SOLVED PROBLEMS IN ADVANCED ORGANIC SYNTHESIS

(FOR CSIR NET & GATE)

SAMPLE COPY

om

Release date: 7th, May 2012

Last updated on: 28th November 2013
No. of problems solved: 220
No. of pages: 190

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1st EDITION

This book is intended for the aspirants of CSIR NET, SLET, APSET, GATE, IISc and other
University entrance exams. Most of the advanced level problems in organic synthesis from previous
year question papers are solved and are thoroughly explained with mechanisms.
It is a dynamic on-line version; updated frequently. You can purchase this book at different rates
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Problem 1.1
O

(IISc 2011)

i) PhMgBr

ii) H

O
a)

Ph

b)

O
Answer: c

Ph

c)

d)

Ph

Ph

OH

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1
ADICHEMISTRY

1,2 addition of Grignard reagent

Ph

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BrMgO

om

i) PhMgBr

ii) H+
:

HO

Ph

acid catalysed and conjugate

bond assisted removal of
OH group

Ph

-H2O

H O H
:

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-EtOH
-H+
Ph

final removal step of EtOH

Think different:
What will happen if 1,4 addition occurs?

i) PhMgBr
O

ii) H+

OH

H+
Ph
O

Ph
O

-EtOH

Ph

1, 4 - addtion of PhMgBr

Same product! So it might be the actual mechanism? But slim chances. Why? The possible explanation
might go like this:
i) the positive charge on 4th position is diminished due to contribution of p-electrons of adjacent ethoxy
O through conjugation (+M effect).

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Explanation
O

om

Ph

Now start arguing!

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Web Resource:
http://www.adichemistry.com/organic/organicreagents/grignard/grignard-reagent-reaction-1.html
Problem 1.2
The most appropriate set of reagents for carrying out the following conversion is:
O

Cl

a) i) EtMgBr; ii) HCl

c) i) C2H5Li; ii) HCl
Answer: d

OH

b) i) (C2H5)2CuLi; ii) HCl

d) i) HCl; ii) EtMgBr

Explanation:
1,4-addition of HCl furnishes 4-chlorobutanone, which reacts with Grignard reagent to get the desired
product.
H+

HCl

Cl

mechanism
Cl
OH

ClH2C

EtMgBr

H3O+

Cl

OH

OH

However, the yields may not be satisfactory due to side reaction that is possible in the second step
with Grignard reagent. It may undergo Wurtz like coupling reaction with -CH2Cl group.
Cl

EtMgBr

O
MgBrCl

What about other options?

Option - a :

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3
ii) The enolate ion form is less stable due to -I effect of O.
iii) We also know that: 1,2 addition is kinetically more favorable than 1,4-addition in case of Grignard
reagents. It is because the R group attached to Mg in GR is a hard nucleophile and prefers carbonyl
carbon with considerable positive charge (hard electrophile).
And if this is the mechanism, the removal of ethanol may give another product, though less likely, as
shown below.

H3O+

EtMgBr

Cl

Cl

HCl

OH

Cl-

Cl-

om

-H2O

* 1,2-addition occurs with Grignard reagent, since the ethyl group attached to Mg has considerable
positive charge and is a hard nucleophile. It prefers to attack 2nd carbon (hard electrophile).
* In the reaction of allylic alcohol with HCl, the Cl- prefers to attack the allylic carbocation from less
hindered end. Hence the major product is 1-chloro-3-methyl-2-pentene.
Option - b
O

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H+

H3O+

Et2CuLi

HCl

Expecting aldol reaction

1,4-addition occurs with Lithium diethyl cuprate, since ethyl group attached to copper is a soft
nucleophile and prefers carbon at 4th position (soft electrophile).
Option-c :
The products are same as in case of option-a. Ethyl lithium also shows 1,2 addition like Grignard
reagent.
Problem 1.3
(CSIR DEC 2011)
Choose the correct option for M & N formed in reactions sequence given below.
O

1) BH3.SMe2
2) PCC

1) PhMgBr

2) TsOH

3) mCPBA
Ph

Ph

a)

M=

N=

Ph

HO Ph

b)

M=

Ph
c)

M=

Ph
N=

Ph
O

d)

M=

N=

Ph
O
N=

Answer: a

Explanation:
* A tertiary alcohol is formed upon 1,2 addition of PhMgBr and is dehydrated in presence of Tosylic
acid.

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major product

5
Ph

HO Ph
PhMgBr

H3O

TsOH

Ph

Ph

Ph
OH

BH3.SMe2

Baeyer Villger
oxidation
Ph
O

PCC

om

* Thus formed product is subjected to hydroboration with BH3.Me2S complex to yield 2phenylcyclohexanol, an anti-Markonikovs product, which is oxidized to a ketone in presence of PCC.
The keto compound is subjected to Baeyer Villiger oxidation with mCPBA to get a lactone. The
PhCH- group is migrated onto oxygen in preference to CH2 group.

mCPBA

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-H2O

Anti Markonikov's
product

Ph-CH- group has more

migratory aptitude than
CH2 group

Problem 1.4
(CSIR JUNE 2011)
The major product formed in the following transformation is:
O

1) MeMgCl, CuCl
Ph
O
a)

2)

Ph
Answer: d

Cl

b)

c)

Ph

d)

Ph

Ph

Explanation:
* The Grignard reagent reacts with CuCl to give Me2CuMgCl, an organocopper compound also
known as Gilman reagent that is added to the -unsaturated ketone in 1,4-manner.
Initially copper associates with the double bond to give a complex, which then undergoes oxidative
addition followed by reductive elimination.
Thus formed enolate ion acts as a nucleophile and substitutes the Cl group of allyl chloride.
The attack on allyl chloride is done from the opposite side of more bulky phenyl group.
2 MeMgCl + CuCl

Me2CuMgCl + MgCl2

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Me
MgCl

Cu

Me2CuMgCl

Me
Cu

Ph

O MgCl

O
Ph

Ph
1,4-addition
+

Cl

CH2

Attack of allyl cation

from sterically less
hindered side.

Me

MgCl
-

CH

Me

om

-Cl

O MgCl

Ph

Ph

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Ph

Me

Me

Ph

Ph

Why 1,4-addition occurs with Gilman reagent?

The methyl group on copper is a softer nucleophile and hence prefers softer electrophile. The carbon
at 4th position is less polar and hence is a softer electrophile. That is why the attack of Me group occurs
at 4th position.
Whereas the carbonyl carbon is more polar and a hard electrophile.
Note: The atoms with more polarity i.e., high charge are harder.

Why not the O- end of the enolate ion forms bond with allyl group?
The very polar O- end is a hard nucleophile whereas the CH- end is a softer nucleophile. The allyl
group with positive charge on carbon is also a softer electrophile and hence the bond is formed
preferentially between the C-end of enolate and allyl group.
Problem 1.5
(CSIR OLD MODEL PAPER)
The major product formed in the reaction, given below, is
CN 1. EtMgBr
2. H3O+

CN

1)

CHO

Explanation:

2)

3)

NH2

4)

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Me

C N -
Et-MgBr

H+

MgBr HOH

-NH3
imine

om

Problem 1.7 (GATE 1991)

Predict the major product in the following reaction.
O i) CH MgBr
3
ii) H3O+

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An imine salt complex

H HOH

Explanation:
* The product mixture contains both axial and equatorial alcohols in equal proportions. There is no
diastereoselectivity observed during this addition reaction due to steric and stereoelectronic effects
operating equally.
axial
attack

CH3

CH3MgBr

OH

51%

H3O+

equatorial
attack

HO

CH3 49%

* When steric factor alone is considered, the moderately bulkier methylmagnesium bromide (GR) prefers
to attack the cyclohexane ring from the convex side i.e. equatorial.
However this steric factor is cancelled out by stereoelectronic effect which favors axial attack of GR.The
stereoelectronic effect can be explained by relatively stronger hyperconjugative interaction between MO of incipient CH 3-C bond and *-MO of axial C-H bond on the adjacent carbon during late transition
state when the GR approaches axially.
MgBr

H3C

-MO of incipient CH3-C bond

O

C
*-MO of axial C-H bond

Relatively stronger hyperconjugative

interaction between -MO of incipient
CH3-C bond and *-MO axial C-H bond
during axial attack.

Hyperconjugative interaction between -MO of incipient CH 3-C bond and *-MO of ring C-C bond
is also possible during equatorial attack. However this is relatively less effective and hence axial attack is
more favored on stereoelectronic grounds.

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8
C

-MO of incipient CH3-C bond

CH3

Relatively weaker hyperconjugative

interaction between -MO of incipient
CH3-C bond and *-MO of ring C-C bond
during equatorial attack.

MgBr
H

om

However steric factor will outweigh stereoelectronic factor and improves the diastereoselectivity by
favoring more equatorial attack, if alkylmagnesium sulfonates (otherwise known as Reetz-Grignard reagents)
are used. The larger the sulfonate group, the more it favors an equatorial approach.
Problem 1.8
Which of the following options is the most likely product formed in the following reaction?
O

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*-MO of ring C-C bond

MgBr

1) BrMg

2) H3O+

OH

HO

OH

HO

1)

2)

OH
Answer: 4

OH

HO

HO

3)

4)

Explanation:
* In this reaction, a lactone is made to react with a bis-Grignard reagent to get a diol. One of the
alcoholic group is tertiary and is derived from the carbonyl group of lactone. The other hydroxyl group is
primary and takes on shape from the ring oxygen of lactone.
This coversion is akin to the reaction of esters with excess of GR.
MgBr

O
O

BrMg

MgBr

MgBr

OMgBr

BrMgO

H3O

OMgBr

MgBr

HO

HO

OH

O
MgBr
OMgBr
OH

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9
(GATE 2012)

O
H

what is the major product?

EtOH

a)

b)

c)

d)

CHO

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Answer: b

Explanation

om

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KOH

OH-

-H2O

The -hydrogen adjacent to

ketone is more acidic and hence
abstracted by base.

Why not the other -hydrogens

are abstracted?

INTRA MOLECULAR ALDOL

REACTION

The -CHO group is more

electrophilic and is attacked
by the C-end of enolate ion.

H2O

O H
HO

OH-

HO

-OH-

Dehydration through
E1cB mechanism.

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Problem 2.1

10

om

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Think different:
Why not other -hydrogens are abstracted leading to different products?
There are three different types of -hydrogens, one adjacent to -CHO group and two adjacent to
keto group. If these hydrogens are abstracted, three different types of products are possible as explained
below.
However formation of 7-membered ring is not favorable due to entropy considerations, even
though the abstraction of proton from CH3 group adjacent to keto group is kinetically favored.
Abstraction of proton adjacent to -CHO group also leads to formation of five membered ring. But
keto group is less electrophilic and the equilibrium does not move in forward direction.

Abstraction
of H-1

OH-

Abstraction
of H-3

Abstraction
of H-2

O
OH

HO

HO

O
O
H

7-membered ring
not entropy favored

Major product
5-membered ring
more electrophilic nature of
-CHO favors this product

Another 5-membered ring

Not a major product
Since the keto carbon is less
electrophilic

Problem 2.2
(IIT JEE 2012)
The number of aldol reaction(s) that occurs in the given transformation is:

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Web Resource:
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11
HCHO

Conc. NaOH

H3C

OH

HO

OH
HO

a) 4

b) 3

c) 2

d) 1

om

Explanation:
* Since there are 3 -hydrogens in acetaldehyde it undergoes crossed aldol reactions with 3 moles of
formaldehyde i.e., three aldol reactions.

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Answer: b

OH-

O -H2O

H
CH2

H O-

CH2 CH2

H2C

H2C

H -OH-

O H2O HO

O
CH2 CH2
(I)

OH

HO

OH H
CH2 CH

O -H2O HO

CH2 C
H
OH-

HO

-OH-

O -H2O HO

H2C

OH

H2O HO

-OH-

CH2 C

(II)

OH

OH
H2C

H2O

CH2 CH

CH2 CH

HO

H2C

H2C

CH2 C
CH2 H
HO
(III)

* Thus formed product (III) contains no -hydrogens and hence undergoes crossed Cannizzaro reaction
with formaldehyde. In this step, formaldehyde is oxidized and -CHO group of (III) is reduced to CH2OH.
The final product formed is also known as pentaerythritol.
OH

OH
HO

H2C

+ HCHO
CH2 C
H
CH2
HO

Mechanism:

Conc. NaOH HO

H2C

CH2 C CH2 + HCOONa

CH2 OH
HO

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12
HO

OH-

O
H
O

H
OH
Hydrate anion

H + R

H
H

OH

O
Dianion

+ R

H2C
HO
R=
CH2 C
CH2
HO

H
H

om

transfer of
hydride ion

What are the other products possible in this reaction?

* Aldol and crotonaldehyde are also formed due to self condensation of acetaldehyde.
Why formaldehyde is preferentially oxidized in the final step?
* The carbonyl group of formaldehyde is more electrophilic due to absence of electron withdrawing
groups and hence the initial attack of OH- occurs on formaldehyde.

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Problem 2.3 (UOH MSC 2012)

The most favorable product obtained in the following reaction is:
O

KOH

CO2H

A)

B)

C)

Answer: D

CO2H

D)

CO2H

Explanation:
* 2,5-diketones undergo aldol condensation reactions in presence of a strong base to give cyclized
products. Among the possible cyclizations, those result in 5 membered ring are more favored over 3
membered ones.
There are two acidic hydrogens on C-1 and C-6, abstraction of which lead to 5 membered rings.
However the abstraction of more acidic hydrogen on C-6 carbon is kinetically more favored.
HO

CO 2H

CO 2H

CO 2H

-H2O

CO 2H

HO

Problem 2.4 (GATE 2005)

In the given reactions, identify the correct combination of their major products P and Q.
[LDA = LiN(i-Pr)2]
O
t-Bu

LDA, THF, -78 oC

P
PhCHO

LDA, THF, -78 oC

Q
PhCHO

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13

A)

t-Bu

Ph

B)

;
Ph

OH

t-Bu

OH

OH

t-Bu

Ph

D)

Ph

Ph

OH

OH

t-Bu

Ph

OH

OH

;
Ph

om

Answer: B

Explanation:
* Above reactions are directed aldol reactions which involve preformed enolate of the carbonyl
compound using strong base like LDA. The lithium enolate is treated with another carbonyl compound
to achieve desired crossed aldol addition.
* The lithium enolate can be either cis (Z) or trans (E). Cis enolate usually gives syn addition product
and trans enolate gives anti addition product. In most of the cases, the cis form is kinetically favored and
hence syn ketol is formed selectively as the major product of addition.
This diastereoselectivity can be explained by the formation of cyclic six membered transition state
(Zimmerman-Traxler transition state) in which the bulky group of carbonyl compound favorably takes
pseudoequatorial position, whereas the bulky group on the enolate has to take pseudoaxial position.
This leads to syn product.

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Ph

C)

OH

O Li

LDA

t-Bu

Ph

OH

t-Bu

t-Bu

cis (or) Z-enolate

Ph

syn (or) erythro

ketol

redraw

t-Bu

t-Bu

CH3

Methyl group gets

pseudoaxial position since
it is 'cis' to enolate oxygen

Ph

O
O

Li

CH3

Ph

O
O

Li

phenyl group favors

pseudoequatorial position

Zimmerman-Traxler six membered ring

transition state

* However with cyclic systems, trans enolates are formed due to ring constraints. Hence anti addition
product is formed as major product. The ring carbon must be at pseudoaxial position in the cyclic
transition state. Hence the anti addition product is formed as major product.

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14

O Li

LDA

Ph

OH

H
anti (or) threo
ketol

redraw

om

trans (or) E-enolate

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Ph

H
ring carbon gets
pseudoequatorial position since
it is 'trans' to enolate oxygen

Ph

O
O

Li

Ph

O
O

Li

phenyl group favors

pseudoequatorial position
Zimmerman-Traxler six membered ring
transition state

Problem 3.1 (GATE 2011)

The most appropriate set of reactions for carrying out the following conversion is:

a) i) peracid; ii) H+; iii) Zn/dil.HCl

b) i) Alkaline KMnO4; ii) NaIO4; iii) N2H4 / KOH
c) i) Alkaline KMnO4; ii) H+; iii) Zn/dil.HCl
d) i) O3/ Me2S; ii) NaOEt; iii) N2H4 / KOH
Answer: d

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15

O
O3 / Me2S

OH

N2H4 / KOH

-H2O

NaOEt

Wolf-Kishner
Reduction

om

Intramolecular
Aldol reaction

Ozonolysis

* Ozonolysis cleaves double bond to give two keto groups.

* Thus formed product, in presence of strong base, NaOEt, undergoes intramolecular aldol reaction
followed by dehydration to give a double bond preferably in conjugation with the keto group.
* Then the remaining keto group is reduced to CH2 group by Wolff-Kishner method. The keto group
is first converted to hydrazone, which loses N2 upon heating with a strong base.

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Note: The student is encouraged to write the mechanisms of above reactions.

What about other options?
These too are illustrated below.

OH

H+

peracid

H+

Zn

dil.HCl

OH

Pinacole
rearrangement

Epoxidation

OH

Alk.KMnO4

NaIO4

N2H4 / KOH

OH

cis-hydroxylation

Wolf-Kishner
Reduction

cleavage

OH
Alk.KMnO4

H+

Zn
?
O

dil.HCl

OH

cis-hydroxylation

Pinacole
rearrangement

Problem 3.2
(JAM 2012)
Write the appropriate structures for R, S and T in the following scheme.

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Explanation