Solved Problems in Advanced Organic Synthesis CSIR NET

1
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ADICHEMISTRY
SOLVED PROBLEMS IN ADVANCED ORGANIC SYNTHESIS

(FOR CSIR NET & GATE)
1st EDITION
SAMPLE COPY
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FOR COMPLETE DETAILS 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 depending on your choice. PRICE DETAILS OPTION-1 Rs. 875/- (If you purchase at this rate, free updates are NOT available. However you can get free updates by contributing your knowledge on forum and by helping the author. For more details contact at the following mail id.)
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Problem 1.1
O
O a) Ph
ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

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VISIT
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(IISc 2011)
i) PhMgBr ? ii) H
+
b)
Ph
c)
Ph
d)
O Answer: c
om
Ph OH
Release date: 7th, May 2012 Last updated on: 11th Nov 2012 No. of problems solved: 200 No. of pages: 174
(This will be updated again)
2
Explanation O
O i) PhMgBr BrMgO Ph 1,2 addition of Grignard reagent
ii) H+
:
HO
Ph
-H2O Ph
-EtOH -H+ Ph
Think different: What will happen if 1,4 addition occurs?

O i) PhMgBr O ii) H+ OH Ph O
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).

O
:
acid catalysed and conjugate bond assisted removal of OH group
H O H
final removal step of EtOH
O H+ Ph O -EtOH
om
O Ph
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.
O
Now start arguing!
Web Resource: http://www.adichemistry.com/organic/organicreagents/grignard/grignard-reagent-reaction-1.html WANT TO PURCHASE THE ENTIRE BOOK? TO KNOW THE METHOD OF PAYMENT MAIL ME AT
Note: Updates & support through forums are only available to those who purchased this book from the author of this book at his site: http://www.adichemistry.com. Problem 1.2 The most appropriate set of reagents for carrying out the following conversion is:
O Cl OH
a) i) EtMgBr; ii) HCl c) i) C2H5Li; ii) HCl Answer: d
Explanation: 1,4-addition of HCl furnishes 4-chlorobutanone, which reacts with Grignard reagent to get the desired product.
H+
ClH2C
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.

ADICHEMADI@GMAIL.COM
b) i) (C2H5)2CuLi; ii) HCl d) i) HCl; ii) EtMgBr
O HCl Cl O EtMgBr H3O+ Cl OH mechanism Cl OH OH
om
Ph
4
Cl O EtMgBr O MgBrCl
What about other options? Option - a :

major product O EtMgBr H3O+ OH H+ -H2O ClHCl
Cl

Et2CuLi H3O+ O HCl
* 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
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) PhMgBr M 2) TsOH Ph a) M=
1) BH3.SMe2 2) PCC 3) mCPBA Ph
HO Ph O O b) M= N=
N=
Ph c) M= N=
Ph O d) M=
Ph N=
Answer: a
om
Cl Cl-
Ph O O Ph O
5
Explanation: * A tertiary alcohol is formed upon 1,2 addition of PhMgBr and is dehydrated in presence of Tosylic acid.
O PhMgBr H3O
+
HO Ph TsOH -H2O
Ph
Ph
BH3.SMe2
Problem 1.4 (CSIR JUNE 2011) The major product formed in the following transformation is:
O
1) MeMgCl, CuCl Ph O a) 2) Cl
Ph Answer: d
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
OMe OF 3C MeO O O O CF 3 MeO CF 3

Ph Ph Baeyer Villger oxidation Ph mCPBA OH PCC O O O Anti Markonikov's product Ph-CH- group has more migratory aptitude than CH2 group
b)
c)
d)
Ph
Ph
Me2CuMgCl + MgCl2
OMe O O
TFAA
om
Ph
* 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.
6
Problem 6.1
(IISc 2009)
C6H6 +
S COOEt a)
CHO b)
? major product EtOOC H H CHO c) EtOOC H
om
d)
H O H C
H EtOOC H
CHO
O H
EtOOC H
Explanation: This is Corey-Chaykovski reaction. Since the sulfur ylide is stable, cyclopropanation occurs majorly through 1,4-addition route. The product is a thermodynamic one. The CHO and COOEt groups get trans positions in the cyclopropane ring. This occurs since they tend to orient as far away as possible during the cyclopropanations step to avoid steric repulsion.
O
-
H S CH + COOEt
+ -

H slow 1, 4 addition irreversible O H S HC
+
Answer: a
EtOOC
+ S
COOEt
H CHO
Stereochemistry of cyclopropanation step
EtOOC
+ + S
CHO & COOEt groups orient in space so as to minimize repulsion. Hence they assume trans postions to each other in cyclopropane ring.
Think different: What will be the product if 1,2-addition occurs? An epoxide is formed. It is kinetically favored product.
But this is minor product. Why? Since 1,2-addition step is reversible, the expulsion of ylide from the intermediate is also more likely.
COOEt S CH
+ -
O + H
faster 1,2 addtion reversible
COOEt S HC
+
EtOOC C H H
O C H
+ S
However, the 1,4-addition step is irreversible due to formation of stronger sigma C-C bond, the equilibrium moves more towards 1,4 addition intermediate and the final outcome is the formation of cyclopropane ring as the major product. Note: But when unstable sulfur ylides are used, the major product is epoxide.
7
Web Resource: http://www.adichemistry.com/organic/namedreactions/coreychaykovsky/corey-chaykovsky-1.html Problem 6.2
cat. O H3C H N H
CO2H , CHCl3, 0 OC
O S
+ -
Ph
a) O

b) c) d) O O O O O O CH3 CH3
Ph
Ph
Ph
om
Ph CH3
? major product
H O
CH3 Answer: b
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8
Explanation
CO 2H H O H
+
-H2O HO H3C
N H H3C
N+
CO 2H
H Ph
-S(CH3)2
N+
Ph
N+
H2O
O Ph
Both -CHO & PhCO groups are cis to each other since they try to avoid -CH3 during the reaction.
H O CH3 O Ph H O O Ph N H
The iminium and PhCO groups try CO 2H to avoid steric N H interaction with adjacent CH3 group during the H O formation of H CH3 cyclopropane ring Ph C and hence both of them are oriented S(CH3)2 trans to methyl group.

Crotonaldehyde froms an iminium ion with Indoline-2-carboxylic acid N+ CO 2H S(CH3)2 O H CH3 Ph CO 2H CH3 S(CH3)2 CO 2H CH3 CO 2H
:
CH3
CO 2H Regeneration of Indoline-2-carboxylic acid CH3
om
Corey-Chaykovsky reaction 1,4-addition of stabilized sulfur ylide and hence the formation of cyclopropane ring.
H H
9
COOMe HC COOMe COOMe + MeOH CHCOOMe
MeO
OH H COOMe CHCOOMe COOMe -H O 2 COOMe COOMe COOMe
Redraw
Stereochemistry of Alder-ene reaction

COOMe ene COOMe reaction H
CO2Me
CO2Me
CO2Me CO2Me
CH3
Problem 16.1
(CSIR June 2011)

OH
p-TSA
OH
major product?
OH (2S)-butane-1,2,4-triol
OH a) HO O O b) HO O O c) O O d) O O
om
COOMe COOMe
CO2Me CO2Me
OH
Answer: c
Explanation: * Butane-1,2,4-triol forms an acetal with 3-pentanone to give a 1,3-dioxolane (a 5 membered ring) as major product. The hydroxy groups on adjacent (1 & 2) positions take part in this reaction. Formation of a 1,3-dioxane (a six membered ring) isomer as in options a & b is less preferred due to steric factors. * p-TSA, p-toluenesulfonic acid serves as acid catalyst.
10
OH OH OH :O OH H p-TSA O OH + H O OH2
+
: OH OH
OH OH
Note: Work out the stereochemistry at chiral carbon. In the option c, the configuration at 2nd carbon is retained and incidentally it has S configuration as in the triol. Problem 17.1 (CSIR Dec 2011) The major products M and N in the following reaction sequence are: Problem 35.2 (GATE 2010) In the reaction sequence,
CH2OH H H OH HO H O
i. Hg(OAc)2/MeOH ii. NaBH4
the major products, X and Y, respectively, are:

O C+ redraw OH OH OH redraw HO O O C C+
(CH3)2CO HCl X Y
om
-H2O
11
A) HO MeO HO O & O HO O MeO O HO B) HO MeO HO O & O O MeO HO O
HO
C) HO HO
HO O & OMe O HO O O
D) HO OMe HO
HO
HO
om
O HO O OMe O O
O & OMe
O OMe
Answer: C
Explanation: * In the solvo-oxymercuration, the Hg attacks from the less hindered side and the OMe approaches from the top side and attacks the carbon-1, adjacent to ring oxygen, since the positive charge on this carbon is stabilized due to +M effect of ring oxygen. * Demercuration is achieved by sodium borohydride to furnish a deoxy sugar. * In the final step, protection of OH groups on 4th and 6th carbons is achieved by using acetone in presence of dry HCl. However, a six membered cyclic acetal is formed instead of five membered one even though there is diaxial interaction for methyl groups on isopropylidene moiety. It is because of inability of formation of trans fusion of 6/5 membered ring that would be created when the OH groups on 3rd and 4th carbons, which are trans to each other, are involved in cyclic acetal formation.
H
CH2OH O H H OH HO H

HOH2C O -OAcHOH 2C O
:
O Me
-H
HO HO
HO HO
HO
HO
AcO Hg OAc
Hg
AcOHg
OAc
HO
NaBH4
HO
HO
O OMe
(CH3)2CO HCl
HO
O OMe
12
I
Pd(OAc)2, PPh3 Et3N I
1) Answer: 3
2)
3)
4)
reductive elimination

I PPh3 Pd HI Ph3P Ph Pd
2+
Explanation: * It is a Heck reaction. 3-phenylcyclohexene is formed as the only product instead of expected 2phenylcyclohexene, due to requirement of syn elimination of hydride.
oxidative addition
Ph3P
PPh3 I
Pd
2+
Ph3P
Ph
Ph
Pd
SYN -hydride elimination
Ph3P
PPh3
Ph
Pd
2+
Ph3P
Problem 36.2 Choose the species that is not an intermediate in the following palladium catalyzed Heck reaction.
om
I PPh3 I
2+
PPh3
SYN addition
13
Br O O
+
O Br Pd(PPh3)2
Pd(PPh3)2 Et3N (Ph3P)2Pd O 3) O
Br O O Pd(PPh3)2 4) O Pd(PPh3)2 O
1)
2)
Answer: 2
O Ph

HBr PPh3 reductive elimination
2+
Explanation:
Pd
PPh3 Br
Ph3P
oxidative addition
Pd
Ph3P
Ph
om
Br PPh3
2+
Br
Pd
Br O O
Ph3P
-complex
Ph
Ph3P
Pd
2+
PPh3
Br
O O -complex PPh3 Br
SYN -hydride elimination
Ph H Ph3P
Ph Ph3P
Pd
2+
Pd
2+
PPh3
Br Rotation of C-C bond to give more stable conformation
Ph Ph3P
SYN addition
Pd
2+
PPh3
Br
Problem 37.1 (GATE 2004) The major product formed on nitration of N, N-dimethylaniline with conc. H2SO4 and conc. HNO3
14
is:
A)
NMe2
B)
NMe2 NO2
C)
NMe2 NO2
D)
NMe2
NO2
Answer: A
NO2
NO2
Why para product is also formed? * In the reaction mixture, small amount of free N,N-dimethylaniline is also present in equilibrium with its anilinium salt. This free form is highly reactive and gives para product and favors the equilibriumto the left side.
Me Me Me N
+
* However, below 83% concentration of H2SO4, meta substitution is seldom observed and the composition of para product and N,N,N,N-tetramethyl benzidine increases with dilution of sulfuric acid. It is also interesting to note that, with dilution of H2SO4, the major product is N,N,N,N-tetramethyl benzidine rather than the para isomer.
Me2N NMe2
For example, 63% of benzidine derivative is formed when 74.7% of H2SO4 is used. This reaction occurs through ion radical-radical pair mechanism. * Ortho product is also possible but formed in less amount due to steric factor. Problem 37.2 (GATE 2004) In electrophilic aromatic substitution reactions, nitro group is meta-directing, because the nitro group: a) increases electron density at meta position. b) increases electron density at ortho and para positions. c) decreases electron density at meta position. d) decreases electron density at ortho and para positions.

N Me H H+ present in less amount but reacts faster to give para isomer present in more amount but reacts slowly to give meta isomer
Explanation: * The nitration of N,N-dimethylaniline using 85% H2SO4 gives 45% meta-nitro product and 38% paranitro product along with N,N,N,N-tetramethyl benzidine. * N,N-dimethyl aniline is protonated in strongly acidic medium by forming an N,N-dimethyl anilinium ion, PhNHMe2+. Since NHMe2+ group is deactivating towards electrophilic substitution due to -I effect, the nitration occurs mostly at meta position.
om
15
Answer: d Explanation: * Nitro group is electron withdrawing group. It withdraws electrons both by inductive as well as mesomeric effect i.e., both -I & -M group. Among these, mesomeric effect has more effect on the reactivity. In the resonance forms that can be written due to -M effect of nitro group, the positive charge is more distributed on ortho and para positions. Hence these positions become less reactive towards electrophilic substitution, when compared to meta position.
O O
-
* The comparison of resonance forms of Wheland intermediates formed during attack of electrophile, E+ is illustrated below. The Wheland intermediates formed, during ortho and para attacks are less stable, since one of the contributing structure is least stable due to presence of positive charges on adjacent carbon atoms. WANT TO PURCHASE THE ENTIRE BOOK? TO KNOW THE METHOD OF PAYMENT MAIL ME AT

The positive charge is more concentrated on ortho and para positions making these site less reactive towards electrophilic substitution
om
+
16
O ortho attack
N H E
H E
N H E
H E
Least stable

meta attack N
+
E+
om
N
+
H E
H E
H E
H E
para attack
Least stable
* The summary of above points are illustrated in the following free energy diagram. Not only the activation free energy required for meta attack is less, and also the Wheland intermediate formed is more stable.
Transition state
Free energy
ortho & para attack meta attack
Wheland intermediate Reaction coordinate
17
1,2-alkyl H
+
HO
shift
HO 1,2-alkyl shift
-H+ HO HO H
* However, the product given under option-1 is also formed as a minor product. The mechanism leading to formation of this is also shown below.
H 1,2-alkyl shift -H+
Why above one is a minor product? In this case, less stable secondary carbocation is formed in the initial step. Problem 39.1 In the following reaction sequence, the major product is:
H MeO
A)
MeO O N H
C) H MeO Answer: A

HO HO HO
i) NH2OH, HCl
ii) ArSO2Cl, Py iii) iv) H2O
HN
HN
B)
H MeO
D) H MeO
H H
om
O N O
18
Explanation: * The keto group is converted to following E-oxime and then tosylated.
Ar O OH N O NH2OH, HCl H H E-Oxime S O Cl -HCl OSO2Ar N
H H MeO
OSO 2Ar N
Beckmann rearrangement
Why not amide as given under option B is formed? * Yes. It is also a possible product. It is formed due to migration of methyl group when it is anti to OH group as in Z-oxime. However the migration of methyl group is slower than the ring and hence the this amide is formed as minor product.
N OH HN O
H Migration of methyl group occurs since it is anti to the OH group in Z-oxime.
Problem 52.1 (CSIR JUNE 2012) The intermediate A and the major product B in the following reaction are:

-
Note: Only part of the reactant is shown. * Thus formed product undergoes Beckmann rearrangement upon heating and subsequent treatment with water to furnish an amide.
OSO 2Ar
OH
H2O
HN
-ArSO3H
om
O
Tosylation
19
O N3 NH2 A intermediate B= B O H N 2) A= an acyl cation B= N H O
1) A= an acyl cation
NH
3) A= an acyl nitrene Answer: 4
B=
NH
4) A= an acyl nitrene
B=
om
N C NH2 H N N H
H N O N H
Explanation: * It is Curtius rearrangement. The acyl azide loses dinitrogen, N2 to give an intermediate acyl nitrene, which undergoes rearrangement of aryl group on to nitrogen and furnishes an isocyanate. * The isocyanate is attacked by nucleophilic amine group to give a heterocyclic ring, 1,3-dihydro-2Hbenzimidazol-2-one.
O
-
N NH2

N N O N N N O -N2 N NH2 NH2 Acyl nitrene
isocyanate
Problem 53.1 (CSIR JUNE 2012) For the following reactions: A & B, the correct statement is:
Br KOBut (excess)
Br
KOBut (excess)
A)
B)
COOH
COOH
1) A gives
B gives
COOK
3) both A & B give
2) A gives Answer: 2
COOK
B gives
4) both A & B give
COOK
20
Explanation: * In case of reaction A, the most stable conformation of cyclohexane is with tert-butyl group on equatorial position. In this conformation, there is a H atom anti periplanar to the Br and hence undergo E2 elimination easily by giving cyclohexene with carboxylic group.
Br O -HBr O H
-
O OBu
t
* However, in reaction B, the carboxylic group itself is antiperiplanar to Br and hence the elimination involves decarboxylation.

Br -CO2 -Br O
-
om

Solved Problems in Advanced Organic Synthesis CSIR NET

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1

SOLVED PROBLEMS IN ADVANCED ORGANIC SYNTHESIS

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

(This will be updated again)

O i) PhMgBr BrMgO Ph 1,2 addition of Grignard reagent

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

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

acid catalysed and conjugate bond assisted removal of OH group

final removal step of EtOH

Now start arguing!

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

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

What about other options? Option - a :

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

Expecting aldol reaction

1) BH3.SMe2 2) PCC 3) mCPBA Ph

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

? major product EtOOC H H CHO c) EtOOC H

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

Stereochemistry of cyclopropanation step

faster 1,2 addtion reversible

Web Resource: http://www.adichemistry.com/organic/namedreactions/coreychaykovsky/corey-chaykovsky-1.html Problem 6.2

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

CO 2H Regeneration of Indoline-2-carboxylic acid CH3

OH H COOMe CHCOOMe COOMe -H O 2 COOMe COOMe COOMe

Stereochemistry of Alder-ene reaction

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

(CSIR June 2011)

i. Hg(OAc)2/MeOH ii. NaBH4

the major products, X and Y, respectively, are:

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

Pd(OAc)2, PPh3 Et3N I

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

SYN -hydride elimination

Pd(PPh3)2 Et3N (Ph3P)2Pd O 3) O

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

SYN -hydride elimination

Br Rotation of C-C bond to give more stable conformation

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

ortho & para attack meta attack

Wheland intermediate Reaction coordinate

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

ii) ArSO2Cl, Py iii) iv) H2O

H Migration of methyl group occurs since it is anti to the OH group in Z-oxime.

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

3) A= an acyl nitrene Answer: 4

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

3) both A & B give

4) both A & B give

ht tp V. :// ww Adi tya w. ad va ich rdh em an ist ry .c

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