Q1.

Answer any five questions from the following:

a) What is the basic difference between Felkin-Ahn Model and Cram’s model?

Felkin-Ahn Model: It focuses on minimizing steric hindrance and considers the influence of
the alpha substituent on the carbonyl carbon during nucleophilic addition reactions. The
nucleophile attacks the carbonyl carbon from the least hindered side.

Cram’s Model: It suggests that the nucleophile attacks the carbonyl carbon from the side
opposite to the largest substituent on the adjacent chiral center, maximizing the steric
interactions.

b) Give an example of Woodward hydroxylation.

An example of Woodward hydroxylation is the conversion of 1,2-dihydronaphthalene to 1,2-

naphthalenediol using singlet oxygen and water.

c) Define stereo specific reaction with proper example.

A stereospecific reaction is one where the reactant forms a specific stereoisomer of the
product. An example is the addition of dibromocarbene to cis-2-butene to give cis-2,3-
dibromobutane.

d) Which form of trans cyclohexane halohydrine gives the formation of epoxide at faster
rate?

Trans-2-chlorocyclohexanol forms an epoxide faster because the trans configuration allows

the chlorine and hydroxyl groups to be in an anti-periplanar arrangement, facilitating the
intramolecular nucleophilic substitution (S_N2) reaction.

e) Mention one key feature for the Beckmann rearrangement.

A key feature of the Beckmann rearrangement is the migration of an alkyl or aryl group from
the carbon to the nitrogen in an oxime, forming an amide.

f) Give an example of Cope rearrangement.

An example of Cope rearrangement is the thermal conversion of 1,5-hexadiene to 1,5-

hexadiene.

g) Which one undergoes oxidation reaction at faster rate of chromic acid oxidation—cis
or isomer of 4-tertbutylcyclohexanol? Why?

The cis-isomer of 4-tertbutylcyclohexanol undergoes oxidation at a faster rate than the trans-
isomer because the axial hydroxyl group in the cis-isomer is more exposed and less sterically
hindered, making it more accessible to the oxidizing agent.

h) Give an example of chemoselective reaction.

An example of a chemoselective reaction is the selective reduction of a ketone in the
presence of an ester using sodium borohydride (NaBH4).

Section 2
Q2. Answer any five questions from the following:

a) Give a synthetic utility of pinacol rearrangement with stereochemistry.

The pinacol rearrangement involves the acid-catalyzed conversion of a 1,2-diol (pinacol) to a

ketone or aldehyde (pinacolone). One synthetic utility is the conversion of pinacol (2,3-
dimethyl-2,3-butanediol) to pinacolone (3,3-dimethyl-2-butanone). The rearrangement
proceeds through a carbocation intermediate, where one of the alkyl groups migrates with
retention of configuration, resulting in a stereochemically defined product.

b) Optically active (R)-2-phenylpropan-2-ol on treatment with HBr loses its optical

activity—explain the fact.

(R)-2-Phenylpropan-2-ol, when treated with HBr, undergoes an S_N1 reaction. The

intermediate carbocation formed is planar and can be attacked by the bromide ion from either
side, leading to a racemic mixture (equal amounts of (R) and (S) enantiomers). This results in
the loss of optical activity due to the formation of a racemic mixture.

c) Differentiate between S_N1 and S_N2 reactions in terms of their stereochemistry.

• S_N1 Reaction: This is a two-step reaction that proceeds via a carbocation

intermediate. The stereochemistry is lost in the intermediate step, leading to
racemization (formation of both enantiomers in equal proportions).
• S_N2 Reaction: This is a one-step bimolecular reaction where the nucleophile attacks
the carbon simultaneously as the leaving group leaves. The reaction proceeds with
inversion of configuration at the stereocenter (backside attack), resulting in a single
enantiomeric product.

d) Write down the structure of product formed when cyclononone is separately reduced
partially with Li/EtNH2 and Na/liquid NH3.

• Partial reduction with Li/EtNH2 (Birch reduction): This typically reduces the
carbonyl compound to a trans-alkene. The product is trans-9-cyclononenone.
• Partial reduction with Na/liquid NH3: This also results in the formation of a trans-
alkene, similar to the Birch reduction. The product is trans-9-cyclononenone.

e) How does stereoelectronic effect provide stability control?

The stereoelectronic effect refers to the stabilization of molecular structures due to the
optimal alignment of orbitals. For example, in cyclohexane conformers, the equatorial
position is preferred for bulky substituents due to less steric strain, which is a stereoelectronic
effect providing stability control.

f) What do you mean by stereoelectronic effect?

The stereoelectronic effect is the influence of the spatial arrangement of electrons (orbitals)
on the stability and reactivity of molecules. It involves the optimal alignment of orbitals to
minimize energy and maximize stability, often observed in reactions where orbital
interactions are crucial, such as in conformational analysis and pericyclic reactions.

g) Mention two examples which are generally used to prepare 1,2-diol from alkene.

1. OsO4 (osmium tetroxide) oxidation: Alkenes are converted to cis-1,2-diols.

2. KMnO4 (potassium permanganate) oxidation: Alkenes are converted to cis-1,2-
diols under mild conditions.

h) Explain the term SAC and PDC with suitable example.

• SAC (Sharpless Asymmetric Catalysis): This involves the use of chiral catalysts to
induce asymmetry in the product. An example is the Sharpless epoxidation, where
allylic alcohols are converted to epoxides using a chiral titanium-tartrate catalyst.
• PDC (Pyridinium Dichromate): This is a reagent used for the oxidation of primary
and secondary alcohols to aldehydes and ketones, respectively. An example is the
oxidation of 1-propanol to propanal.

Section 3
Q3. Answer any three questions from the following:

a) i) What do you mean by chiral auxiliary? Give an example.

A chiral auxiliary is a stereogenic group temporarily introduced into a substrate to control

the stereochemistry of the subsequent chemical reactions. Once the desired stereochemical
configuration is achieved, the chiral auxiliary can be removed.

Example: Evans' auxiliary, such as (S)-4-benzyl-2-oxazolidinone, is used in enantioselective

alkylation reactions.

a) ii) Write the expected product with stereochemistry when (E)-2-methylpent-2-en-1-ol

is treated with (+) Diethyl tartrate and t-BuOOH, Ti(OiPr)4 in CH2Cl2? Does replacing
(+) Diethyl tartrate with (-) Diethyl tartrate exhibit same result?

The treatment of (E)-2-methylpent-2-en-1-ol with (+) Diethyl tartrate and t-BuOOH,

Ti(OiPr)4 in CH2Cl2 refers to Sharpless asymmetric epoxidation.

The product will be an epoxide, specifically (2R,3R)-2-methyl-3-pentyloxirane, when using

(+) Diethyl tartrate.

If you replace (+) Diethyl tartrate with (-) Diethyl tartrate, the product will be the enantiomer
(2S,3S)-2-methyl-3-pentyloxirane. Thus, the stereochemistry of the epoxide changes
depending on the chirality of the diethyl tartrate used.

b) i) Give a suitable experiment to establish that the group anti to the oxime hydroxy
migrates in the Beckmann rearrangement.
One experiment involves using a symmetrical ketone like cyclohexanone, which forms a
single oxime. Treat the oxime with acid under Beckmann rearrangement conditions. The
product, caprolactam, confirms that the anti group (trans to the hydroxyl group of the oxime)
migrates, as there is no possibility for regioisomers.

b) ii) Provide reaction of 2-amino-cyclohexanol by nitrous acid.

The reaction of 2-amino-cyclohexanol with nitrous acid (HNO2) results in the formation of
2-hydroxy-cyclohexanone via diazotization and subsequent hydrolysis.

H2N−C6H10-OH+HNO2→OH−C6H10-OH+N2+H2O\text{H}_2\text{N}-
\text{C}_6\text{H}_{10}\text{-OH} + \text{HNO}_2 \rightarrow \text{OH}-
\text{C}_6\text{H}_{10}\text{-OH} + \text{N}_2 + \text{H}_2\text{O}H2N−C6H10-
OH+HNO2→OH−C6H10-OH+N2+H2O

c) i) Write down the stable conformation of 1,4-di-tert-butylcyclohexane. Explain your

choice.

The stable conformation of 1,4-di-tert-butylcyclohexane is the diaxial conformation. This is

because placing the bulky tert-butyl groups in the axial positions avoids 1,3-diaxial
interactions that would be severe if both groups were equatorial. The steric repulsion between
axial tert-butyl groups is less destabilizing compared to the interactions in the diequatorial
conformation.

c) ii) Give an example of organo catalyst.

An example of an organocatalyst is (S)-proline, which is used in the aldol reaction to catalyze

the formation of carbon-carbon bonds with high enantioselectivity.

c) iii) Carry out the following conversion: 1-phenyl ethanol to 2-phenyl ethanol.

The conversion of 1-phenyl ethanol to 2-phenyl ethanol can be achieved through the
following steps:

1. Oxidation of 1-phenyl ethanol to acetophenone using PCC (Pyridinium

chlorochromate).
2. Conversion of acetophenone to 2-phenyl ethanol via a Grignard reaction. Treat
acetophenone with ethylmagnesium bromide followed by hydrolysis to yield 2-phenyl
ethanol.

PhCH(OH)CH3→PCCPhCOCH3→EtMgBrPhCH(OH)CH2CH3\text{PhCH(OH)CH}_3
\xrightarrow{\text{PCC}} \text{PhCOCH}_3 \xrightarrow{\text{EtMgBr}}
\text{PhCH(OH)CH}_2\text{CH}_3PhCH(OH)CH3PCCPhCOCH3EtMgBrPhCH(OH)CH2
CH3

d) i) What do you mean by merged substitution-elimination reaction?

Merged substitution-elimination reactions are those reactions where both substitution and
elimination processes occur simultaneously or in a stepwise manner from a common
intermediate. The outcome depends on the reaction conditions and the nature of the reactants,
leading to a mixture of substitution and elimination products.

d) ii) Provide a suitable mechanism for Woodward hydroxylation.

Woodward hydroxylation involves the hydroxylation of alkenes using osmium tetroxide

(OsO4) followed by sodium periodate (NaIO4). The mechanism is as follows:

1. The alkene reacts with OsO4 to form an osmate ester intermediate.

2. Hydrolysis of the osmate ester gives a 1,2-diol.
3. Cleavage of the 1,2-diol with NaIO4 yields two carbonyl compounds.

e) i) Cis-but-2-ene in presence of moist I2/AgOAc gives cis diol. Show the mechanism for
the formation of product. Do you think the same starting material in presence of
I2/AgOOCCH3 in benzene shows same results? Justify your answer.

Mechanism for cis-but-2-ene in the presence of moist I2/AgOAc:

1. The alkene reacts with I2 to form a cyclic iodonium ion intermediate.

2. Water (moist condition) attacks the less hindered carbon, leading to the formation of a
trans diol intermediate.
3. The product is a cis diol due to syn addition.

If the reaction is conducted in benzene (non-aqueous solvent) with I2/AgOOCCH3, the

absence of water will not provide the nucleophile needed for diol formation. Thus, the
reaction will not yield the same cis diol product. Instead, it may result in the formation of
different products or remain unreacted.

These are the complete solutions to section 3 of your document. Let me know if you need
further assistance or have any more questions!

4o
Solve section 4
ChatGPT

Sure, I'll solve the fourth section (Q4) for you.

Q4. Answer any one question from the following:

a) i) What do you mean by regio-specific reaction? Give an example of regio-specific

reaction.

A regio-specific reaction is a chemical reaction that yields one predominant or exclusive

structural isomer when multiple positional isomers are possible. In other words, the reaction
proceeds in such a way that it favors the formation of a product at a specific position on the
molecule.
Example: The hydroboration-oxidation of alkenes is regio-specific. When propene undergoes
hydroboration-oxidation, the boron adds to the less substituted carbon (anti-Markovnikov
addition), resulting in the formation of 1-propanol as the main product.

CH3CH=CH2+BH3→CH3CH2CH2B(OH)2→CH3CH2CH2OH\text{CH}_3\text{CH}=\tex
t{CH}_2 + \text{BH}_3 \rightarrow
\text{CH}_3\text{CH}_2\text{CH}_2\text{B}(\text{OH})_2 \rightarrow
\text{CH}_3\text{CH}_2\text{CH}_2\text{OH}CH3CH=CH2+BH3→CH3CH2CH2
B(OH)2→CH3CH2CH2OH

a) ii) What major product do you expect when (S)-phenylbutan-2-one is treated with
LAH? Explain your choice.

When (S)-phenylbutan-2-one is treated with lithium aluminum hydride (LAH), it undergoes

reduction to form (S)-2-phenylbutan-2-ol. LAH is a strong reducing agent that reduces
ketones to secondary alcohols.

(S)-Ph-CH2CH2COCH3→LAH(S)-Ph-CH2CH2CHOHCH3\text{(S)-Ph-
CH}_2\text{CH}_2\text{COCH}_3 \xrightarrow{\text{LAH}} \text{(S)-Ph-
CH}_2\text{CH}_2\text{CHOHCH}_3(S)-Ph-CH2CH2COCH3LAH(S)-Ph-CH2CH2
CHOHCH3

The reduction retains the stereochemistry at the chiral center, resulting in (S)-2-phenylbutan-
2-ol.

a) iii) Explain the final product when cis-1,2-cyclohexane diol is treated with acid
followed by treatment with hydroxylamine and hydrolysis in the presence of acid.

1. Initial acid treatment of cis-1,2-cyclohexane diol: The cis-1,2-cyclohexane diol can

undergo dehydration in the presence of acid to form cyclohexene.

cis-1,2-cyclohexane diol→H+cyclohexene+H2O\text{cis-1,2-cyclohexane diol}

\xrightarrow{\text{H}^+} \text{cyclohexene} + \text{H}_2\text{O}cis-1,2-
cyclohexane diolH+cyclohexene+H2O

2. Treatment with hydroxylamine: The cyclohexene reacts with hydroxylamine to

form cyclohexanone oxime.

cyclohexene+NH2OH→cyclohexanone oxime\text{cyclohexene} + \text{NH}_2\text{OH}

\rightarrow \text{cyclohexanone oxime}cyclohexene+NH2OH→cyclohexanone oxime

3. Hydrolysis of cyclohexanone oxime in the presence of acid: The oxime undergoes

Beckmann rearrangement to form ε-caprolactam.

cyclohexanone oxime→H+ε-caprolactam\text{cyclohexanone oxime}

\xrightarrow{\text{H}^+} \text{ε-caprolactam}cyclohexanone oximeH+ε-caprolactam

b) i) Suggest a suitable method for the preparation of cyclohexylenemethanol from

methylenecyclohexane.
 1. Hydroboration-oxidation: Treat methylenecyclohexane with borane (BH3) followed
by hydrogen peroxide (H2O2) and sodium hydroxide (NaOH). This converts the
terminal alkene to an alcohol, resulting in cyclohexylenemethanol.

methylenecyclohexane→BH3/H2O2,NaOHcyclohexylenemethanol\text{methylenecyclohexa
ne} \xrightarrow{\text{BH}_3/\text{H}_2\text{O}_2,\text{NaOH}}
\text{cyclohexylenemethanol}methylenecyclohexaneBH3/H2O2,NaOH
cyclohexylenemethanol

b) ii) Show how enantioface differentiation can be used to get enantioselective reduction
of an achiral unsymmetrical ketone to alcohols using chiral Grignard reagent.

Enantioselective reduction using a chiral Grignard reagent involves the addition of the
Grignard reagent to an achiral ketone. The chirality of the reagent induces stereoselectivity in
the product.

Example: Treating acetophenone with (R)-methylphenylmagnesium bromide yields (R)-1-

phenyl-1-propanol predominantly.

PhCOCH3+(R)-MePhMgBr→(R)-PhCH(OH)Me\text{PhCOCH}_3 + \text{(R)-
MePhMgBr} \rightarrow \text{(R)-PhCH(OH)Me}PhCOCH3+(R)-MePhMgBr→(R)-
PhCH(OH)Me

The chiral center in the Grignard reagent controls the face of attack on the carbonyl group,
resulting in enantioselective reduction.

Section 4
Q4. Answer any one question from the following:

a)

i) What do you mean by regio-specific reaction? Give an example of regio-specific

reaction.

• Regio-specific reaction: A reaction that yields one predominant or exclusive

structural isomer when multiple positional isomers are possible.
• Example: Hydroboration-oxidation of alkenes, where propene reacts to form 1-
propanol.

ii) What major product do you expect when (S)-phenylbutan-2-one is treated with
LAH? Explain your choice.

• Product: (S)-2-phenylbutan-2-ol.
• Explanation: LAH reduces the ketone to a secondary alcohol, retaining the
stereochemistry.
iii) Explain the final product when cis-1,2-cyclohexane diol is treated with acid followed
by treatment with hydroxylamine and hydrolysis in presence of acid.

• Products and Mechanism:

1. Acid treatment: cis-1,2-cyclohexane diol to cyclohexene.
2. Hydroxylamine treatment: cyclohexene to cyclohexanone oxime.
3. Hydrolysis with acid: cyclohexanone oxime to ε-caprolactam.

b)

i) Suggest a suitable method for the preparation of cyclohexylenemethanol from

methylenecyclohexane.

• Method: Hydroboration-oxidation using BH3 followed by H2O2/NaOH.

ii) Show how enantioface differentiation can be used to get enantioselective reduction of
an achiral unsymmetrical ketone to alcohols using chiral Grignard reagent.

• Example: Reduction of acetophenone with (R)-methylphenylmagnesium bromide to

(R)-1-phenyl-1-propanol.

iii) Explain how triacetoxy-2-acetoxycyclohexyl tosylate on acetolysis with sodium

acetate in acetic acid gives racemic trans-1,2-diacetoxycyclohexane. Explain.

• Mechanism:
1. Formation of cyclohexyl carbocation.
2. Attack by acetate ion from either side, forming racemic mixture of trans-1,2-
diacetoxycyclohexane.

c)

i) What is Lindlar catalyst? Write the product with stereochemical configuration when
such catalyst is applied on 3-hexyne followed by KMnO4 oxidation and subsequent
hydrolysis.

• Lindlar Catalyst: Palladium catalyst poisoned with lead acetate and quinoline.
• Product: cis-3-hexene, which upon oxidation and hydrolysis yields cis-hexane-3,4-
diol.

ii) Do you think cis and trans 4-tertbutylcyclohexylamine on treatment with HNO2 give
same products or different products? Provide the possible products with mechanism.

• Products: Different products.

o cis-4-tertbutylcyclohexylamine to cis-4-tertbutylcyclohexanol.
o trans-4-tertbutylcyclohexylamine to trans-4-tertbutylcyclohexanol.

iii) Draw the possible products when (E)-1,3-diphenylprop-2-en-1-one (Chalcone) is

treated separately with PhMgBr and PhLi. Produce different products. Write the
possible products with mechanism.
 • Products and Mechanism:
o PhMgBr and PhLi both add to the carbonyl group of chalcone, forming (1,3-
diphenyl-2-propen-1-ol) after protonation.

b) iii) Explain how triacetoxy-2-acetoxycyclohexyl tosylate on acetolysis with sodium

acetate in acetic acid gives racemic trans-1,2-diacetoxycyclohexane. Explain.

Mechanism:

1. Formation of Carbocation Intermediate: The tosylate group (a good leaving group)

leaves, forming a cyclohexyl carbocation.

triacetoxy-2-acetoxycyclohexyl tosylate→cyclohexyl carbocation\text{triacetoxy-2-

acetoxycyclohexyl tosylate} \rightarrow \text{cyclohexyl carbocation}triacetoxy-2-
acetoxycyclohexyl tosylate→cyclohexyl carbocation

2. Attack by Acetate Ion: The acetate ion from sodium acetate attacks the carbocation
from either side, leading to the formation of both (R) and (S) forms of 1,2-
diacetoxycyclohexane.

cyclohexyl carbocation+AcO−→racemic trans-1,2-

diacetoxycyclohexane\text{cyclohexyl carbocation} + \text{AcO}^- \rightarrow
\text{racemic trans-1,2-
diacetoxycyclohexane}cyclohexyl carbocation+AcO−→racemic trans-1,2-
diacetoxycyclohexane

Because the carbocation intermediate is planar, the acetate ion can attack from either the top
or bottom face, leading to the formation of both enantiomers and resulting in a racemic
mixture.

c) i) What is Lindlar catalyst? Write the product with stereochemical configuration

when such catalyst is applied on 3-hexyne followed by KMnO4 oxidation and
subsequent hydrolysis?

Lindlar Catalyst: Lindlar's catalyst is a palladium catalyst poisoned with lead acetate and
quinoline, used for the selective hydrogenation of alkynes to cis-alkenes.

When 3-hexyne is treated with Lindlar's catalyst, it is selectively hydrogenated to cis-3-

hexene.

3-hexyne→Lindlar’s catalystcis-3-hexene\text{3-hexyne} \xrightarrow{\text{Lindlar's

catalyst}} \text{cis-3-hexene}3-hexyneLindlar’s catalystcis-3-hexene

Subsequent oxidation with KMnO4 and hydrolysis would give hexane-3,4-diol as the
product, with both hydroxyl groups in a cis configuration.

c) ii) Do you think cis and trans 4-tertbutylcyclohexylamine on treatment with HNO2
give same products or different products? Provide the possible products with
mechanism.
Cis and trans 4-tertbutylcyclohexylamine will give different products when treated with
HNO2 due to their different stereochemistry.

1. Cis-4-tertbutylcyclohexylamine:
o The amine will be diazotized to form the diazonium salt.
o The diazonium salt will undergo a substitution reaction to form a hydroxyl
group, resulting in the formation of 4-tertbutylcyclohexanol.

cis-4-tertbutylcyclohexylamine+HNO2→4-tertbutylcyclohexanol (cis)\text{cis-4-
tertbutylcyclohexylamine} + \text{HNO}_2 \rightarrow \text{4-tertbutylcyclohexanol
(cis)}cis-4-tertbutylcyclohexylamine+HNO2→4-tertbutylcyclohexanol (cis)

2. Trans-4-tertbutylcyclohexylamine:
o The same diazotization and substitution process will occur.
o However, due to the trans configuration, the resulting product will be trans-4-
tertbutylcyclohexanol.

trans-4-tertbutylcyclohexylamine+HNO2→4-tertbutylcyclohexanol (trans)\text{trans-4-
tertbutylcyclohexylamine} + \text{HNO}_2 \rightarrow \text{4-tertbutylcyclohexanol
(trans)}trans-4-tertbutylcyclohexylamine+HNO2→4-tertbutylcyclohexanol (trans)

Thus, the cis and trans isomers will give different products due to their stereochemistry.

c) iii) Draw the possible products when (E)-1,3-diphenylprop-2-en-1-one (Chalcone) is

treated separately with PhMgBr and PhLi. Produce different products. Write the
possible products with mechanism.

1. Treatment with PhMgBr (Grignard Reagent):

o The Grignard reagent will add to the carbonyl group of chalcone to form an
intermediate alcohol, followed by protonation to give the alcohol.

Chalcone+PhMgBr→(1,3-diphenyl-2-propen-1-ol (after protonation))\text{Chalcone} +

\text{PhMgBr} \rightarrow \text{(1,3-diphenyl-2-propen-1-ol (after
protonation))}Chalcone+PhMgBr→(1,3-diphenyl-2-propen-1-ol (after protonation))

2. Treatment with PhLi (Organolithium Reagent):

o The organolithium reagent will also add to the carbonyl group of chalcone
similarly to form an intermediate alcohol.

Chalcone+PhLi→(1,3-diphenyl-2-propen-1-ol (after protonation))\text{Chalcone} +

\text{PhLi} \rightarrow \text{(1,3-diphenyl-2-propen-1-ol (after
protonation))}Chalcone+PhLi→(1,3-diphenyl-2-propen-1-ol (after protonation))

Both reagents (PhMgBr and PhLi) will produce the same type of product, which is the
alcohol, but their mechanisms of addition may slightly differ due to the difference in
nucleophilicity.