Suggest a way how to convert cyclopentanone to the following compound?
O

Answer:

OH
CH3Li

H+

minor

major

We use methyllithium as a nucleophile, and react it with cyclopentanone. This is an

addition reaction which forms the alcohol. The product then eliminates water by the
addition of a strong acid to give the olefine. The olefine that is generated as the major
product is the more substituted. Methyllithium is prepared from methylbromide using
transmetallation reaction with BuLi.
2.57) Suggest a method how to convert 2-bromo-propane to 1-bromo-propane?
Answer:

61

Br

HBr

KOH

Br

H2O2
The first step of a possible conversion is to prepare the double bond from the bromide
by the elimination reaction and then do antimarkownikoff addition of HBr using
hydrogen proxide to get the desired product.
2.58) Given to you cyclopentanone and cyclohexane. Suggest a method how to
prepare the following compound?

Answer:
O
Br
Br2

MgBr
Mg
OH

Light
H2 / Pd

H+
OH

First, we activate the cyclohexane ring by its bromination with molecular bromine and
light. We then prepare from it the Gringard reagent by its treatment with magnesium
metal in ether. This nucleophilic compound then reacts with cyclopentanone to give
structure 1, which upon dehydration using a strong acid followed by catalytic
hydrogenation gives the desired product.
2.59) How to prepare cis-di-hydroxy cyclohexane from cyclohexane?
Answer:
OH

Br
Br2
Light

62

KOH

Cold, dilute
KMnO4

OH

The first step of this conversion is to activate the cyclohexane by its light induced
bromination. We then eliminate HBr to form cyclohexene by the action of the base
KOH. We then accomplish the synthesis by treating cyclohexene with cold and
diluted Potassiumpermanganate.
2.60) Suggest a method how to realize this conversion?
O

Answer:
Br

Br
Br2

KOH

Light

Br2

OH

NaOH

Br
O

BuLi

OH

We start with cyclopentane. We then activate the ring by its light induced
bromination. After we accomplish this step we eliminate HBr and form cyclopentene
by the action of KOH on the cyclopentylbromide. We then treat the cyclopentene
with a solution of KOH and Br2 to get 1-bromo-2-hydroxy ccylopentane. This
compound when treated with a strong base such as BuLi deprotonate the hydroxyl
group and cyclize by the departure of Br- to give the epoxide which is the desired
product.
2.61) Suggest a method how to synthesize ethylacetate?
Answer:

O
MgBr

O
Cl

We can prepare ethylacetate in one step by the reaction of ethylmagnesiumbromide

with methylchlorate. Ethylmagnesiumbromide is the Gringard reagent prepared from
ethylbromide and magnesium metal in ether solution.
2.62) How to prepare the following compound?

63

OH

Answer:
O

O
LDA

OH

OH
KOH

H2 / Pd

OH
LiAlH4

We start the preparation with cyclohexanone and by treating it with LDA we obtain
the nucleophilic intermediate the enolate. This enolate reacts with the aldehyde to
give the -hydroxy ketone, which upon treatment with a base gives the ,
unsaturated ketone. Then catalytic hydrogenation removes the double bond and
reduction of the ketone with LiAlH4 gives the hydroxyl compound and the desired
targeted material.
2.63) How to make the following conversion?

Answer:
We start the synthesis from cyclohexene and add to it HBr acid to form the
cyclohexylbromide. We then prepare the Gringard reagent from it by the
action of magnesium metal in ether solution. We react the Gringard reagent
with formaldehyde to form the alcohol which upon treatment with PCC ( a
mild oxidant) we get the desired product.

64

Br
HBr

MgBr
Mg
ether

MgBr

OH
PCC

2.64) Suggest a way how to convert cyclohexene to cyclohexanone?

Answer:

OH
H2O / H+

PCC

This conversion can be accomplished in two steps only. The first step in this
conversion is to add acidic water across the double bond to form the alcohol, which is
then oxidized with PCC to give cyclohexanone.
2.65) Suggest a way how to make the following conversion?
OH

COOH

Answer:
OH
PBr3

Br
Mg
ether

MgBr
CO2

65

COOH

MgBr

In this synthesis we need to extend the alkyl chain by one carbon. We start with the
alcohol and converts it to the bromide by the action of PBr3 to be able later to prepare
the Gringard reagent. After preparing the alkylbromide we prepare the Gringard
reagent by its treatment with magnesium metal in ether. We have in the product an
acid and the chain is added by only one carbon so we choose carbon-dioxide for this
purpose. We react the Gringard reagent with CO2 to give the carboxylate ion which
when acidified gives the neutral acid.
2.66) How to prepare the following compound from cyclopentane?

Answer:
Br

OH

KOH

Br2

H2O / H+

Light
OH

O
PCC

O
OH-

OH

LiAlH4

Aldol
OH
H2SO4
OH

We start the synthesis by the activation of cyclopentane ring by its light induced
bromination. We then obtain cyclopentene by the action of KOH on the
cyclopentylbromide. This is an elimination reaction. We then add acidic water across
the double bond to obtain the alcohol which is then oxidized to the ketone by the
action of PCC. After we get the cyclopentanone we do aldol condensation of this
molecule by its treatment with LDA. As a result we obtain the -hydroxy ketone.
Reduction of the ketone with LiAlH4 gives the dialcohol which upon treatment with
an acid gives the conjugated double bonds.
2.67) Suggest a way how to make the following conversion?

66

Cl
OH

Answer:

HCl

OH

Cl-

Cl

We have a cyclobutyl group adjacent to a potential carbocation center. We have a

tertiary alcohol which upon treatment with HCl gives a tertiary carbocation. Because
cyclobutane is a strained ring it finds relief in expanding to the five membered ring by
migration to the carbocationic center. The rearranged carbocation then adds chloride
to give the product.
2.68) Suggest a way how to synthesize the following comound?
O

Answer:
O

NaOH

_
O

NaOH
OH

We start with cyclohexanone and prepare its enolate by its treatment with a strong
base such as LDA. After that we react it with 1-bromo-5-hydroxy-pentane. We then
convert the hydroxyl group to the bromide by the action of PBr3. We then form once

67

again the enolate by the treatment of the product with LDA. Then an intramolecular
cyclization happens to form the product.
2.69) Suggest a method how to synthesize the following compound?

Answer:

Br

O
O-

Br

We start with 2,5 hexanone and treat it with LDA to form the enolate which then
makes an intramolecular aldol condensation to form the -hydroxy ketone, which
upon treatment with a base gives the , unsaturated ketone.
2.70) How to make the following conversion?
O

Answer:
In order to obtain the desired product we start with cyclohexanone and do aldol
condensation by its treatment with LDA. As a result a -hydroxy ketone is formed
which eliminates water when treated with a base to form the , unsaturated ketone.
The ketone group can be removed using hydrazine and KOH to obtain the desired
product.

68

2.71) How to make the following conversion?

Answer:
Br
Br2

O3

KOH
light

OH
LiAlH4

Br

OH

OH

PBr3

O
BuLi

The first step of the conversion is the bromination of cyclohexane in order to activate
the ring. Next we use KOH to get the double bond in cyclohexene. After that we
ozonize the double bond to get the di-aldehyde. Next we reduce the aldehyde to the
alcohol, and then we convert one alcohol to the bromide using one mole of tri
bromophosphine. We then use a strong base to cyclize the ring to get the desired
product.

69