CHE603 Advanced Synthetic Methods

YASHWANTRAO CHAVAN MAHARASHTRA OPEN UNIVERSITY
SCHOOL OF SCIENCES
(FORMERLY SCHOOL OF ARCHITECTURE, SCIENCE & TECHNOLOGY)
V154: M.Sc. Chemistry

2023 {As per NEP 2020}
Pattern
CHE603
ADVANCED SYNTHETIC
METHODS
(2 Credits)
Semester - III
Email: director.ast@ycmou.ac.in
Website: www.ycmou.ac.in
Phone: +91-253-2231473
Yashwantrao Chavan CHE603
Maharashtra Open Advanced Synthetic

University Methods
Brief Contents
Vice Chancellor’s Message ......................................................................... 3
Foreword By The Director ......................................................................... 4
Credit 01 .......................................................................................................... 5
Credit01-Unit 01: Disconnection approach ......................................... 6
Credit01-Unit 02: Group Disconnections ........................................... 31
Credit01-Unit 03: Retro-Synthesis ...................................................... 48
Credit01-Unit04: Retro-Synthesis of Aromatic Hetrocyles ........... 95
Credit 02...................................................................................................... 122

Credit02-Unit 01: Reagents and Reaction In Synthesis-1 ............ 123
Credit02-Unit 02: Reagents and reaction in synthesis-2 ............. 172
Credit02-Unit 03: Name Reaction-1 .................................................. 201
Credit02-Unit 04: Name Reaction-2 .................................................. 223
Feedback Sheet for the Student ............................................................ 234
CHE603: Advanced Synthetic Methods Page 1

CHE134: Advanced Synthetic Methods
Yashwantrao Chavan Maharashtra Open University
Vice-Chancellor: Prof. Sanjeev Sonawane
School of Architecture, Science and Technology
Director of the School: Dr. Chetana Kamlaskar
Programme Advisory Committee
Dr. Chetana Kamlaskar Dr Sunanda More
Director & Associate Professor, Former Director, School of Sciences,
School of Sciences, YCMOU, Nashik YCMOU, Nashik
Prof. Dr. S. D. Delekar, Professor, Prof. Dr. Nandkishor N. Karade, Dr. Arvind Vinayak Nagawade
Deptt of Chemistry, Shivaji Deptt of Chemistry, Rashtrasant Vice Principal& Head Deptt of
University Tukadoji Maharaj Nagpur Chemistry, Ahmednagar College
Kolhapur - 416004
University, Ahmednagar,
Nagpur 440033 Dist: Ahmednagar, 414001
Dr. Tukaram. S. Thopate, Prof. Shamrao Golekar Associate Dr. Borhade Ashok Vishram
Professor and Ex Vice Principal, Professor and Head Deptt of Associate Prof., Deptt of
Deptt of Chemistry, New Arts, Chemistry Jamkhed College
Commerce Science College, Chemistry, H.P.T. Arts & R.Y.K.
Jamkhed,
Parner, Taluka Parner, Dist:
Dist: Ahmednagar 413201 Science College, Nashik 422001
Ahmednagar 414302
Dr. Amol Haridas Kategaonkar Dr. Bharat More

Assistant Prof. in Chemistry, Academic Coordinator, School of
MVP Samaj’s KSKW Arts Science and Commerce Architecture, Science and Technology,
College, CIDCO, YCMOU, Nashik-422 222
Nashik 422008
Development Team
Instructional Course Coordinators Book Writer Book Editor
Technology Editor
Dr. Sunanda More 1. Dr. Bharat More Dr. Amol H. Kategaonkar Dr. Tukaram. S.
Former Director, School 2. Mr. Ghanshyam Patil Assistant Prof. in Thopate,
of Sciences, YCMOU, Academic Coordinator, Chemistry, MVP Samaj’s Vice Principal and
Nashik-422 222 School of Sciences, GMD Arts, BW Commerce Head Deptt of
YCMOU, and Science College, Chemistry, New Arts,
Nashik-422 222 Sinnar, Nashik-422 103 Commerce Science
College, Parner,
Taluka Parner, Dist:
Ahmednagar 414302
This work by YCMOU is licensed under a Creative Commons Attribution-

NonCommercial-ShareAlike 4.0 International License.
 Book Publication: 26-October-2023 Publication No: 2887
 Publisher: Mr. B. P. Patil, Registrar(I/C), YCMOU, Nashik- 422 222, MS
 ISBN: 978-81-19791-94-1
 This SLM V142: M.Sc. Chemistry {2022 Pattern}, dtd. 26/10/2023
Book used in V154: M.Sc. Chemistry {2023 Pattern}, dtd. 31/08/2023

VICE CHANCELLOR’S MESSAGE
Dear Students,
Greetings!!!
I offer cordial welcome to all of you for the Master’s degree programme of Yashwantrao
Chavan Maharashtra Open University.
As a post graduate student, you must have autonomy to learn, have information and
knowledge regarding different dimensions in the field of Chemistry and at the same time intellectual
development is necessary for application of knowledge wisely. The process of learning includes
appropriate thinking, understanding important points, describing these points on the basis of
experience and observation, explaining them to others by speaking or writing about them. The
science of Education today accepts the principle that it is possible to achieve excellence and
knowledge in this regard.
The syllabus of this course has been structured in this book in such a way, to give you
autonomy to study easily without stirring from home. During the counseling sessions, scheduled at your
respective study centre, all your doubts will be clarified about the course and you will get
guidance from some qualified and experienced counsellors/ professors. This guidance will not
only be based on lectures, but it will also include various techniques such as question-answers,
doubt clarification. We expect your active participation in the contact sessions at the study
centre. Our emphasis is on ‘self-study’. If a student learns how to study, he will become
independent in learning throughout life. This course book has been written with the objective of
helping in self-study and giving you autonomy to learn at your convenience.
During this academic year, you have to give assignments, complete laboratory activities, field
visits and the Project work wherever required. You have to opt for specialization as per programme
structure. You will get experience and joy in personally doing above activities. This will enable
you to assess your own progress and thereby achieve a larger educational objective.
We wish that you will enjoy the courses of Yashwantrao Chavan Maharashtra Open
University, emerge successful and very soon become a knowledgeable and honorable
Master’s degree holder of this university.
I congratulate “Development Team” for the development of this excellent high quality
“Self- Learning Material (SLM)” for the students. I hope and believe that this SLM will be
immensely useful for all students of this program.
Best Wishes!
- Prof. Dr. Sanjeev Sonawane
Vice-Chancellor, YCMOU

FOREWORD BY THE DIRECTOR
Dear Students,
Greetings!!!
This book serves the primary goal of acquainting postgraduate level students,
particularly those in the field of Science, with the conceptual and practical
foundations of Chemistry essential for their study. It offers a complete exploration
of Chemistry principles and their practical applications. Throughout the book, you
will find numerous illustrative examples designed to enhance your understanding
and skills.
We have taken a "learn at your own pace" approach, so each unit of the book is
designed to be as user-friendly as possible. To do this, the book is written in a self -
instructional format, making sure that each unit follows a carefully structured
approach. This not only facilitates comprehension but also keeps the learning
process engaging.
Each unit of book commences with clearly defined learning objectives, using
action verbs aligned with Bloom's Taxonomy to help you understand what you'll
achieve. Additionally, each unit begins with an introduction to stimulate the
learner's curiosity and enthusiasm for the upcoming content. As you progress, you'll
encounter detailed explanations supported by tables, figures, exhibits, and solved
illustrations, all thoughtfully included enhancing the ability to learn.
This SLM book is written in simple language with conversational style, concise
sentences and covers the entire syllabus. The topics within each unit are presented
in a logical sequence, starting from simple concepts and progressing to more
complex one, ensuring that the material is approachable for learners with varying
levels of intellectual capacity.
To enrich learning experiences, each unit contains a diverse range of exercises,
including multiple-choice questions, conceptual questions, and practical problems.
These exercises aim to guide students in understanding every aspect of a particular
concept, gradually building their knowledge and skills.
We are grateful to the learners, resourceful writers, diligent editors, and the
dedicated School faculty and staff who contributed to the development of this Self -
Learning Material (SLM) book.
Hope this book becomes a valuable companion to support your academic
pursuits and enrich your understanding of content covered in this course.
Let’s Grow Together….Best Wishes to all of you!!
- Dr. Chetana Kamlaskar

Director,
School of Sciences, YCMOU

CREDIT 01

CREDIT01-UNIT 01: DISCONNECTION APPROACH
LEARNING OBJECTIVES
After successful completion of this unit, you will be able to
 Define the concept of retrosynthetic analysis.
 Describe the various termed involved in the retrosynthesis.
 Discuss about the different disconnection approaches with chemo selectivity
and reversal of polarity.
 Explain the protecting groups for different functional groups.
 Explore the C-C one group and two-group disconnections by their
applications in different organic reactions.
 Discuss about the concept of ring synthesis with the help of retrosynthesis.
 Discuss about the synthesis of some complex molecules using disconnection
approach.
INTRODUCTION
This retrosynthetic approach is about making molecules or rather it is to

help you design your own synthesis by logical and sensible thinking. This is not a
matter of guesswork but requires a way of thinking backwards that we call the
disconnection approach.
When you plan the synthesis of a molecule, all you know for certain is the
structure of the molecule you are trying to make. It is made of atoms but we don’t
make molecules from atoms: we make them from smaller molecules. But how to
choose which ones? If you wanted to make, say, a wooden joint, you would look in
a do-it-yourself book on furniture and you would find an ‘exploded diagram’
showing which pieces you would need and how they would fit together.

The disconnection approach to the design of synthesis is essentially the
same: we ‘explode’ the molecule into smaller starting materials on paper and then
combine these by chemical reactions. It isn’t as easy as making wooden joints
because we have to use logic based on our chemical knowledge to choose these
starting materials. The first chemist to suggest the idea was Robert Robinson who
published his famous tropinone synthesis in 1917. His term was ‘imaginary
hydrolysis’ and he put dashed lines across a tropinone structure.
This was a famous synthesis because it is so short and simple and also
because it makes a natural product in a way that imitates nature. The reaction is
carried out at pH 7 in water. In fact, Robinson didn’t use acetone, as suggested by
his ‘imaginary hydrolysis’, but acetone dicarboxylic acid. This procedure is an
improved one invented by Sch¨opf in 1935.
Amazingly, nobody picked up the idea until the 1960s when E. J. Corey at
Harvard was considering how to write a computer program to plan organic
syntheses 3 . He needed a systematic logic and he chose the disconnection approach,
also called retrosynthetic analysis. The computer program is called LHASA and the
logic survives as a way of planning syntheses used by almost all organic chemists.
It is more useful to humans than to machines.
Routine for Designing a Synthesis
1. Analysis
(a) Recognize the functional groups in the target molecule.
(b) Disconnect with known reliable reactions in mind.
(c) Repeat as necessary to find available starting materials.
2. Synthesis
(a) Write out the plan adding reagents and conditions.
(b) Modify the plan according to unexpected failures or successes in the
laboratory.

01-01: AN INTRODUCTION TO SYNTHONS AND SYNTHETIC
EQUIVALENTS
Synthesis of Aromatic Compounds:
The benzene ring is a very stable structural unit. Making aromatic

compounds usually means adding something(s) to a benzene ring. The
disconnection is therefore almost always of a bond joining a side chain to the
benzene ring. All we have to decide is when to make the disconnection and which
reagents to use. You will meet the terms synthon and functional group
interconversion (FGI) in this section.
Disconnection and FGI
You already know that disconnections are the reverse of known reliable
reactions so you should not make a disconnection unless you have such a reaction
in mind. In designing a synthesis for the local anesthetic benzocaine 1, we see an
ester group and know that esters are reliably made from some derivatives of an acid
2 and an alcohol (ethanol). We should disconnect the C–O ester bond. From now on
we will usually write the reason for a disconnection or the name of the forward
reaction above the arrow.
The sign for a disconnection on a molecule is some sort of wiggly line

across the bond being disconnected. The ‘reaction arrow’ is the ‘implies’ arrow
from logic. The argument is that the existence of any ester implies that it can be
made from an acid and an alcohol.
Disconnection of either the -NH 2 or the -CO 2 H group is not a good reaction
corresponding to those disconnections. We need to change both groups into some
other groups that can be added to a benzene ring by a known reliable reaction. This
process is called functional group interconversion (FGI) and is an imaginary
process, just like a disconnection. It is the reverse of a real reaction. Here, we know
that we can make amino groups by reduction of nitro groups and aryl carboxylic
acids by oxidation of alkyl group.
We ‘oxidized’ the amino group first and then ‘reduced’ the acid group. The
order is unimportant but is something we come back to in the forward reaction.

What matters is that we have found a starting material 4 that we know how to make.
If we disconnect the nitro group 4a we shall be left with toluene 5 and toluene can
be nitrated in the para-position with a mixture of nitric and sulfuric acid.
Now, we should write out the synthesis. You cannot of course predict
exactly which reagents and conditions will be successful and no sensible organic
chemist would attempt to do this without studying related published work. It is
enough to make suggestions for the type of reagent needed. We shall usually give
the reagents used in the published work and conditions where they seem to matter.
Here it is important to nitrate first and oxidize second to get the right substitution
pattern.
Introduction to Retro-synthetic Analysis and Synthetic planning:

1) Linear Synthesis
 Synthesis composed of sequential steps
 For a linear synthesis, the overall percent yield is equal to the product of the
yields of the individual steps.
 The three-step synthesis will have an overall yield of (0.80) x (0.80) x
(0.80) = (0.80)3 = 0.51, or 51%.
 The six-step synthesis will have an overall yield of 26%.
Examples of Linear Synthesis

1. Linear Synthesis of Paracetamol
2. Linear Synthesis of Musk Ambrette (perfume)

Overall Yield and Number of Steps
How Overall Yield in a Synthesis is affected by the number and yield of

individual steps
2) Convergent Synthesis
In a convergent synthesis, portions of a target molecule are synthesized
separately and are assembled together at a later stage. The yield can generally be
improved.

Example of convergent synthesis: Synthesis of Benadryl
Linear synthesis versus Convergent synthesis
3) Divergent Synthesis-
A divergent synthesis is a strategy with the aim to improve the efficiency of

chemical synthesis. It is often an alternative to convergent synthesis or linear
synthesis. In this strategy, divergent synthesis aims to generate a chemical
compound (1) by first reacting a molecule with a set of reactants. The next
generation of compounds are generated by further reactions with each compound in
generation 1. This methodology quickly diverges to large numbers of new
compounds.

Retrosynthetic Analysis:
 Elias J. Corey (1928) of Harvard University pioneered a new method of
designing a synthesis scheme, called retrosynthetic analysis.
 The basis of retrosynthetic analysis is the transform, which is the proposed
undoing of a single reaction or set of reactions.
 An open arrow, called a retrosynthetic arrow is the convention used to
indicate a transform and is drawn from the target to the precursor.
SOLVED PROBLEMS 01
1) Problem 01-01: What are synthons and their synthetic equivalents?
Solution: Synthetic equivalent: A reagent carrying out the function of a

synthon which cannot itself be used, often because it is too unstable.
Synthon: A generalized fragment, usually an ion, produced by a

disconnection. (Some people also use synthon for a synthetic equivalent).
2) Problem 01-02: What are the different types of synthons?
Solution: Synthons are classified as donor and acceptor synthons.
(a) Donor Synthons: These are negatively polarized synthons denoted by

symbol’d’.
(b) Acceptor Synthons: These are positively polarized synthons denoted by

symbol 'a'.
SHORT ANSWER QUESTIONS WITH MODEL ANSWER 01

1) SAQ 01-01: What is the mechanism of synthon reaction?
Answer: The mechanism of the reaction involves C-C pi-bond attack onto an
iminium ion, usually formed in situ from the condensation of an amine and an
aldehyde.

2) SAQ 01-02: What is the synthon approach in organic chemistry?
Answer: Synthon approach is a very useful analytical tool. It is an analytical
approach to Organic Synthesis in which the target molecule is broken into
fragments through a series of logical disconnection to get the best plausible and
likely starting materials (ie. synthons or building blocks) for the target
molecule.
01-02: DISCONNECTION APPROACH
During the retrosynthetic analysis of compound 2 the retrosynthetic

cleavage (or disconnection) leads to a nucleophile 3 and an electrophile 4. The
correct alternative based in known chemical transformations is in this case leading
to 3 and 4.
Retro-Synthetic design involves two distinct steps:

1. Retrosynthetic analysis and
2. Subsequent translation of the analysis into a "forward direction" synthesis.
In the analysis, the chemist recognizes the functional groups in a molecule
and disconnects them proximally by methods corresponding to known and reliable
reconnection reactions.

Retro-analysis of Paracetamol:
Synthesis of Paracetamol:
Terms used in retro-synthesis:

 Target Molecule: The molecule whose synthesis is being to be planned.
 Retrosynthesis: The logical processes of analyzing the structure of the
target molecule to discern a possible synthesis step by step and is
represented by
 Disconnection: A conceptual cleavage of a bond to break the molecule into
possible starting materials.
 Transformations (tfs): A disconnection of a strategic bond in the target
molecule.
 Synthons: the charged species formed during the disconnection process.
 Retron: The functional group containing portion of the target material.
 Synthetic equivalents: A chemical compound available commercially for a
synthon.
 FGA (Functional group Addition)- addition of Functional group during a

strategic bond breaking.
 FGI (Functional Group Interchange)-Changing of one functional to

another to disconnect a bond.
 Functional group Removal (FGR): Deletion of functional group in the

target molecule for the successive steps to form synthons.
 Ring Disconnection (RGD): Cyclic ring structure is disconnected to form

aliphatic molecules.
 Chain Disconnection (CHD): Acyclic structure or appendage in the ring

structure is removed.
Arrow Notations:
Guidelines for Retrosynthesis:
1. Recognize the functional group in the TM.

2. Disconnect the TM into fragments with known reliable chemical reactions
using FGI.

3. During FGI, changing one Functional group to another may alter its reactivity
dramatically.
 Alcohols and aldehydes are converted by redox reactions with the carbonyl
groups are electron withdrawing and alcohols are electron donating groups.
4. Disconnections in the TM proceeds with-
i. Disconnect at the middle of the TM
ii. Disconnect at the branch point
iii. Disconnect rings from the chains.
a. Bonds next to carbonyl group
b. Bonds joining the aromatic ring to the rest of the molecule.
c. Using two-group disconnections.
5. Some substituents (e.g. -OMe) are difficult to add in that case it is best to
retain them for the synthesis.
6. Some groups are added to the aromatic ring by electrophilic substitution
reaction which requires an electron withdrawing group like nitro at ortho to
leaving group.
7. When a series of reactions has been proposed, start a reaction which gives a
single product rather than a mixture.
8. When two-groups are of equal reactivity, one group is selectively reacted by
suitable reagents.
9. When two-groups of unequal reactivity, the more reactive can be made to react
first.
Synthons and Synthetic equivalent:
Heterolytic retrosynthetic disconnection of a carbon-carbon bond in a

molecule breaks the TM into an acceptor synthon, a carbocation, and a donor
synthon, a carbanion. In the reverse reaction, the formation of a C-C bond involves
the union of an electrophilic acceptor synthon and a nucleophilic donor synthon.
Chemical bonds can be cleaved heterolytically, homolytically, or through
concerted transform (into two neutral, closed-shell fragments). The following
discussion will focus on heterolytic and cyclic disconnections.

Common Donor Synthons:
Synthon Derived reagent Synthetic equivalent

Common Acceptor Synthons:
Synthon Synthetic equivalent

Summary of Important Disconnections:
Alternating polarity disconnections:

Functional groups may be classified as follows:
E class: Groups conferring electrophilic character to the attached carbon (+):
-NH 2 , -OH, -OR, =0, =NR, -X (halogens)
G class: Groups conferring nucleophilic character to the attached carbon (-):
-Li, -MgX, -AlR 2 , -SiR 3
A class: Functional groups that exhibit ambivalent character Carbon (+ or -):
-BR 2 , C=CR 2 , CECR, -NO 2 , EN, -SR, -S(O)R, -SO 2 R
The positive charge (+) is placed at the carbon attached to an E class
-
functional group (e.g., -O , -OH, -Br) and the TM is then analyzed for consonant
and dissonant patterns by assigning alternating polarities to the remaining
carbons. In a consonant pattern, carbon atoms with the same class of functional
groups have matching polarities, whereas in a dissonant pattern, their polarities
are unlike.
Consonant pattern: Positives charges are placed at carbon atoms bonded to the E
class groups

Dissonant pattern: One E class group is bonded to a carbon with a positive charge,
whereas the other E class group resides on a carbon with a negative
charge.
If a consonant pattern is present in a molecule, a simple synthesis often be

achieved.
SOLVED PROBLEMS 02
3) Problem 01-03: What is the basic principle of disconnection approach?
Solution: An approach for designing organic synthesis which involves

breaking down of target molecule into available starting material by
imaginary breaking of bonds (disconnection) and/ or by functional group
interconversion (FGI) is known as disconnection approach or retrosynthetic
analysis or retrosynthesis or synthesis
4) Problem 01-04: What is the importance of disconnection approach?
Solution: Disconnection approach is a helping tool for the design of their

synthesis. This is also known as the retrosynthetic analysis. This is the
reverse method of observing a molecule keeping their synthesis in mind.
This is a synthetic route to the target molecule from the simpler molecule
or simpler starting materials.

3) SAQ 01-03: What is the basic retrosynthetic approach?
Answer: Retrosynthesis is a technique chemists use to identify how to

synthesize a molecule through approaching the problem backwards. Effectively
retrosynthesis starts from the wanted product and wo rks backwards chopping
and changing the molecule into smaller pieces to identify what the previous
molecule can be made from.
4) SAQ 01-04: What is a target molecule?

Answer: In medicinal chemistry, target molecules or drug targets refer to the
key molecules (such as carbohydrates, proteins, and nucleic acids) that are
involved in certain metabolic pathways leading to certain diseases. These target
molecules are inhibited when the drug molecules bind to the active sites.
01-03: FGI (FUNCTIONAL GROUP INTERCONVERSIONS:

Functional group interconversion is the conversion of one functional
group into another without affecting the carbon skeleton by substitution, addition,
elimination, reduction or oxidation.
Functional group addition (FGA):

Acyclic or cyclic saturated hydrocarbons are usually unreactive.
Disconnections of such hydrocarbons are difficult because the hydrocarbon is a
compound having no functional group which is guiding signal for disconnection.
Functional Group Removal (FGR):
Functional group removal is the process of converting one functional group
into another without affecting the carbon skeleton and remove after achieving the
required pattern on TM by substitution, addition, elimination, and reduction or
oxidation reactions.

Synthesis of Hydrocarbon
SOLVED PROBLEMS 03
5) Problem 01-05: What is FGI in chemistry with example?
Solution: Functional group interconversion is the process of converting one

functional group into another during retrosynthetic analysis. FGI mostly
involve oxidation, reduction, and substitution. It is applicable where we do
not have real and workable reaction reverse to a disconnection.
6) Problem 01-06: What is functional group interconversion with example?
Solution: The functional group interconversion (FGI) reactions are among

the most common synthetic processes. In this experiment, the conversion of

cinnamic aldehyde is performed by reduction with LiALH 4 into two
different products, depending upon the order of addition of reactants.

SAQ 01-05: What is a detail note on the functional group interconversion?
Answer: It was defined by Stuart Warren as "the process of converting one

functional group into another by substitution, addition, elimination, oxidation or
reduction, and the reverse process used in (retrosynthetic) analysis."
5) SAQ 01-06: What are 4 examples of functional groups?
Answer: Functional groups are specific groupings of atoms within molecules

that have their own characteristic properties, regardless of the other atoms
present in a molecule. Common examples of functional groups are alcohols,
alkenes, alkynes, amines, carboxylic acids, aldehydes, ketones, esters, and
ethers, among others.

01-04: IMPORTANCE OF THE ORDER OF EVENTS IN ORGANIC
SYNTHESIS.
The order of events in the retro-synthesis
1) Examine the relationship between the functional groups and its orientation in the
synthesis which give the correct substitution pattern as was on TM.
2) If there is a choice, disconnect first (that is add last) the most electron
withdrawing substituents because it deactivates the aromatic ring and difficult to
add further.

3) If FGI is needed during the synthesis, it may well alter the directing effect of the
group and the other substituents may therefore be added either before or after the
FGI.
4) Many groups can be added by nucleophilic substitution on a diazonium salt made

from aniline. Adding other groups at the amine stage may be advisable as the
amino group is strongly o/p-directing.
5) A dummy amino group is added to achieve the required substitution pattern as

needed and then removed by diazotization and reduction.

Example:
Synthesis
6) Look for substituents which are difficult to add and its often-good strategy not to
disconnect these at all but to use a starting material containing the substituent
such as –OH and –OR.

7) Avoid sequences which may lead to unwanted reactions at other sites in the
molecule. Thus, nitration of benzaldehyde gives only 50% m-nitrobenzaldehyde
since nitric acid oxidizes –CHO to –COOH.
SOLVED PROBLEMS 04
7) Problem 01-07: Suggest a synthesis of the starting material.
Solution: Grignard reagents are made from the corresponding halide and the rest
of the analysis used simple C–X disconnections.
It turns out that the addition of HBr to the unsaturated aldehyde (trivially known
as acrolein) and the protection as an acetal can be carried out in a single step as
both are acid-catalyzed.

8) Problem 01-08: Propose a retrosynthetic analysis of the following compound.
Solution:
The conjugated double bond can easily be prepared by dehydration. Thus,

we can perform an FGI to give the aldol product. The β-hydroxy carbonyl
compound disconnects very easily. Of course, in the forward direction the reaction
is not quite that simple; we have two carbonyl groups so we must selectively form
the correct enolate but this should be possible by low temperature lithium enolate
formation prior to the addition of cyclohexanone.

6) SAQ 01-07: How would you synthesize?
from
Answer:
The key to this one is fictionalization of the hydrocarbon. This is achieved by

radical bromination.

from
Answer:
CHECK POINT 01-01

(Fill in the Blanks)
1. Synthesis is nothing more than taking an available molecule is called
the……………. and transforming it by a series of reactions into a molecule that
is required for some purpose the ………….
2. Protocol has been developed that takes the target and simplifies it by a series of
mental bond-breaking steps called…………
3. Disconnect products; sometimes they are called………..
4. Disconnect fragments to real molecules involves the use of a…………

SUMMARY
 Organic molecules are diverse in nature and have applications in all fields of
life.
 The synthesis of organic molecules is a challenging field.
 The synthesis requires the help of disconnection approach or retrosynthesis.
 The backward way of observing a reaction is known as retrosynthetic
analysis.
 Retrosynthetic (or antithetic) analysis is a problem resolving method for
converting the structure of a synthetic target (TGT) molecule to a sequence of
gradually simpler structures through a path which eventually leads to simple
or commercially available starting materials for a chemical synthesis.
 Through the disconnection method, we break the entire molecule into smaller
starting materials on paper and then join these by chemical reactions.
 The toughest job in planning a retrosynthetic analysis is recognizing where to
make the disconnections.
 The organic synthesis is an inseparable part of organic chemistry and is
involved in the construction of organic compounds using different types of
appropriate organic reactions.

 Synthons are the chemical fragments obtained from the disconnection of
bond(s) of the target molecule. The disconnection of bond(s) is possible in
three ways:
i. Homolytic cleavage
ii. Heterolytic cleavage
iii. Concerted transform
 Synthetic equivalents are the chemical species which is used to generate
synthons. They are the actual substrates used for the forward reaction and
hence forward synthesis.
 The construction of a synthetic pathway by working backward from the target
molecule is called retrosynthetic analysis.
 The design of a synthetic pathway for any molecule needs to take into
account some of the important aspects.
KEY WORDS
Disconnection approach or Retro synthesis; Synthons; Synthetic equivalents;
Retrosynthetic analysis;
ANSWER TO CHECK POINT 01-01
1. Starting material, target 2. Disconnections
3. Retrons 4. Synthetic equivalent
REFERENCES
MOOCS
https://onlinecourses.nptel.ac.in/noc22_cy30/preview
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=pEnf4e -cyVI
https://www.youtube.com/watch?v=-eT5R1-PyRo
WIKIPEDIA
https://en.wikipedia.org/wiki/Retrosynthetic_analysis
OER
----
REFERENCE BOOKS
Organic Synthesis: The Disconnection Approach; Stuart Warren; John Wiley &
Sons, 2007- 404 pages

CREDIT01-UNIT 02: GROUP DISCONNECTIONS
LEARNING OBJECTIVES
After successful completion of this unit, you will be able to-
DISCUSS ABOUT ONE GROUP C-X DISCONNECTION APPROACH
 Explain the synthetic approach to carbonyl derivatives.
 Demonstrate the synthesis of ethers
 Demonstrate the synthesis of sulfides
 Synthesize the compounds made from alcohols
 Explain about the basics of two-group C-X disconnection approach or

retrosynthetic analysis.
 Analyze the 1,2-disconnection approach
 Analyze the 1,1-disconnection approach
 Analyze the 1,3-Disconnection approach
 Design and write the synthetic steps based on two-group C-X disconnection
approach for molecules
INTRODUCTION
The C-X disconnection approach is mainly applicable to a carbon chain
attached to any of the heteroatom like O, N, or S. Here, a bond joins the heteroatom
(X) to the rest of the molecule like a C-O, C-N, or C-S group. This point is good
point to initiate a disconnection. This is called a ‘One-group’ C-X disconnection as
one would need to identify only one functional group like ester, ether, amide etc. to
make the disconnection.
The two-group disconnection is an approach to organic synthesis is
retrosynthetic analysis. If target molecules possess two functional groups, then the
two-group disconnection approach between the functional group may be applied.
This method of retrosynthetic analysis produces two possible synthons. The two-
group disconnection may be due to heterolytic cleavage or homolytic cleavage.
02-01: ONE GROUP C-X DISCONNECTIONS
The equivalent reactions are mainly ionic that involve nucleophilic
displacement by SN 1 , SN 2 or carbonyl substitution with amines, alcohols and thiols
on carbon electrophiles. The normal polarity of the disconnection of R-X (1) will
be a cationic carbon synthon (2) and an anionic heteroatom synthon (3)

characterized by acyl or alkyl halides (4) as electrophiles and amines, alcohol or
thiols (5) as nucleophiles ( Figure 1) .
Figure 1.
Alternatively, there is also a possibility to use the reverse polarity with a
nucleophilic carbon synthon (6) and an electrophilic heteroatom synthon (7).
These types of disconnections are possible only with second or third row
elements such as S, Si, P and Se. These synthons are characterized by
organometallic compounds RLi (8) or RMgBr (9) and compounds such as RSCl,
Me 3 SiCl and Ph 2 PCl (10) (Figure 2).
Figure 2. Disconnection with anionic Synthon

 Carbonyl derivatives RCO.X
The carbonyl derivatives RCO.X correspond to carboxylic acid and their
derivatives. In these molecules, the point of disconnection is the bond between
the heteroatom and the carbonyl group. Therefore, we can make esters (11) and
amides (13) from acid (acyl) chlorides (12) and alcohols or amines respectively
(Figure 3).
Figure 3.
For example, an ester (14) is simply made this way. This ester has been
used both as an insect repellent and as a solvent for perfumery. The analysis
discloses two accessible compounds: benzyl alcohol (15) and benzoyl chloride
(16). Merging the two with pyridine as solvent and catalyst provides the ester
(14) (Figure 4).

Figure 4.
Acid chlorides are regularly used in these syntheses as they are the most
electrophilic of all acid derivatives and as they can be synthesized from the
acids themselves with PCl 5 or SOC1 2 . The other significant acid derivatives can
be made from acid chlorides or from any compound above them in the chart of
reactivity. So, we can make amides from acid chlorides, anhydrides or esters
(Figure 5).
Figure 5. Hierarchy of reactivity of acid derivative

Propanil (17) is another simple example which is used on rice fields as
weedicide. Amide disconnection yields the amine (18) which can be made from
o-dichlorobenzene (20) by nitration and reduction (Figure 6).
Figure 6.
The synthesis is quite simple. There is only point worth noticing is the
usage of catalytic hydrogenation for the reduction instead of the messy tin (Sn)

and HCl. Industry significantly favors catalytic methods with no toxic by-
products (Figure 7).
Figure 7.
The other disconnection approach for the ester (21) into alkyl group and
the heteroatom is possible by the use of the anion of the acid (22) and an alkyl
halide (R 2 Br) (Figure 8).
Figure 8.
For example, an ester (23) can be prepared by this disconnection
approach.
 The Synthesis of ethers

The disconnection approach for the synthesis of ethers also targets the
bond between C-O. There is a possibility of bond cleavage from either side of
‘O’ as there are two ‘C-O’ bonds present in the ethers.
For example, the synthesis of ether (24) can be possible by two methods
‘a’ and ‘b’ ( Figure 9). In this case, for the synthesis, the starting materials will
be an alcohol (26) or (27) and an alkyl halide, like (25) or (28).
Figure 9.
The reaction can take place by allowing the reaction of alcohol (26) with
a base sodium hydride. The alcohol gets converted to alkoxide anion (29), which
further reacts with benzyl chloride (25) to the ether (24) in 85% yield (Figure

10). We prefer route ‘a’ as benzyl chloride (25) is more reactive and cannot
undergo elimination while there is a possibility with (28) to undergo elimination
and give alkene as side product.
Figure 10.
Let us consider another example, in the case of allyl phenyl ether (32),
there are two disconnections are possible, path a and path b (Figure 11). The
allyl phenyl ether through path ‘a’ can be disconnected to bromobenzene (30)
and the allylic alcohol (31). The disconnection through path ‘b’ is possible with
phenol (33) and the allylic bromide (34).
Figure 11.
The route ‘b’ is more favourable because nucleophilic substitutions on
bromobenzene are very difficult. Hence the possible synthetic pathway is as
given in (Figure 12).
Figure 12.
 The Synthesis of Sulfides
Sulfides are the organic compounds having chemical structure as R-S-R where R
= R or R ≠ R. The former is called symmetrical sulphides whereas later is called
unsymmetrical sulphides. The disconnection approaches for the sulphides are similar to
the ethers as we only replaced heteroatom ‘O’ with ‘S’.
For example, the anion (41) of a thiol (42) will combine with an alkyl halide (40)
to make a new C–S bond and can give R1-S-R2 (39) (Figure 13). The reaction is simpler
with sulphur in comparison to ethers. Thiols are more acidic than alcohols and hence is
more acidic than water (H2O). Sulfide anion (41) are more nucleophilic towards
saturated carbon than are alkoxides and the risk of elimination is quite less in this case.

Figure 13.
Chlorbenside (43) which is also known by other names like chlorparaside
and chlorsulfacide, is a pesticide and is most commonly used as an acaricide
being used to kill mites and ticks. The disconnection of this molecule yields an
acidic thiophenol (44) and a reactive alkyl halide (25) (Figure 14). The synthesis
involves combining these two in ethanol with NaOEt as base.
Figure 14.
Symmetrical sulfides can be synthesized from the alkyl halide and (Figure 15).
The product form in the first step is the monoanion required to prepare the
second C–S bond. The synthesis is merely the combination of the alkyl bromide
with Na 2 S in ethanol.
Figure 15.
 Compounds made from Alcohols
Several nucleophiles we haven’t stated can be used in these reactions. In
every case a nucleophilic heteroatom displaces a leaving group from a
compound derived from an alcohol. Alcohol is a good starting material for
compounds like ethers, sulphides, thiols, alkyl halides etc. (Figure 16).

Figure 16.
SOLVED PROBLEMS 01
9) Problem 02-01: What is a one group CX disconnection?
Solution: The separation of a bond that joins the heteroatom (X) to the rest of
the molecule. Like C-O, C-N or C-S constitutes 'One-group' C-X disconnection
approach. • Acid chlorides are regularly used in the synthesis of carbonyl
derivatives as they.
10) Problem 02-02: Why acid chlorides are used in the synthesis of carbonyl
derivatives?
Solution: Acid chlorides are regularly used in the synthesis of carbonyl derivatives
as they are the most electrophilic of all acid derivatives.

9) SAQ 02-01: How esters, amides and ethers are synthesized?
Answer: Esters and amides can be made from acid (acyl) chlorides and alcohols or
amines. Ethers can be synthesized from alcohol and alkyl halides.
10) SAQ 02-02: Explain the disconnection approaches for the sulphides.
Answer: The disconnection approaches for the sulphides are similar to the ethers as
we only replaced heteroatom ‘O’ with ‘S’. Thiols and alkyl halide may be a good
starting material for sulphide synthesis.
02-02: TWO-GROUP C-X DISCONNECTIONS

Retro-aldol type transformation is an example of heterolytic two-group
disconnection (Figure 1) whereas retro-acyloin transformation is an example of
homolytic two-group disconnection (Figure 2). The two-group disconnections are
also written in short form as ‘diX’.
Figure 1. Heterolytic Two-group disconnection
Figure 2. Homolytic Two-group disconnection

 Types of Two-group Disconnections

This has been observed that the two-group disconnections are better than
one-group disconnections. In the two-group C-X disconnections, the numbering
starts from the carbon atom bearing the functional groups (Figure 3). By 1,2-
disconnection approach we mean that the two functional groups being disconnected
are at relative 1 and 2 positions. The short form of two-group 1,2-disconnection
approach is 1,2-diX. Hydroxy ethers and amino alcohols are the best examples for
1,2-disconnection approach. Figure 4 shows a typical 1,2-disconnection approach
for hydroxy ether. The retrosynthesis of amino alcohols from amine and epoxide is
another example of 1,2-disconnection approach (Figure 5). From the Figure 5, one
can see that the epoxides along with amines can be used for the synthesis of amino
alcohols.
1,2- disconnection
Figure 3
Figure 4
Figure 5
Let us consider another example which utilizes 1,2-disconnection
approach. A number of biologically active molecules possess 1,2-functional
group. A number of drugs are amino alcohol derivatives. The molecule like
fenyramidol or phenyramidol is a muscle relaxant and sold with the trade name
of ‘Cabral’. The IUPAC name of the molecule is 1-phenyl-2-(pyridin-2-ylamino)
ethanol. The disconnection approach or retrosynthetic analysis of this molecule
follows the path of two-group disconnection and can be made from 2-amino
pyridine and styrene oxide (Figure 6). The disconnection of phenyramidol (1)

gave two molecules, 2-amino pyridine (3) and the synthon (2). The synthon (2)
is obtained from the reagent styrene oxide (4). The synthesis of (1) has been
achieved by the reaction of (3) and (4) in the presence of strong base like
sodamide in liquid ammonia (Figure 7).
Figure 6
Figure 7
 1,1-Disconnection approach
Here, 1,1 means, the same carbon atom holds two functional groups. The
short form of two-group 1,1-disconnection approach is 1,1-diX. The best example is
the disconnection approach for acetals which falls in this category. For acetal, one
can use one oxygen atom to help disconnect the other (Figure 8).
Figure 8
The important application of acetals in synthesis is as protecting groups for
aldehydes and ketones.
Another group of compounds include cyclic acetals. They are generally used
for ketones. The disconnection is similar to that for acetals. The disconnection
approach and synthetic pathways for compound (5) is given in Figure 9 and
Figure 10 respectively.

Figure 9
Figure 10
 1,3-Disconnection approach
The 1,3-disconnection approach is applicable to 1,3-difunctionalized
compounds. A number of biologically active molecules possess 1,3-functional
group and this disconnection approach finds its applications in drug design and
synthesis. From the Figure 11, one can see the 1,3-disconnection approach for the
synthesis of 1,3-functionalized compounds.
Figure 11
Compound (8) is an example of 1,3-functionalized molecule. The
retrosynthetic analysis of (8) shows that it can be synthesized from the reagent,
unsaturated carbonyl compound (10). The synthon for this disconnection approach
is (9). This is a Michael reaction type and is applicable for all the carbonyl
compounds and most of the nucleophiles. This type of retroanalysis is equally
applicable for cyanides and nitrocompounds.
Let us consider 1,3-Aminoethers can easily be synthesized by taking the
help of 1,3-disconnection approaches (Figure 12 and 13).

Figure 12
Using the above disconnection approach, one can design the forward
reaction as given below:
 1,4-Difunctional compounds
A brief analysis of them to show you how much of this subject lies
beyond what we can do in this book. If we start with a 1,4-dicarbonyl compound
we might consider first disconnection of the central bond.
We can use an enolate for one reagent but the other will have to have
umpolung. This is not a very serious kind of umpolung as an α-bromo carbonyl
compound will do the job nicely if we select our enol (ate) equivalent carefully.
The synthesis of 1,4-diketone becomes:
 1,5-Related functional groups

This compound has a 1,5 rather than a 1,3 relationship between two
carbonyl groups. Disconnection to give an enolate as one reagent therefore
requires an a 3 rather than an a 1 synthon: in other words, a Michael acceptor.
The synthesis will be successful only if (1) the right reagent enolizes and
the nucleophile (2) undergoes conjugate (and not direct 1,2-) addition to the
unsaturated carbonyl compound. Malonate derivatives enolize easily and do
Michael additions and are therefore a good choice for this type of reaction.
Michael addition of enolates to α, β-unsaturated compounds is a good

way of making 1,5-difunctionalized compounds, and you should look for these
1,5-relationships in target molecules with a view to making them in this way.
Our example is rogletimide, a sedative that can be disconnected to a 1,5-diester.
Further 1,5-diCO disconnection gives a compound we made earlier by ethylation
of the ester enolate.
Rogletimide: retrosynthetic analysis
The synthesis was most efficient with an unsaturated amide as Michael acceptor.
SOLVED PROBLEMS 02
11) Problem 02-03

Suggest which C-X bond would be your first choice for disconnection in these
two compounds, explaining your reasons. Draw your proposed starting materials.
Solution: Though there are many C-X bonds in both molecules, the first
disconnection should be of the ester 4a and of the amide Sa both because we know
of good ways to make these functional groups and because the disconnections are in
the middle of the molecules. You might have drawn 6 and 8 as acid chlorides or as
acids, as we have done, deciding to work out the reagents later.
12) Problem 02-04

Identify the relationships between the functional groups in these molecules.
Solution: It has l,3-diX (whichever way round the ring you go) and 1,4-diX
relationships 1a. The other compound has a simple 1,2-relationship and you
probably saw the 1, l-diO relationship in the acetal at the right hand end. You might
also have called the amide at the other end a 1,1-diX relationship.

11) SAQ 02-03: Find the I, l-diX relationships in these molecules and disconnect
them, drawing the starting materials. What do you think are your chances of making
these molecules this way?
Answer: We draw the black blob where the carbonyl group is hidden, 3a. You may
or may not do this as you choose and the 1,1 - disconnection of the acetal reveals a
keto-triol- 5, better appreciated as a redrawn 5a. Although another acetal could in
theory be formed from the terminal diol, this would have a seven-membered ring
and thermodynamically less likely.
If we do the same thing with 4, the acetal disconnections 4a also give a

keto-triol- 6, redrawn as 6a. Again, the synthesis looks good but did you notice that
5 and 6 are the same) The acid-catalyzed cyclization of 5 or 6, whichever you want
to call it, will be thermodynamically controlled and will give either 3 or 4 or
perhaps a mixture of the two. If our ring size argument is right, 3 may be favored.
If you suggested that the stereochemistry of the two secondary alcohols

could be relevant, you might well be right. The cis compound cis-5 or 6 might give
3 while the trans compound trans-5 or 6 might give 4.
12) SAQ 02-04: Can you use both in· a synthesis of sibutramine, 30 an anti-
depressant?
30
Answer: The reductive amination seems the best way to make the amine and the
ketone 31 might come from a Grignard or organo-lithium addition to the nitrile 32.
Now a double alkylation with 1,3-dibromopropane looks ideal.

The published synthesis found a short cut. The double alkylation went well
and addition of the Grignard to the nitrile 32 led, surprisingly, to the quite stable
imine 33 that could be reduced to the primary amine and methylated with
formaldehyde.
CHECK POINT 01-02
(True or False)
1) The disconnection approach for the synthesis of ethers also targets the bond
between C-N.
2) The separation of a bond that joins the heteroatom (X) to the rest of the molecule like
C-O, C-N or C-S constitutes ‘One-group’ C-X disconnection approach.
3) The 1,3-disconnection approach is applicable to 1,5-difunctionalized
compounds.
4) Hydroxy ethers and amino alcohols are the best examples for 1,2-
SUMMARY
 The separation of a bond that joins the heteroatom (X) to the rest of the
molecule like C-O, C-N or C-S constitutes ‘One-group’ C-X
 Acid chlorides are regularly used in the synthesis of carbonyl derivatives
as they are the most electrophilic of all acid derivatives.
 Esters and amides can be made from acid (acyl) chlorides and alcohols or
amines.
 Ethers can be synthesized from alcohol and alkyl halides.
 Alkyl halides are made from alcohols by treatment with reagents such a s
PBr 5 or HCl and a Lewis acid or PCl 5 or SOCl 2 .

 The designing of ether synthesis can be done from two alcohols as
starting materials, where one can be converted to corresponding halides.
 The disconnection approaches for the sulphides are similar to the ethers
as we only replaced heteroatom ‘O’ with ‘S’. Thiols and alkyl halide may
be a good starting material for sulphide synthesis.
 If target molecules possess two functional groups, then a two-group
disconnection approach between the functional group may be applied.
 The two-group disconnection may be due to heterolytic cleavage or
hemolytic cleavage.
 The two-group disconnections are better than one-group disconnections.
 Hydroxy ethers and amino alcohols are the best examples for 1,2-
 The molecule like phenyramidol follows the path of two-group
disconnection and can be made from 2-amino pyridine and styrene oxide.
 The 1,3-disconnection approach is applicable to 1,3-difunctionalized
compounds.
 1,3-Aminoethers can easily be synthesized by taking the help of 1,3-
disconnection approaches.
KEY WORDS
One group C-X, Two group disconnections
REFERENCES
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1) False
2) True
3) False
4) True
MOOCS
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YOUTUBE VIDEOS
https://www.youtube.com/watch?v=IHeQZTD8Sy4
https://www.youtube.com/watch?v=OubHRyiLqFk
https://www.youtube.com/watch?v=ug0WJPiZ8S4

WIKIPEDIA
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OER
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REFERENCE BOOKS
Organic Synthesis: The Disconnection Approach; Stuart Warren; John Wiley &
Sons, 2007- 404 pages

CREDIT01-UNIT 03: RETRO-SYNTHESIS
LEARNING OBJECTIVES
● Discuss about the retrosynthetic analysis and synthesis.
● Explain the analysis of selectivity and stereo chemical problems.
● Demonstrate the functional group interconversion and protective group
methodology.
● Explain the modern methods for carbon-carbon, and carbon-heteroatom bond
formations.
● Explain the use of reagents and chemical transformation
INTRODUCTION
Retrosynthesis: Retrosynthesis (Retro reverse, synthesis preparation) is an
approach in organic synthesis where reverse of forward direction reaction is
carried (i.e., formation of reactants from product). Retrosynthesis is considered
to be an imaginary process (breaking of bond) where the target molecule is
change to the possible starting material by some set of rules known as
disconnection approach and functional Group Interconversion (FGI).
The simple theme of this approach is to find out simple molecule which
could be employed for generation of any target (desired) molecule. For this
purpose, some specific chemically established reaction and procedures are
required to be followed with use of some well -known chemicals/reagents. If
fragments/chemicals which doesn’t exist, is difficult to find or is expensive then
they can be carried for the process of FGI. Retrosynthesis do also have benefit
of establishing alternate route for synthesis of any target molecule, thus can be
helpful in generating benefits especially in pharma sector.
Retrosynthesis and disconnection approach involves various terms and
species, which should be known well to a reader so as to apply the approach in
right manner to get the molecule of interest.
03-01: ALKENE, ACETYLENES AND ALIPHATIC NITRO ALCOHOLS AND

CARBONYL COMPOUNDS , AMINES.
Alkene:
An alternative route to olefins is by an immediate disconnection of the
double bond. This corresponds to the Wittig reaction:
Example

Choosing to disconnect the double bond outside the ring as this will give us two
fragments:
Retro-Analysis
Synthesis
Example: Synthesis of Alkane via Alkene
Retro-Analysis
Synthesis
Example: Alkene via Acetylene
This cis olefin will presumably come from an acetylene: we can then use an
acetylene anion:
Retro-Analysis

Synthesis
Examples: use of acetylene in synthesis
Retro-Analysis
Synthesis
Examples: Carbonyl condensations

Retro-Analysis
Synthesis
 C-C disconnections of alcohols

Alcohol compounds are an important class of compounds in organic
chemistry. Any compounds possessing the group ‘R-OH’ where R is alkyl group
comes under the category of alcoholic compounds or its derivatives. The
different kind of alcohols includes primary alcohols, secondary alcohols and
tertiary alcohols (Figure 1). Alcohols have wide applicability in our daily life.
They are useful as synthetic intermediates, cleansers, cosmetics, fuels, alcoholic
beverages, etc. The synthetic and retrosynthetic analysis of alcoholic
compounds are required for their utility.
Figure 1
The C-C disconnections of alcohols are more challenging because of
their vast numbers and it becomes very difficult to identify, which C-C bond to
disconnect for carbocation and carbanion. However, there are reagents available
for the generation of carbanion like RMgX and carbocation like RBr.
 Synthesis of alcoholic compounds by 1,1 C-C disconnections
Any compound bearing an alcoholic group can be disconnected at the C-
C bond adjacent to oxygen. The starting materials for these types of compounds
are an aldehyde or ketone and Grignard reagent (Figure 2).

Figure 2
For example, 2-Methyl-2-propanol (1) can be made from acetone (4) and Methyl
magnesium bromide (5).
Retrosynthetic analysis:
The retrosynthetic pathway of 2-methyl-2-propanol (1) is given in figure
3. The C-C bond adjacent to oxygen has been disconnected to give cation (2)
and anion (3) as synthons. The reagent for the cation (2) is acetone (4) and
reagent for carbanion 3 is Grignard reagent, methyl magnesium bromide (5).
Figure 3
Synthesis:
The synthetic pathway of 2-Methyl-2-propanol (1) is given in figure 4.
The reaction of methyl bromide (6) with magnesium in the presence of dry ether
gives Grignard reagent, methyl magnesium bromide (5). The reaction of methyl
magnesium bromide (5) with acetone (4) gives the target molecule (1).
Figure 4
 Synthesis of branched side chain alcohol

The retrosynthetic pathway of branched side chain alcohol, 2,3-
Dimethylbutan-2-ol (7) is given in (Figure 5). The C-C bond adjacent to oxygen
has been disconnected to give cation (8) and anion (3) as synthons. The reagent
for the cation (8) is 3-methylbutan-2-one (9) and reagent for carbanion (3) is
Grignard reagent, methyl magnesium bromide (5), through path ‘a’. An
alternative and more popular is through pathway ‘b’.
Figure 5
Synthesis:
The synthetic pathway of 2,3-Dimethylbutan-2-ol (7) is given in (Figure
6). The reaction of methyl bromide (6) with magnesium in the presence of dry
ether gives Grignard reagent, methyl magnesium bromide (5) (Figure 4). The
reaction of methyl magnesium bromide (5) with 3-methylbutan-2-one (9) gives
the target molecule (7). The synthetic method through pathway ‘b’ disconnection
approach is given in (Figure 7).
Figure 6
Figure 7

Nitroalkenes are an uncommon intermediate in the synthesis of primary
amines owing to the harsh conditions required to effect reduction, however they
are easily prepared from aldehydes or ketones with a nitroalkane via the Henry
reaction. (Figure 8)
Figure 8 Synthesis of primary amines from nitroalkenes. Retrosynthesis of

nitroalkenes via the Henry reaction (nitro-aldol)
 C-C disconnections of Carbonyl compounds-I
Carbonyl compounds in organic chemistry is a functional group consists
of a carbon atom possessing a double bond to an oxygen atom (>C=O). This is
common to several classes of organic compounds. These compounds are useful
in food, pharmaceuticals and other materials. The C=O double bond in the
carbonyl group is very susceptible to chemical reactions. Aldehydes, ketones,
carboxylic acids and their derivatives including amides, esters etc. (Figure 1)
are the class of compounds possessing carbonyl group.
Figure 1
 Carbonyl compounds from alkynes
Carbonyl compounds can be synthesized using various starting material.
Alkynes are important starting materials to synthesize carbonyl compounds.
Terminal alkynes are very useful reagent for making C-C bond in organic
synthesis. Alkyne anion acts as an acyl anion equivalent in the synthesis of
ketones as shown in figure 2.

Figure 2
Synthesis of Acetone
Acetone is the simplest ketone having IUPAC name propan-2-one. The
retrosynthetic and synthetic pathways are given in figures 3 and 4 respectively.
Figure 3
Synthesis:
Acid catalyzed hydration of alkynes in the presence of HgSO 4 results in

the formation of enol, which are tautomerized to form carbonyl compounds.
Here, propyne reacts with water in the presence of HgSO 4 /H 2 SO 4 to give the
enol form which tautomerizes to acetone (Figure 4).
Figure 4
Synthesis of butan-2-one
Butan-2-one or 2-butanone is a four carbon carbonyl compound. The
retrosynthetic and synthetic pathways are given in figures 5 and 6 respectively.
The butan-2-one can be synthesized from 1-butyne (Figure 5)
Figure 5
Synthesis:
The reaction of 1-butyne with water in the presence of HgSO 4 /H 2 SO 4
gives the enol form which tautomerizes to 2-butanone (Figure 6).

Figure 6
 Carbonyl compounds from organometallic compounds
These are the compounds having at least one C-M bond. Metal being
more electropositive than C, acquires positive charge while carbon acquires
negative charge and thus is electron-rich. This is shown below:
Thus, organometallic compounds provide nucleophilic carbon capable of

donating an electron pair to an electrophile.
Various substrates react with organometallic compounds to form carbonyl
compounds.
Acyl chlorides (RCOCl) form carbonyl compounds on reaction with
organocadmium compounds, lithium dialkylcuprates etc.
(a) Organocadmium compounds (R 2 Cd):
Grignard reagents on reaction with cadmium chloride (CdCl 2 ) form
organocadmium compounds (R 2 Cd) as shown below:
(b) Preparation of Gilman reagent (Lithium dialkylcuprate):

Organolithium compounds (RLi) on reaction with copper iodide (CuI)
form Gilman reagent as shown below:
Synthesis of symmetrical ketone:

Pentan-3-one is a symmetrical ketone. The disconnection approach and
synthetic pathways of pent-3-one is given in figures 7 and 8 respectively.
Retrosynthetic analysis of pentan-3-one undergoes heterolytic cleavage
between C-C bond where one carbon is the carbonyl carbon, leading to the

formation of cation and anion. The cation portion can be obtained from acyl
chloride and carbanion from lithium dialkylcuprate or organocadmium
compounds (Figure 7).
Synthesis:
The synthesis of pentan-3-one can be achieved by two methods (Figure

8)
Method 1: Diethyl cadmium (C) reacts with propanoyl chloride (A) and form
pent-3-one as shown below:
Method 2: Lithium diethyl cuprate (B) reacts with propanoyl chloride (A) and
form pent-3-one as shown below:
Figure 8
Synthesis of unsymmetrical ketones:
Butanone is an unsymmetrical ketone. The disconnection approach and
synthetic pathways of butanone is given in figures 9 and 10 respectively.
Retrosynthetic analysis of butanone undergoes heterolytic cleavage
between C-C bond where one carbon is the carbonyl carbon, leading to the
formation of carbocation and carbanion. The cation portion can be obtained
from acyl chloride as shown is the reaction for symmetrical ketones and
carbanion from lithium dialkylcuprate or organocadmium compounds (Figure 9).

Synthesis:
The synthesis of butanone can be achieved by two methods (Figure 10)
Method 1: Dimethyl cadmium (C) reacts with propanoyl chloride (A) and form
but-2-one as shown below:
Method 2: Lithium dimethyl cuprate (B) reacts with propanoyl chloride (A) and
form but-2-one as shown below:
Figure 10
 Carbonyl compounds from Nitriles
Nitriles react with Grignard reagents (RMgX) and form imines. Imines
are further hydrolyzed under acidic conditions to form ketones as explained in
the following sections.
Synthesis of acetophenone:
Acetophenone (or 1-Phenylethan-1-one or methyl phenyl ketone)
undergoes heterolytic cleavage between C-C bond where one carbon is the
carbonyl carbon, leading to the formation of carbocation and carbanion. The
cation portion can be obtained from nitrile and carbanion from Grignard reagent
(Figure 11).

Synthesis:
The synthesis of acetophenone can be achieved in three steps from
phenyl magnesium bromide and acetonitrile (Figure 12).
Figure 12
Step1: Phenyl bromide reacts with magnesium in the presence of dry ether and
form phenyl magnesium bromide (B).
Step2: Phenyl magnesium bromide (B) reacts with acetonitrile (A) and form
imine.
Step3: Imine on acidic hydrolysis form acetophenone.
 Synthesis of carbonyl compounds by dithiane method
The design and synthesis of 1-cyclohexyl-4-phenylbutan-2-one (8) is
explained using retrosynthetic analysis.
The bond between C 2 -C 3 of 1-Cyclohexyl-4-phenylbutan-2-one (8) is
cleaved to get two fragments, one positive charge and other is negative charge
(Figure 1). These fragments further get cleaved to get the desired synthons.
Figure 1
Synthesis:

The 1-Cyclohexyl-4-phenylbutan-2-one (8) has been synthesized in 6
steps using the retrosynthetic analysis explained in figure 1 (Figure 2).
Step 1: Carbonyl group of formaldehyde (1) is protected using propane-1,3-
dithiol (2) using a Lewis acid or Bronsted acid to form protected carbonyl
compound (3).
Step 2: The compound 3 on reaction with a base BuLi forms the corresponding
carbanion (4).
Step 3: Carbanion 4 reacts with bromomethyl cyclohexane and form 5.
Step 4: The compound 5 on reaction with a base BuLi forms the corresponding
carbanion 6.
Step 5: Carbanion 6 on reaction with (2-bromoethyl) benzene forms the
condensed product 7.
Figure 2
 Carbonyl compounds by Aldol condensation
In organic chemistry, an aldol condensation is a condensation reaction
where reaction takes place between a carbonyl compound and an enol or an
enolate ion to form a β-Hydroxyaldehyde or β-Hydroxyketone. This is followed
by dehydration to give a conjugated enone. The synthesis of 7a-Methyl-
1,2,5,6,7,7a-hexahydroinden-4-one (9) involves aldol condensation. Figures 3
and 4 give retrosynthetic analysis and synthesis of this compound respectively.
7a-Methyl-1,2,5,6,7,7a-hexahydroinden-4-one (9) undergoes functional group
interconversion to develop hydroxyl group at -position of the molecule 9.

Further fragmentation gives desired synthons and corresponding reagents
(Figure 3).
Figure 3
Synthesis:
The synthesis of 7a-Methyl-1,2,5,6,7,7a-hexahydroinden-4-one (9) can
be achieved in 6 steps as shown in figure 4.
Step 1: Carbonyl group of 3-bromopropanal (10) is protected by using ethylene
glycol (11) under acidic conditions to form protected carbonyl compound
(12).
Step 2: The protected carbonyl compound 12 on reaction with Li followed by
cuprous iodide forms organocuprate or Gilman’s reagent (13).
Step 3: The Gilman’s reagent 13 (II) reacts with conjugated carbonyl compound,
3-methylcyclohex-2-enone (14) to form 15.
Step 4: The product 15 is deprotected by hydrolysis under acidic conditions to
form
compound 16.
Step 5: The compound 16 under basic conditions undergoes Aldol condensation
to form 17.
Step 6: The aldol product 17 undergoes dehydration on heating to form the
product 7a-Methyl-1,2,5,6,7,7a-hexahydroinden-4-one (9).

Figure 4
 Disconnection approach for amines
The aliphatic and aromatic derivatives of ammonia are known as amines.
They are weak bases and possess unshared electron pair on the nitrogen atom.
Amines are classified based upon the number of alkyls, or aryl, groups attached
to nitrogen atom (Figure 1). Those amine compounds that have only one alkyl or
aryl group attached to the nitrogen atom are primary, while those with two or
three alkyl or aryl groups attached to the nitrogen atom are secondary and
tertiary, respectively. The quaternary amine compounds possess four alkyl or
aryl substituents. The derivatives of amines are very important to human kind
and present in many pharmaceutical molecules. This makes their synthesis
important.
Figure 1
 Synthesis of Amines by reduction of nitro group

Nitro group can be reduced to amines using various reducing agents like
Sn/HCl, Pd/C-H 2 , lithium aluminium hydride (LiAlH 4 ), and Raney nickel (Ni)
etc.
Synthesis of aniline
The amines like aniline can be obtained from nitrobenzene. The functional
group interconversion of amine from nitro group is shown in figure 2.
Figure 2
Synthesis:
Nitrobenzene can be reduced to aniline using Sn/HCl as a reducing agent
(Figure 3).
Figure 3
Synthesis of N-(4-hydroxyphenyl)-acetamide
The retrosynthetic analysis of N-(4-hydroxyphenyl)-acetamide takes
place through various functional group interconversions (Figure 4).
Figure 4
Synthesis:
The synthesis of N-(4-hydroxyphenyl)-acetamide takes place in three
steps starting from phenol (Figure 5).
Step 1: Phenol on nitration using nitration mixture (HNO 3 + H 2 SO 4 ) forms 4-
nitrophenol.

Step 2: 4-Nitrophenol is reduced to 4-aminophenol using Sn/HCl as reducing
agent.
Step 3: 4-Aminophenol is acetylated using acetic anhydride and form N-(4-
hydroxy-phenyl)-acetamide.
Figure 5
Synthesis of 4-bromophenylamine
The disconnection approach for the synthesis of 4-Bromophenylamine suggest
that the functional group interconversion (FGI) plays important role for its
synthesis. The retrosynthetic analysis is shown in figure 6. The disconnection
requires initial

FGI to a N-(4-bromophenyl)-acetamide.
Figure 6
Synthesis:
The synthesis of 4-bromophenylamine can be done in four steps starting
from a simple reagent nitrobenzene (Figure 7).
Step 1: Nitrobenzene is reduced to aniline using Sn/HCl as the reducing agent.
Step 2: Aniline is acetylated using acetic anhydride to form N-phenylacetamide.
Step 3: N-phenylacetamide is brominated using bromine to N-(4-bromophenyl)-
acetamide.
Step 4: N-(4-bromophenyl)-acetamide is hydrolyzed to 4-bromophenylamine.
Figure 7
 Synthesis of Amines by reduction of amide group
Amides (RCONR '2 ) can be reduced to the amine (RCH 2 NR '2 ) by
conversion of the C=O to -CH 2 - using LiAlH 4 or sodium borohydride (NaBH4)
as the reducing agent.
Synthesis of benzylamine
The retrosynthetic analysis of benzylamine can easily be explained by
FGI (Figure 8). Benzylamine is obtained from benzamide which can be obtained
from benzoyl chloride and ammonia.

Figure 8
Synthesis:
The synthetic steps for benzylamine synthesis are given in figure 9.
Step 1: Benzoic acid on reaction with thionyl chloride (SOCl 2 ) forms benzoyl
chloride.
Step 2: Benzoyl chloride on reaction with ammonia forms benzamide.
Step 3: Benzamide on reduction with lithium aluminum hydride (LiAlH 4 )
followed by hydrolysis forms benzylamine.
Figure 9
Synthesis of Benzylphenylamine
The benzylphenylamine can be synthesized by the reduction of N-
phenylbenzamide as seen from its retrosynthetic analysis given in figure 10.
Figure 10
Synthesis:
The synthesis of benzylphenylamine is shown in two steps and given in figure
11.
Step 1: Benzoyl chloride on reaction with aniline in the presence of a base form
N-phenyl-benzamide.
Step 2: N-Phenylbenzamide on reduction with lithium aluminum hydride
(LiAlH 4 ) followed by hydrolysis gives benzylpheylamine.

Figure 11
Synthesis of N-Benzyl-1-phenylethanamine
The retrosynthetic analysis of N-benzyl-1-phenylethanamine is given in
figure 12. The FGI on target molecule (TM) shows that this molecule can be
synthesized from N-(1-phenylethyl) benzamide. Further disconnection of N-(1-
phenylethyl) benzamide is possible due to the cleavage of CO-NH bond.
Figure 12
Synthesis:
The synthesis of benzyl-(1-phenylethyl)-amine is given in figure 13. The
TM can easily be synthesized from the simple starting materials ammonia and
acetophenone.
Step 1: Acetophenone on reaction with ammonia under acidic condition forms
1-phenylethylamine.
Step 2: 1-Phenylethylamine on reaction with benzoyl chloride in the presence of
a base forms N-(1-phenylethyl)-benzamide.
Step 3: N-(1-phenylethyl)-benzamide on reduction with lithium aluminum
hydride (LiAlH 4 ) followed by hydrolysis forms benzyl-(1-phenylethyl)-
amine.

Figure 13
 Synthesis of Amines by reductive amination

The reductive amination is also known as reductive alkylation. It
involves the reaction of a carbonyl group (>C=O) of aldehydes or ketones with
ammonia (NH 3 ), primary aliphatic amine (RNH 2 ) or primary aromatic amine
(C 6 H 5 NH 2 ) in the presence of acid catalyst (or pH <4) to form an imine
intermediate (=NH). Intermediate imine is reduced to amine using a reducing
agent.
Synthesis of cyclohexylamine
The retrosynthetic analysis if cyclohexylamine is given in figure 14. The
FGI on cyclohexylamine gives corresponding imine.
Figure 14
Synthesis:
Step1: Cyclohexanone on reaction with methylamine form the intermediate
imine.
Step2: Intermediate imine on catalytic reduction with Pd-C/H 2 forms the
product 1-methylcyclohexylamine.

Figure 15
Synthesis of Dicyclohexylamine
The retrosynthetic analysis of dicyclohexylamine is shown in figure 16.
The FGI shows that the TM can easily be obtained from corresponding imine.
The disconnection of C=N of imine gives the starting materials cyclohexamine
and
Cyclohexanone.
Figure 16
Synthesis:
The synthesis of dicyclohexylamine is given in figure 17 and explained in two
steps.
Step 1: Cyclohexanone on reaction with cyclohexylamine form the intermediate
imine.
Step 2: Intermediate imine on catalytic reduction with Pd-C/H 2 forms the
product dicyclohexylamine.
Figure 17

SOLVED PROBLEMS 01
13) Problem 03-01: What is retro synthesis of alkene?

Solution: Retrosynthesis could be described as a logical Disconnection at
strategic bonds in such a way that the process would progressively lead to
easily available starting material(s) through several synthetic plans. Each plan
thus evolved, describes a 'ROUTE' based on a retrosynthesis.
14) Problem 03-02: What are the short notes on amines?
Solution: Amines are organic compounds that contain nitrogen atoms with a
lone pair. Basically, they are derived from ammonia (NH 3 ) in which one or
more hydrogen atoms is replaced by an alkyl or aryl group, and so they are
known as alkylamines and arylamines respectively.

13) SAQ 03-01: What are aliphatic nitro compounds called?
Answer: Aliphatic nitro compounds also called as ni troparaffins are colourless

liquids, used chiefly as industrial solvents eg nitromethane, nitroethane and
nitropropane. They are further classified as primary, secondary or tertiary
depending upon whether the nitro group is bonded to primary, secondary or tertiary
carbon atom.
14) SAQ 03-02: What is retrosynthesis with example?
Answer: Retrosynthesis is a technique chemists use to identify how to synthesize a

molecule through approaching the problem backwards. Effectively retrosynthesis
starts from the wanted product and works backwards chopping and changing the
molecule into smaller pieces to identify what the previous molecule can be made
from.

03-02: IMPORTANCE OF THE ORDER OF EVENTS IN ORGANIC SYNTHESIS
 Order of Events in a Synthesis:
An organic synthesis may involve many steps one after another. The
required product can be got only when the reactions are carried out in a
particular order, which is known as order of events.
The order of events is very important in the cases of synthesizing
aromatic target molecules.
Guide lines for order of events in synthesizing aromatic targets.
1. All the groups have to be disconnected in turn and the reverse reactions are to
be examined for right orientations.
2. If there is a choice, the most electron withdrawing group is disconnected first

as their presence makes further reactions difficult.

3. If a FGI is needed during the synthesis, it may alter the directing effect of the
substituent. Therefore, other substituents have to be added either before or
after FGI accordingly.
4. Many groups can be easily introduced through amines. The amine group is
strongly o/p attempted at this stage.

5. In some difficult cases like adding two introduced and removed later. Usually
it is amino group, later removed through diazotization.
6. The groups that cannot be introduced easily should not be disconnected.

Instead, the starting molecule should have that group as for as possible. e.g. -
OH or -OR groups.
7. For a TM with a difficult combination of groups, readily available starting
molecules with such substituents are sought.
8. The sequences which may lead to unwanted side reactions should be avoided.
e.g. On nitrating benzaldehyde, only 50% m-nitrobenzaldehyde is formed. So,
the benzoic acid is nitrated first and then reduced to m-nitrobenzaldehyde.
9. If o/p directing substituents are involved, one position can be blocked to get
the required product.
SOLVED PROBLEMS 02
15) Problem 03-03: What is the role of FGI?
Solution: FGI is needed during the synthesis; it may alter the directing
effect of the substituent. Therefore, other substituents have to be added
either before or after FGI accordingly.
16) Problem 03-04: What is the role of amine groups?

Solution: Many groups can be easily introduced through amines. The amine
group is strongly o/p attempted at this stage.

15) SAQ 03-03: What is diazotization?
Answer: In some difficult cases like adding two introduced and removed later.
Usually it is amino group, later removed through diazotization.
16) SAQ 03-04: How to avoid unwanted side reactions?
Answer: The sequences which may lead to unwanted side reactions should be
avoided. E.g. On nitrating benzaldehyde, only 50% m-nitrobenzaldehyde is
formed. So, the benzoic acid is nitrated first and then reduced to m-
nitrobenzaldehyde.

03-03: CHEMO SELECTIVITY, REGIOSELECTIVITY
 Chemo selectivity and Regioselectivity
The plants, animals or microorganisms produce a number of chiral and
achiral complicated structures. Some of the groups of compounds include
antibiotics, alkaloids, chlorophyll, steroids, biopolymers, carbohydrates, fats,
vitamins, dyes etc. The chemist determines the structures of these compounds
and try to synthesize them using disconnection approaches. The synthesis of
these compounds becomes important due to their wide applications. Synthesis
from simple starting materials with predictable regioselectivity and
stereochemistry requires the utility of retrosynthetic analysis.
There are three types of selectivity possible for any synthesis:
(i) Chemoselectivity is deciding which group reacts.
(ii) Regioselectivity is where the reaction takes place in that group.
(iii) Stereoselectivity is how the group reacts with respect to the stereochemistry
of the product.
Selectivity can be attained by selecting appropriate starting materials,
reagents, solvents, reaction conditions and most importantly protecting and
deprotecting methods.
A protecting group or protective group is entered into a molecule through
chemical modification of a functional group for obtaining the chemoselectivity
in a chemical reaction. It plays an important role in multistep organic synthesis.
Some of the common protecting groups are listed in table below.
Sr. No. Functional group Protection group
1. Alcohol protecting group Ester; Ether; Ether silyl
2. Amine protecting group Substituted amine; Amide;

Carbamate; Sulphonamide
3. Carboxylic acid protecting group Ester, Ester silyl; Oxazoline
Functions of protection group:

a. Through the protection of sensitive functional groups it becomes possible to
make reagents that would otherwise be unstable.
b. Protection allows us to overcome simple problems of chemoselectivity.
c. The other important function of protecting groups is to stop a reagent from
attacking itself.

A more detail about protection and deprotection is given in module 9.
The following sections will discuss the role of stereochemistry in retrosynthetic
analysis.
Chemo selectivity:
Chemoselectivity plays important role in organic synthesis. This is
helpful in those molecules which possess more than one functional group. The
selective reactivity of one functional group in the presence of others is
controlled by chemoselectivity. The chemoselectivity is supported by protection
and deprotection. Following examples will explain the chemoselectivity in
organic reactions.
Selective Reduction:
The selection of proper reagent plays important role in chemoselectivity.
The selective reduction of either the double bond or the carbonyl group in
cyclopent-2-enone (1) is reagent specific. For the chemo selective reduction of
C=C bond over C=O bond is performed by catalytic hydrogenation (Figure 1).
Hence, the reaction of cyclopent-2-enone (1) with hydrogen in the presence of
palladium (H 2 /Pd) gives cyclopentanone (2).
Figure 1
The reduction of C=O bond over C=C bond is performed by reducing
agent sodium borohydride (Figure 2). The reaction of cyclopent-2-enone (1)
with sodium borohydride (NaBH 4 ) gives cyclopent-2-enol (3). In this case, only
the carbonyl group (>C=O) is selectively reduced to hydroxyl group (-OH).
Whereas in the former case (figure 1), the double bond is selectively reduced to
single bond.
Figure 2

Another example of chemoselectivity is the chemo selective reduction of
α, β-unsaturated esters in presence of alkenes. The reduction of the compound 4
with magnesium (Mg) in the presence of methanol reduced the double bond
present at the α, β- position of the α, β- unsaturated esters giving the product 5
(Figure 3).
Figure 3
 Regioselectivity
Regioselectivity gives preference for bond making at a particular place
when there is possibility of bond formations at other possible positions also. In
other words, there is a preference of one reactive site with respect to another
reactive site. The best example to explain this is Markovnikov and anti-
Markovnikov addition reactions. The reaction of hydrobromic acid (HBr) with
styrene (vinylbenzene, (6) gives 1-bromoethylbenzene (8) through Markovnikov
addition (Figure 4). The same reaction, if performed in the presence of peracids
undergoes Anti-Markovnikov addition to give 2-bromoethylbenzene (7) (Figure
4). This information of regioselectivity is important for the retrosynthetic
analysis.
Figure 4
Birch reduction is another important example of regioselectivity. In this

reduction method, aromatic rings undergo a 1,4-reduction to provide
unconjugated cyclohexadiene. This reaction is performed by sodium or lithium
metal in liquid ammonia and in the presence of an alcohol. Here, the site of
reduction is dependent upon the type of substitution present in the aromatic ring.
Without any substitution in the aromatic ring, the reduction of simple benzene
(9) gives cyclohexadiene (10) (Figure 5).

Figure 5
Figures 6 and 7 shows the regioselectivity in Birch reduction when
electron donating (-OCH 3 ) (Figure 6) and electron withdrawing (-COOH)
(Figure 7) groups are attached. The preference is based on the mechanism of the
reaction where the radical-anion is protonated initially determines the structure
of the product. While performing the retrosynthetic analysis, these preferences
play important role in the synthetic design of any molecule(s).
Figure 6
Figure 7
SOLVED PROBLEMS 03
17) Problem 03-05: What do you mean by chemoselectivity?
Solution: IUPAC defines chemoselectivity as “the preferential reaction of a

chemical reagent with one of two or more different functional groups,” a
definition which describes in rather understated terms the single greatest
obstacle to complex molecule synthesis.
18) Problem 03-06: What is chemoselectivity with example?
Solution: Chemoselectivity can be difficult to predict, but observing selective

outcomes in cases where many reactions are plausible, is common. Examples
include the selective organic reduction of the greater relative chemoselectivity
of sodium borohydride reduction versus lithium aluminium hydride reduction.

17) SAQ 03-05: Why is regioselectivity?
Answer: Regioselectiviy occurs in chemical reactions where one reaction site is
preferred over another. For example, the addition of an asymmetric reagent (such as

H-Cl) to an asymmetric alkene may yield two different products. Th e reaction is
regioselective if one of the two products is preferred over the other.
18) SAQ 03-06
Question: What is the definition of regioselectivity in organic chemistry?
Answer: It refers to the process of selection, where one atom is selected over other
atoms by some specific reagent. It determines which chemical product from that
specific reaction is the major product and which is the minor product in a chemical
process with many products.
03-04: PROTECTING GROUPS , DIELS-ALDER REACTION, MICHAEL

ADDITION AND ROBINSON ANNULATION.
 Protecting groups
Protection and deprotection is an important part of organic synthesis.
During the course of synthesis, we many times desire to perform reaction at only
one of the two functional groups in any single organic molecules. For example,
in an organic compound possessing two functional groups like ester and ketone,
we have to perform reaction at only ester group, them the keto group needs to be
protected. If we want to reduce the ester group, then keto group will also get
reduced. To avoid this type of complications, protection and deprotection of
functional groups are necessary.
 Protecting groups for carbonyl compounds:
The protecting groups allow the masking of a particular functional group
where a specified reaction is not to be performed. The protection is required as
it interferes with another reaction. Let us take the example of reduction of the
keto-ester 1 to the alcohol 2 with a nucleophilic reagent such as NaBH 4 that
attacks only the more electrophilic ketone. In order to make alcohol 3 by the
reduction of ester, it is important to protect the ketone as an acetal 4 that allows
the reduction of the ester with the more nucleophilic LiAIH 4 (Figure 1).
Figure 1

In another example, 3-oxocyclohexanecarboxylic acid methyl ester (6)
undergoes reduction with lithium aluminium hydride (LiAlH 4 ) to
3-hydroxymethylcyclohexanol (7). If we want to go for selective reduction, then
the role of protection and deprotection comes.
During the protection, ketone from the compound

3-Oxocyclohexanecarboxylic acid methyl ester (6) forms ketals on reaction with
methanol (CH 3 OH) under acidic conditions. The protection reaction can be
reversed by treatment with water under acidic conditions as shown below.
The characteristics of protecting group are as follows:

1. It must be easy to put in
2. It must be resistant to reagents that would attack the unprotected function
group.
3. It must be easily removed
 Protecting groups for alcohols:

Methyl ethers and simple amides are easy to synthesize and are quite
resistant to variety of reagents. From below reaction, we can see that reaction
takes place to turn R 1 in 13 into R 2 in 16. But the protection is not very helpful
as extreme conditions are required to remove them. These can be used when the
molecule is stable enough to bear deprotection condition.

The Achilles Heel Strategy:
The Achilles Heel for the functional group ether is the use of
tetrahydropyryl group (THP group). This converts ether into an acetal. The
compound used to give THP derivative is dihydropyran, DHP 24. The
protonation of 24 yield the compound with positive charge on oxygen 25. This is
further reacted with alcohol (ROH) to give the acetal 26 shown in following
reaction. The compound 2-methoxytetrahydropyran (when R = CH 3 ) is known as
the ‘the THP derivative’. For deprotection of alcohol from the protecting group,
hydrolysis only requires the weak aqueous acid.
There is another way to make an ether easier to eliminate is to convert it

into benzylic form as given in figure 6. The alcohol can be protected as benzylic
ether and easily deprotected to give the desired product. For example, the
alcohol 27 on reaction with benzyl chloride in the presence of base like sodium
hydride (NaH) gives the alcohol protected as benzylic ether 28. We can do any
reaction on the protected alcohol group and deprotection will be done by simple
hydrogenation in the presence of catalyst.
Other popular method to protect the alcohol group is to convert them to

trimethylsilyl ether. This can be done by treating the alcohol with
chlorotrimethylsilane and a tertiary amine.
 Protecting groups for amines
Amines are the compounds that exist as R-NH 2 . They are further
classified as primary, secondary and tertiary amines based on the number of
substitutions at the nitrogen atom. In all the cases, nitrogen possesses an
unshared pair of electrons that causes the problem in a synthesis. This requires
protection. The amines are mainly protected as amides and carbamates.

The conversion of amine to amide decreases the activity of the amino
group. Amine (17) can easily be converted to corresponding amide (18) form by
using acetyl chloride as shown below. The formed amide or we can say
protected amine undergoes desired reaction to get converted to 19. The
deprotection of 19 can easily be done with sodium hydroxide to get the free
amine group 20.
Another example is the bromination of aniline. On brominating aniline

(21) the 2,4,6-tribromo derivative (22) is formed. As we can see the yield is
quantitative, but we want mono brominated product and for that excessive
bromination need to be stopped. To overcome the excess bromination, the
protection of NH 2 - group is essential. The acetylation of aniline converts aniline
to acetanilide (23). The amide 23 on bromination gives only in the para position
(the N-acetyl group is larger than
-NH 2 ) and the hydrolysis does not destroy the benzene ring.
Another protecting group include carbamate. This is also an amide bond

but with some other functionality attached that allows them to be removed under
mild reaction condition in comparison to simple amide group. For example, the

reaction of primary amine with tertiary-butyl chloroformate forms a carbamate
under basic condition.
The protected amine can undergo any reaction and further deprotected to give
the desired product.
 Diels-Alder Reactions
 Retro Diels-Alder Reactions

Regioselectivity of Diels-Alder Reactions
Example-1
Example- 2
Retro-Analysis
Synthesis

Example-3
Retro-Analysis
Synthesis
Example- 4
Retro-Analysis
Synthesis

Example- 5
Retro-Analysis
Synthesis
 Carbonyl compounds using Michael reaction:

The Michael addition is a thermodynamically controlled 1,4-addition of
resonance-stabilized carbanions. The reaction donors are active methylene
compounds possessing acidic proton such as malonates and nitroalkanes etc. The
acceptors for these reactions are the activated olefins such as α, β-unsaturated
carbonyl compounds.
Synthesis of 1,5-Dicarbonyl compounds (heptane-2,6-dione):
The disconnection approach for hept-2,6-dione (18) is given in figure 1.
The heterolytic cleavage of C 3 -C 4 bond gives the carbanion 19 and carbocation
20. These compounds can be obtained from the reagents 21 and 22.
Figure 1
Synthesis:

The synthesis of hept-2,6-dione (18) can be achieved in 3 steps as per the
disconnection approach explained in figure 2.
Step 1: The reaction of acetone (21) with a base sodium hydroxide forms the
resonance stabilized carbanion.
Step 2: The carbanion reacts with but-3-en-2-one (22) to give the corresponding
condensed product (23).
Step 3: 23 on acidic hydrolysis forms the enol (24), which undergoes keto-enol
tautomerism to form the product heptanes-2,6-dione (18).
Figure 2
Synthesis of 4-Oxo-2,6-diphenyl-cyclohexane-1,1-dicarboxylic acid diethyl
ester:
The retrosynthetic analysis of 4-oxo-2,6-diphenyl-cyclohexane-1,1-
dicarboxylic acid diethyl ester (25) is given in figure 3. According to the
disconnection approach, the compound 25 can be synthesized from 1,5-
diphenyl-penta-1,4-dien-3-one (26) and diethyl malonate (27).
Figure 3
Synthesis:
The synthesis of 4-oxo-2,6-diphenyl-cyclohexane-1,1-dicarboxylic acid
diethyl ester (25) can be achieved in 4 steps as per the disconnection approach
explained in figure 4.
Step 1: The reaction of diethyl malonate (27) with a base sodium ethoxide
forms the resonance stabilized carbanion (28).

Step 2: The carbanion (28) reacts with 1,5-diphenylpenta-1,4-dien-3-one (26) to
give the corresponding condensed product (29).
Step 3: 29 on acidic hydrolysis forms the enol (30), which undergoes keto-enol
tautomerism to form the product 31, keto form.
Step 4: 31 undergoes cyclization to give the enol form 32 that on
tautomerization gives the desired product 25.
Figure 4
 Michael Addition and Robinson Annulation Reaction
Retro-Analysis:
This sequence of Micheal reaction and cyclisation is known as tile

Robinson Annulation since it makes a ring.

Synthesis
Example-1
Retro-Analysis
Synthesis
Example- 2: Symmetrical α, β-unsaturated carbonyl linkages:
Retro-Analysis:

Synthesis:
SOLVED PROBLEMS 04
19) Problem 03-07: How would you make these compounds?
Solution: The first is simply a case of reductive amination. We cannot form an

amide so it has to proceed by the imine.
Here, disconnection of an alcohol by C-C cleavage; addition of Grignard to

a carbonyl and hence the disconnections are:
The best route to the acid is via alkylation of diethyl malonate. The latter is
easily enolized, will only undergo two additions, is fairly robust yet will readily
undergo decarboxylation.
The final compound is a primary amine. This could either be prepared by

reductive amination of the appropriate ketone (oxidation of the secondary alcohol)
or by substitution of an appropriately derivatized secondary alcohol (tosylation of
the secondary amine) with azide followed by reduction.

20) Problem 03-08: Perform the retrosynthetic analysis of the following
compound. Remember, your planned synthesis must be synthetically possible and
shouldn’t suffer from regio- or chemoselectivity issues.
Solution:

from

Answer:
20) SAQ 03-08: A synthesis of this enantiomerically pure ant pheromone was
required for the purposes of pest control. Given a supply of the enantiomerically
pure alkyl bromide as a starting material, suggest a synthesis of the pheromone.
Answer: We know what the disconnection must be, since we have been given one
starting material. This looks like an enolate alkylation, and we need to use a
specific enolate to stop the ketone self-condensing. The best enolate equivalent will
be one that is not too basic, to avoid competing elimination. The simplest solution
is probably to use a keto-ester, easily made by Claisen condensation with diethyl
carbonate. After alkylation, the ester group is removed by decarboxylation.
CHECK POINT 01-03

(Fill in the Blanks)
1) Grignard reagents on reaction with cadmium chloride (CdCl 2 ) form

…………….compounds
2) Benzamide on reduction with lithium aluminum hydride (LiAlH4) followed
by hydrolysis forms…………..
3) ………….is deciding which group reacts.
4) ………………is where the reaction takes place in that group.

SUMMARY
 Retrosynthetic analysis: The process of imaginary breaks down of a
molecule into progressively simpler starting materials. The reactions are
viewed in the retrosynthetic direction i.e., starting with the product and
going back to the reactants along a pathway that is reverse of a synthetic
direction.
 As a fundamental problem in chemistry, retrosynthesis aims at designing

reaction pathways and intermediates for a target compound. The goal of
artificial intelligence (AI)-aided retrosynthesis is to automate this
process by learning from the previous chemical reactions to make new
predictions.
 The Retrosynthesis Arrow. The open arrow here doesn't actually show a
“reaction”, per se, but instead more of a mental exercise. The
retrosynthetic arrow is meant to depict the process of breaking down a
complex molecule to simpler starting materials.
KEY WORDS
Retro-synthesis; alkene, acetylenes and aliphatic nitro alcohols and carbonyl
compounds, amines; Order of events in organic synthesis, Chemoselectivity,
Regioselectivity; Protecting groups, Diels -Alder reaction, Michael addition and
Robinson anulation.
REFERENCES
----

1) Organocadmium
2) Benzylamine
3) Chemoselectivity
4) Regioselectivity
MOOCS
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YOUTUBE VIDEOS
https://www.youtube.com/watch?v=lD02HC4h6yw
https://www.youtube.com/watch?v=zlclJzdrtBI
https://www.youtube.com/watch?v=nHa-MOwxJ7Y

https://www.youtube.com/watch?v=J5q5BxXc_Xk
https://www.youtube.com/watch?v=hY1PRK_ztb0
https://www.youtube.com/watch?v=e9i-aAFj_b4
https://www.youtube.com/watch?v=wCIBIP-yhcM
https://www.youtube.com/watch?v=qS0jZmydXlI
https://www.youtube.com/watch?v=q_wDRc3AtR4
https://www.youtube.com/watch?v=QUhdJC-boY0
https://www.youtube.com/watch?v=cKTwIwVGbzY
WIKIPEDIA
OER
----
REFERENCE BOOKS
1. March J., and Smith M., Advanced Organic Chemistry, 5th Edition, John -
Wiley and Son, 2001.
2. Gould E. S., Mechanism and Structure in Organic Chemistry Holt, Rinehart

and Winston Inc., 1959.
3. Carey A. Francis, and Sundberg J Richard., Part A and Part B Advanced

Organic chemistry, 5th edition, Springer, 2007.
4. Jonathan Clayden, Nick Greeves and Stuart Warren., Organic Chemistry,

2nd Edition, Oxford Publishers, 2012.
5. Finar I. L., Organic Chemistry, 6th Edition, Pearson Education Asia, 2004.
6. House H.O., Modern Synthetic Reactions, W.A. Benjamin Inc, 1972.

CREDIT01-UNIT04: RETRO-SYNTHESIS OF AROMATIC HETROCYLES
LEARNING OBJECTIVES
 Describe methods for synthesis and transformation of the most common

functional groups
 Identify, analyses and evaluate synthetic routes to target molecul es using retro
synthesis
 Apply organometallic reagents and reactions in organic synthesis
04-01: 3 MEMBERED RINGS:

Carbocyclic compounds are the compounds possessing a ring composed
mainly of carbon atoms. A cyclic compound, which is also known as ring
compound, possesses atoms that are connected to form a ring. When these
compounds are completely saturated, they are known as alicyclic compounds.
These compounds resemble both aliphatic and cyclic compounds in their
properties. The saturated alicyclic compounds have the general formula C n H2n
(same as that of the alkene and are isomers of alkene); they do not have double
bond but possess a ring structure. The ring forming reactions are an important
part of the retrosynthetic analysis because a number of carbocyclic compounds
find their applications in food, pharmaceuticals, cosmetics and material
sciences. Some rings are formed very easily than others. During the formation of
rings, the study of transition state stability is significant and hence Baldwin
formulated ring closure rules.
There are three important strategies usually considered when a
carbocyclic synthetic target is synthesized.
a) Any reactants already containing a carbocycle of the required size may be
used.
b) A one-bond disconnection can be used in the same way as used for the
formation of chains or branched structures.
c) A two-bond disconnection can be used corresponding to a cycloaddition
reaction.
 Synthesis of three membered rings: Synthesis of cyclopropane

Retrosynthetic analysis

The disconnection or retrosynthetic analysis of cyclopropane is given in
figure 1. Here, a one-bond disconnection approach has been utilized to a
cyclopropane ring. The use of a functional group oriented approach is required.
The only difference between this disconnection and elongation of a carbon chain
using same approach is that, here, the nucleophilic carbon and the electrophilic
carbon are on the same molecule and separated by just one carbon.
Figure 1
Synthesis
1,3-Dibromopropane is cyclized using either sodium metal (also known
as Wurtz coupling) or zinc metal to give cyclopropane as given in figure 2.
Synthesis of cyclopropanecarboxylic acid

The retrosynthetic analysis of cyclopropane carboxylic acid (4) is given
in figure 3. Here, a one-bond disconnection approach has been utilized to a
cyclopropane ring. The cleavage is heterolytic in nature leading to the
nucleophilic carbon and the electrophilic carbon (5). The compound 5 can be
obtained from compound 6 which cab further be obtained from compounds 9 and
10.

Synthesis:
The synthesis of cyclopropane carboxylic acid (4) is given in figure 4.
Step 1: The reaction of diethylmalonate (10) with strong base gives carbanion.
Step 2: The carbanion reacts with 1,2-dibromoethane to give monobrominated
compound 11.
Step 3: Further reaction of compound 11 with strong base like sodium ethoxide
give another carbanion 12.
Step 4: Carbanion 12 undergoes cyclization to give the cyclopropane derivative
13.
Step 5: The hydrolysis and decarboxylation of the cyclopropane derivative 13
gives the target molecule, cyclopropane carboxylic acid (4).

Another synthetic method of cyclopropane carboxylic acid (4) is through
ring contraction of pyrazole derivative 16.
Step 1: Activated alkene like but-2-enedioic acid diethyl ester (14) reacts with
diazomethane (15) at 1 and 3-position forming the corresponding
pyrazole derivative, 4,5-dihydro-3H-pyrazole-3,4-dicarboxylic acid
diethyl ester (16). This is an example of 1,3-Dipolar cycloaddition
(Figure 5).
Step 2: Pyrazole derivative, 4,5-dihydro-3H-pyrazole-3,4-dicarboxylic acid
diethyl ester (16) on either photochemical or thermal decomposition loses
one molecule of nitrogen (N2) and form cyclopropane derivative (13)
(Figure 6). This step is also known as nitrogen removal step.
Step 3: The hydrolysis and decarboxylation of the cyclopropane derivative 13
gives the target molecule, cyclopropane carboxylic acid (4) (Figure 4).

If the above reaction is done using potassium hydroxide (KOH) and
platinum as catalyst via thermal route, it is known Kishnner cyclopropane
synthesis.
SOLVED PROBLEMS 01
21) Problem 04-01: What is a 3-membered ring with sulfur?
Solution: Thiiranes and thiirenes are highly reactive substances with three-
membered ring structures containing a sulfur atom, and show characteristic
properties different from alkyl and aryl sulfides lacking three -membered rings.
22) Problem 04-02: Can a three membered ring be aromatic?
Solution: Despite the tetravalent arrangement of atoms around silicon, the

three‐membered silicon‐boron‐silicon ring is aromatic, as evidenced by NMR
spectroscopy, nucleus independent chemical shift calculations, first ‐principles
electronic structure studies using density functional theory (D FT) and natural
bond orbital (NBO).

21) SAQ 04-01: What is a 3 membered ring system?
Answer: Three-membered rings. The three-membered ring heterocycles containing

single atoms of nitrogen, oxygen, and sulfur—aziridine, oxirane (or ethylene
oxide), and thiirane, respectively—and their derivatives can all be prepared by
nucleophilic reactions, of the type shown.
22) SAQ 04-02: Why is 3-membered ring unstable?
Answer: The bond angles in a three-membered ring are significantly distorted from
the ideal 120 degrees, causing increased strain and instability. This makes the
bonds more prone to breaking and undergoing reactions.

04-02: SYNTHESIS OF FOUR MEMBERED RINGS:
The four membered rings difficult to make due to strained ring angles.
Sometimes, the most favourable conformations of the starting materials do not
cyclize to give the target molecules.
Synthesis of Cyclobutane carboxylic acid

The retrosynthetic analysis of cyclobutane carboxylic acid (18) is given
in figure 7. The disconnection of one C-C bond of cyclobutane adjacent to the
carbon attached to –COOH group gives synthon 19 which further get cleaved
through another C-C bond to give two synthons 20 and 21. The compounds, 1,3-
dibromopropane (22) and diethylmalonate (10) are their synthetic equivalents
respectively (Figure 7).
Synthesis:
The synthesis of cyclobutane carboxylic acid (18) is given in figure 8.
The synthesis is explained in the following steps.
Step 1: The active methylene compound, diethylmalonate (10) reacts with
strong base sodium ethoxide to generate carbanion.
Step 2: The carbanion reacts with 1,3-dibromopropane (22) to give
monobrominated compound 23, which still can act as active methylene
compound.
Step 3: The base sodium ethoxide abstract proton from compound 23 to generate
carbanion 24 which undergoes intramolecular cyclization to afford the
cyclobutane derivative 25.
Step 4: The hydrolysis and decarboxylation of 25 gives the target molecule 18.

Synthesis of benzocyclobutanes
The synthetic exploration of benzocyclobutanes is important because of
the diverse applications of these molecules. Various methods of their synthesis
are available having their own limitations and strength. One important method is
discussed here.
7-Bromobicyclo [4.2.0] octa-1,3,5-triene (26)
The retrosynthetic pathways for 7-Bromobicyclo [4.2.0] octa-1,3,5-triene
(26) is given in figure 9. The disconnection of one C-C bond of cyclobutane as
shown in figure 9 gives the synthetic equivalent compound 27.
Synthesis
The synthesis of 7-Bromobicyclo [4.2.0] octa-1,3,5-triene (26) based on
the retrosynthetic pathways is given in figure 10 and explained in two steps.
Step 1: The fluoride mediated reaction of 28 leading to 1,4-elimination to yield
compound 27.
Step 2: The cyclization of 27 gives the target molecule 7-Bromobicyclo [4.2.0]
octa-1,3,5-triene (26).

The cyclobutanes are also synthesized by the inter- and intramolecular
[2+2] photocyclo addition. For example, the intramolecular photocycloaddition
of 29 gives 30.
h
4,5-Dimethylenecyclohexane Bicyclo[4,2,0]oct-3-ene
29 30
Figure 11
The carbocyclic compounds have played and going to play very
important role in chemistry. The interest towards macrocycles has increased due
to their wide applications. The development is mainly due to their fascinating
structural symmetries and new stereochemical aspects. They are also helpful as
building blocks in supramolecular chemistry. The saturated alicyclic compounds
have the general formula CnH2n (same as that of the alkene and are isomers of
alkene); they do not have double bond but possess a ring structure.
Monocyclic compounds have been classified on the basis of number of
carbon atoms in the ring in the following way:
Small rings: 3-4 carbon atoms
Common/normal rings: 5-7 carbon atoms
Medium rings: 8-11 carbon atoms
Large rings: >12 carbon atoms
The carbocyclic rings are present in many natural product compounds.
For example, paclitaxel is a plant derived terpenoid. This is a multi-ring
structured compound and possesses four-, six- and eight-membered rings.

 Synthesis of normal ring compounds:
Synthesis of cyclopentane
The retrosynthetic analysis of cyclopentane (1) is given in figure 1.
The functional group interconversion shows that the cyclopentane can be
obtained from cyclopentanone (2) which further can be obtained from
2-oxocyclopentanecarboxylic acid ethyl ester (3). The C-C disconnection of
2-oxocyclopentanecarboxylic acid (4) shows that this can be obtained from
diethyl hexanedioate (5).
Synthesis:
Cyclopentane is synthesized from diethyl hexanedioate using Dieckmann
condensation on the basis of retrosynthetic analysis (Figure 2).
Step 1: Diethylhexanedioate (5) on reaction with a base form the corresponding
anion (6), which undergoes cyclization, followed by ethoxide ion (-OEt)
removal to form 2-oxoethylcyclopentanoate (3).
Step 2: 2-Oxoethylcyclopentanoate (3) upon hydrolysis forms 2-oxocyclopentanoic
acid (4).
Step 3: 2-Oxocyclopentanoic acid (4) on heating undergoes decarboxylation and
form cyclopentanone (2).
Step 4: Cyclopentanone (2) undergoes Clemmenson’s reduction using Zn-Hg/HCl
and forms cyclopentane (1).

Synthesis of cyclohexane
The retrosynthetic analysis of cyclohexane (7) is given in figure 3. The
functional group interconversion shows that the cyclohexane can be obtained from
cyclohexanone (8) which further can be obtained from 2-oxocyclohexanecarboxylic
acid ethyl ester (9). The C-C disconnection of 2-oxocyclohexanecarboxylic acid (9)
shows that this can be obtained from diethylheptanedioate (11).
Synthesis:
Cyclohexane is synthesized from diethylheptanedioate (11) using Dieckmann
condensation as shown in figure 4.
Step 1: Diethylheptanedioate (11) on reaction with a base form the corresponding
anion (12), which undergoes cyclization, followed by ethoxide ion (-OEt)
removal to form 2-oxoethylcyclohexanoate (9).
Step 2: 2-Oxoethylcyclohexanoate (9) upon hydrolysis forms 2-
oxocyclohexanecarboxy-lic acid (10).
Step 3: 2-oxocyclohexanecarboxylic acid (10) on heating undergoes
decarboxylation and form cyclohexanone (8).
Step 4: Cyclohexanone (8) undergoes Clemmenson’s reduction using Zn-Hg/HCl
and forms cyclohexane (7).

Synthesis of cyclohex-4-ene-1,2-dicarboxylic acid
The retrosynthetic analysis of cyclohex-4-ene-1,2-dicarboxylic acid (13) is
given in figure 5. The disconnection approach explains that the cycloaddition of
‘diene’ and ‘en’ can built a cyclohexane ring.
Synthesis:
Cyclohex-4-ene-1,2-dicarboxylic acid is synthesized from 1,3-butadiene and
eth-1,2-dienoic acid using Diels-Alder reaction (Figure 6). When buta-1,3-diene
and eth-1,2-dienoic acid are heated, they form the cyclohex-4-ene-1,2-dicarboxylic
acid.
 Synthesis of medium and large ring compounds

Figures 7 and 8 show the general retrosynthetic and synthetic pathways for
the design and synthesis of medium and large ring compounds.
The retrosynthetic analysis of carbocyclic ring compounds possessing
medium to large rings is given in figure 7. These compounds can be synthesized
from aliphatic dicyanides. The functional group interconversion (FGI) on
carbocyclic compound 16 shows that it can be prepared from compound of the type

17. The compound 17 can be obtained from 18 which on C-C disconnection give
synthon 19. The synthetic equivalent of synthon 19 is the dicyanide compound 20.
Synthesis:
The synthetic pathways of carbocyclic ring compounds possessing medium
to large rings is given in figure 8. These compounds can be synthesized from
aliphatic dicyanides through intramolecular condensation of aliphatic dicyanides.
Step 1: Aliphatic dicyanide (20) in the presence of base gives a carbanion 21 which
is stabilized with metal ion (lithium metal, in present case).
Step 2: The carbanion 21 undergoes cyclization to give the carbocyclic ring 22.
Step 3: The carbocyclic ring 22 undergoes acidic hydrolysis where C=NH get
converted to C=O and –CN get converted to –COOH (compound 17).
Step 4: The decarboxylation of compound 17 gives cyclic ketone 23, which can be
further reduced to cyclic alkanes via Clemmensen reduction using Zn-Hg/
HCl.
Figure 8
Synthesis of 2-methylcyclohept-3-enol (24)

The retrosynthetic pathway of 2-methylcyclohept-3-enol is given in
figure 9.
Synthesis
The synthesis of 2-methylcyclohept-3-enol (24) is given in figure 10. In
this case, allylsilane-based strategies have been utilized to build up
cycloheptane derivatives. The intramolecular cyclization of functionalized
allylsilanes has been utilized for the synthesis of seven membered
hydroxycycloalkenes and oxacycloalkenes. The functionalized allylsilanes (26)
has been achieved from allylic alcohols (27).
The other possible methods for the synthesis of carbocyclic compounds

include expanding or contracting an existing ring. Using these methods, it is
possible to access structures that would be difficult with a single cyclization
reaction due to slow rate of formation. The expansion of rings is usually done
either by a migration or insertion or opening of a bicycle to a single larger ring.
SOLVED P ROBLEMS 02
23) Problem 04-03: What are 4 membered nitrogen containing rings?
Solution: 4-Membered nitrogen-containing heterocycles, such as β-lactams

(i.e., 2-azetidinones) and azetidines, are useful substrates in organic chemistry for
the design and preparation of biologically active compounds by functionalization of
the different positions of the ring.
24) Problem 04-04: What are the four-membered rings containing oxygen?

Solution: Four-membered rings with one oxygen atom include the oxetanes
(trimethylene oxides), alkoxyoxetanes and oxetanols, oxetanones, and four -
membered rings with one sulfur atom, such as thietanes (trimethylene sulfides),
thietes or thietenes and their oxides, and thietanones.

23) SAQ 04-03: Explain the retro synthetic analysis of cyclopentane.
Answer: Retrosynthetic analysis of cyclopentane:
The retrosynthetic analysis of cyclopentane (1) is given in figure 1.

The functional group interconversion shows that the cyclopentane can be
obtained from cyclopentanone (2) which further can be obtained from
2-oxocyclopentanecarboxylic acid ethyl ester (3). The C-C disconnection of
2-oxocyclopentanecarboxylic acid (4) shows that this can be obtained from
diethyl hexanedioate (5).
24) SAQ 04-04: What is the retrosynthetic analysis of cyclohex-4-ene-1,2-

dicarboxylic acid?
Answer: Retrosynthetic analysis of cyclohex-4-ene-1,2-dicarboxylic acid:
The retrosynthetic analysis of cyclohex-4-ene-1,2-dicarboxylic acid (13) is

given in figure 5. The disconnection approach explains that the cycloaddition of
‘diene’ and ‘en’ can built a cyclohexane ring.

04-03: HETEROCYCLIC RINGS:
Heterocycles are the cyclic compounds that contains apart from carbon
atoms, one or more heteroatom like oxygen, nitrogen and sulphur. Presence of
heteroatom makes the ring easy to make by a ring-closing reaction or easy to
break by a ring-opening reaction. The ring fixes the orientation of the
heteroatom and in a particular fix the orientation of its lone pairs relative to the
atoms around it. Heterocycles can be saturated as well as unsaturated. Examples
of saturated heterocycles are tetrahydrofuran (THF), aziridines, pyrrolidine etc.
Tetrahydrofuran are well known solvents for organic reactions. Saturated
heterocycles occur as components of natural products. For example, aziridine
are found in the mitomycin, anti-tumour agents from Streptomyces lavendulae
and Thiirane-2-carboxylic acid is plant product isolated from Asparagus.
 Synthesis of pyrrolidine and pyrrolizidine :

Synthesis of Pyrrolidine
The design and synthesis of pyrrolidine (1) is explained using
retrosynthetic analysis.
The retrosynthetic analysis of pyrrolidine (1) is given in figure 1.
According to the disconnection approach, the compound (1) can be synthesized
from 1,4-dibromobutane (2) and ammonia (3).
Figure 1
Synthesis:
The synthesis of pyrrolidine (1) can be achieved in 2 steps as per the
disconnection approach explained in figure 1.
Step 1: The C δ+ -Br δ- bond of 1,4-dibromobutane is polar so lone pairs of
ammonia can attack the carbon which is slightly positive. This leads to the

formation of bromide ion which removes a proton to give 4-bromobutan-1-
amine (4) and HBr.
Step 2: Compound (4) undergoes cyclisation via an intramolecular nucleophilic
displacement to give (1).
Figure 2
Synthesis of 2,2-dimethyltetrahydrofuran
The design of synthetic steps of 2,2-dimethyltetrahydrofuran (5) can be
explained by disconnection approach.
The retrosynthetic analysis of 2,2-dimethyltetrahydrofuran (5) shows that
it can be synthesized by 5-Chloro-2-methyl pentan-2-ol (6). This is achieved by
the one-bond C-O disconnection.
Figure 3
Synthesis:
The synthesis of 2,2-dimethyltetrahydrofuran (5) can be achieved by
intramolecular Williamson ether synthesis. The synthesis is achieved in two
steps as shown in figure 4.
Step 1: Sodium hydride is a strong base so it abstracts acidic proton of hydroxyl
group forming alkoxide ion (7).
Step 2: Oxygen containing negative charge attacks carbon of C δ+ - Cl δ- bond
which has partial positive charge leading to cyclisation of compound (7)
and elimination of metal halide.
Synthesis of pyrrolizidine

Pyrrolizidine (9) is a heterocyclic organic compound and is the central
chemical structures of variety of alkaloids found in plants and are used in
various traditional medicinal systems like Ayurveda. To understand the synthesis
of this important compound retrosynthetic analysis is helpful.
Applying disconnection approach to the compound (9) we can see that the
carbon adjacent to the nitrogen undergoes functional group interconversion
(FGI) to develop aldehyde group on both ends (Figure 5).
Synthesis:
The synthesis of pyrrolizidine (9) involves the concept of reductive
amination (Figure 6). Condensation of secondary amines (10) with an aldehyde
or a ketone gives an iminium salt which on reduction with NaBH 3 CN gives a
tertiary amine (9). The synthesis is carried out in four steps.
Step 1: The lone pair of NH 2 group attacks the carbonyl carbon to form iminium
salt (12).
Step 2: The iminium salt (12) formed is reduced with NaBH 3 CN to give
secondary amine (10). NaBH 3 CN reduces iminium ions selectively in
presence of carbonyl group.
Step 3: The lone pair of secondary amines (10) attacks the carbonyl carbon to
form iminium salt (13).
Step 4: The iminium salt (13) formed is reduced with NaBH 3 CN to give a
tertiary amine (9).

 Synthesis of aziridines and oxiranes
Synthesis of aziridines
Aziridines are reactive substrates in ring opening reactions with many
nucleophiles due to the strain in their ring.
Disconnection approach shows that aziridine (14) is formed by 1,2-
aminoalchols (15).
Synthesis:
Step 1: The hydroxy group of β-amino alcohol (15) is converted to good leaving
group (16)
Step 2: The compound 16 loses a proton in the presence of base sodium
hydroxide to give the intermediate 17.
Step 3: The lone pairs of -NH 2 (17) attacks the α-carbon eliminating the leaving
group and formation of 2-phenylaziridine (14) takes place.
SOLVED P ROBLEMS 03
25) Problem 04-05: Write a note on Retrosynthetic analysis of Pyrrolidine.

Solution: Retrosynthetic analysis of Pyrrolidine:
The retrosynthetic analysis of pyrrolidine (1) is given in figure 1.

According to the disconnection approach, the compound (1) can be synthesized
from 1,4-dibromobutane (2) and ammonia (3).
26) Problem 04-06: Explain the Retrosynthetic analysis of aziridines.
Solution: Retrosynthetic analysis of aziridines:
Disconnection approach shows that aziridine (14) is formed by 1,2-

aminoalchols (15).
SHORT A NSWER QUESTIONS WITH MODEL ANSWER 03

25) SAQ 04-05: What is retrosynthetic analysis of pyrrolizidine?
Answer: Retrosynthetic analysis of pyrrolizidine:
Applying disconnection approach to the compound (9) we can see that the
carbon adjacent to the nitrogen undergoes functional group interconversion
(FGI) to develop aldehyde group on both ends (Figure 5).

26) SAQ 04-06: Explain Retrosynthetic analysis of 2,2-dimethyltetrahydrofuran.
Answer: Retrosynthetic analysis of 2,2-dimethyltetrahydrofuran:

The retrosynthetic analysis of 2,2-dimethyltetrahydrofuran (5) shows that
it can be synthesized by 5-Chloro-2-methyl pentan-2-ol (6). This is achieved by
the one-bond C-O disconnection.
Figure 3
04-04: REVERSAL OF POLARITY (UMPOLUNG)
 Reversal of polarity (Umpolung): In German ‘Umpolung’ means reversal of
polarity.
In the above table, synthons 1 and 4 are common and can be realized
from the normal reactions. But the synthons 2 and 3 are not formed in normal
reaction i.e., they are assuming opposite charges at the carbon atoms when
compared to other synthons. This reversal of polarity on the carbon atoms of the
synthons is called Umpolung.
This reversal of polarities can be introduced by different methodologies.
1. Enolization: By enolizing a ketonic moiety with an electrophile at 2nd

carbon we can make a terminal carbon at 2 nd position as
negative.

2. Epoxidation: Epoxidation of an alkene gives an epoxide which can give the
synthon 2.
3. Using dithiane: Using dithianes in presence of strong bases, the carbonyl

carbons are made negative (which usually become positive).
Example-1

Example-2
Example-3
Salbutamol

 ONE GROUP C-C DISCONNECTIONS:
SOLVED P ROBLEMS 04
27) Problem 04-07: What is the umpolung reagent?
Solution: The actual umpolung reaction involves conjugate addition of a
nucleophile to a ketene dithioacetal, followed by hydrolysis. Ketene dithioacetals
function as the umpolung equivalent for R(CO)CH 2 CH 2 −, but the reactive center is
more distant from the carbonyl, making it more difficult to generate the umpolung
reagent.
28) Problem 04-08: What is an example of umpolung?

Solution: UMPOLUNG IN CARBONYL COMPOUNDS
Dithiane chemistry is a classic example of polarity inversion. Ordinarily the
oxygen atom in the carbonyl group is more electronegative than the carbon
atom and therefore the carbonyl group reacts as an electrophile at carbon.

27) SAQ 04-07
What is enolization in Umpolung?

Answer: Enolization: By enolizing a ketonic moiety with an electrophile at 2nd
carbon we can make a terminal carbon at 2 nd position as negative.
28) SAQ 04-08: What is epoxidation in Umpolung?

Answer: Epoxidation: Epoxidation of an alkene gives an epoxide which can
give the synthon 2.
C HECK POINT 01-04

(True or False)
1) Aziridines are reactive substrates in ring opening reactions with many

nucleophiles due to the strain in their ring.
2) 2-Oxoethylcyclohexanoate upon hydrolysis not forms 2-
oxocyclohexanecarboxylic acid.
3) 1,3-Dibromopropane is cyclized using either sodium metal (also known as
Wurtz coupling) or zinc metal to give cyclopropane.
4) The saturated alicyclic compounds have the general formula CnH2n (same as
that of the alkene and are isomers of alkene); they do have double bond but
possess a ring structure.
SUMMARY
 Organic molecules are diverse in nature and have applications in all
fields of life.

 The synthesis of organic molecules is a challenging field.
 The synthesis requires the help of disconnection approach or
retrosynthesis.
 The backward way of observing a reaction is known as retrosynthetic
analysis.
 Retrosynthetic (or antithetic) analysis is a problem resolving method for
converting the structure of a synthetic target (TGT) molecule to a
sequence of gradually simpler structures through a path which eventually
leads to simple or commercially available starting materials for a
chemical synthesis.
 Through the disconnection method, we break the entire molecule into
smaller starting materials on paper and then join these by chemical
reactions.
 The toughest job in planning a retrosynthetic analysis is recognizing
where to make the disconnections.
 The organic synthesis is an inseparable part of organic chemistry and is
involved in the construction of organic compounds using different types
of appropriate organic reactions.
 Synthons are the chemical fragments obtained from the disconnection of
bond(s) of the target molecule. The disconnection of bond(s) is possible
in three ways:
(i) Homolytic cleavage
(ii) Heterolytic cleavage
(iii) Concerted transform
 Synthetic equivalents are the chemical species which is used to generate
synthons. They are the actual substrates used for the forward reaction and
hence forward synthesis.
 The construction of a synthetic pathway by working backward from the
target molecule is called retrosynthetic analysis.
 The design of a synthetic pathway for any molecule needs to take into
account some of the important aspects.
 The separation of a bond that joins the heteroatom (X) to the rest of the
molecule like C-O, C-N or C-S constitutes ‘One-group’ C-X
 If target molecules possess two functional groups, then a two-group
disconnection approach between the functional group may be applied.

 Any compound bearing an alcoholic group can also be disconnected at
the C-C bond next to the adjacent bond to the oxygen atom. This is
known by 1,2 C-C disconnections.
 The retrosynthetic and synthetic pathways of symmetrical and
unsymmetrical ketones have been explained.
 The carbonyl carbon is sp2 hybridized, with its three attached atoms
lying in the same plane.
 Retrosynthetic analysis provides important inputs for synthesis from
simple starting materials with predictable regioselectivity and
chemoselectivity.
 Protection and deprotection is an important part of organic synthesis.
 The retrosynthetic analysis of amines and related compounds takes place
through various functional group interconversions.
KEY WORDS
3, 4, 5 and 6 membered carbocyclic and heterocyclic rings. Reversal of polarity
(Umpolung).
REFERENCES:
A NSWER TO CHECK POINT 01-04
1) True
2) False
3) True
4) False
MOOC S
https://mooc.es/course/a-study-guide-in-organic-retrosynthesis-problem-solving-
approach/
https://onlinecourses.nptel.ac.in/noc22_cy30/preview
Y OU T UBE V IDEOS
https://www.youtube.com/watch?v=_pDrQ15C5dI&pp=ygUgcmV0cm9zeW50aGVz
aXMgb3JnYW5pYyBjaGVtaXN0cnk%3D
https://www.youtube.com/watch?v=lD02HC4h6yw
https://www.youtube.com/watch?v=aBTwv_4M6sQ
W IKIPEDIA

R EFERENCE B OOKS
1. R. Robinson, J. Chem. Soc., 1917, 111, 762.
2. C. Sch¨opf and G. Lehmann, Liebig’s Annalen, 1935, 518, 1.
3. E. J. Corey, Quart. Rev., 1971, 25, 455; E. J. Corey and X. -M. Cheng, The Logic
of Chemical Synthesis, Wiley, New York, 1989.
4. Stuart Warren and Paul Wyatt, Organic Synthesis: The Disconnection Approach,
2nd Edition John Wiley & Sons Ltd, ISBN: 978-1-119-96553-4 August 2011.
5. March J., and Smith M., Advanced Organic Chemistry, 5th Edition, John-Wiley
and Son, 2001.
6. Gould E. S., Mechanism and Structure in Organic Chemistry Holt, Rinehart and
Winston Inc., 1959.
7. Carey A. Francis, and Sundberg J Richard., Part A and Part B Advanced Organic
chemistry, 5th edition, Springer, 2007.
8. Jonathan Clayden, Nick Greeves and Stuart Warren., Organic Chemistry, 2nd
Edition, Oxford Publishers, 2012.
9. Finar I. L., Organic Chemistry, 6th Edition, Pearson Education Asia, 2004.
10. House H.O., Modern Synthetic Reactions, W.A. Benjamin Inc, 1972.

CREDIT 02

CREDIT02-UNIT 01: REAGENTS AND REACTION IN SYNTHESIS-1
LEARNING OBJECTIVES
After successful completion of this unit, you will be able to-
 Explore the advanced knowledge of organic synthesis in general and
classical and modern reagents and methods in synthesis in particular.
 Explain metal-mediated reactions and common metal-based reagents,
oxidation-reduction reactions and reagents and rearrangement reactions will
be gained.
 Evaluate to predict reagents and conditions needed for specific conversions.
INTRODUCTION
The success of modern organic synthesis mostly relies upon the selection
and implementation of proper reagents, which may be either used under specific or
variety of conditions. The main purpose of using these reagents is to target the
conversion of a specific functional group without affecting the other, a challenging
task, and to give higher yields as far as possible. A good reagent must give least
problems while working up the reaction.
The qualities of a good reagent suitable for modern organic synthesis are:
 The reagent should be cheap.
 It should be eco-friendly i.e., poses less risk to the environment and could
be recycled whenever required.
 It should be versatile i.e., works under variety of conditions.
 The reagent may require to target specific functional group.
 It should give a good yield of the desired product.
 The workup conditions must be less tedious.
Now a days plenty of reagents for modern organic synthesis are available
to the organic chemist to choose among and carry out the reaction smoothly to the
desired product on both laboratory and industrial scales.
Application of the following reagents and reaction in synthesis,
 Lithium diisopropylamide (LDA)

 Dicyclohexyl carbodiimide (DCC),
 Lead tetra acetate,
 PPA

01-01: LITHIUM DI-ISOPROPYL AMIDE (LDA)
Lithium Diisopropyl Amide ( LDA ), A Strong, Sterically Hindered Base

Lithium diisopropylamide can be used for the generation of carbanion or
enolate anions from carbonyl group-containing compounds.
It can also be used as a base in:
 The direct alkylation and acylation of ketones.
 The aldol condensation reaction.
 α-Selenation reaction.
 The synthesis of α, β- unsaturated carbonyl compounds from carbonyl
compounds.
 The alkylation of acids, esters, amides, and nitriles.
 The initiation of anionic polymerization.
Formation of Less Hindered (“Kinetic”) Enolates with LDA

In other words: LDA is a strong, bulky base. The most common use of LDA is in
the formation of enolates. In the example below, notice how both carbons flanking
the C=O have C-H bonds? LDA will remove the proton selectively from the carbon
substituted with the fewest number of carbons:
Also note the temperature (–78 °C). There’s nothing special about –78° C
relative to –72° C or –60° C for this to work it’s just that cold temperatures
improve the selectivity, and –78°C happens to be the temperature of a very cheaply
prepared cold bath (dry ice and acetone). A common solvent for this is
tetrahydrofuran (THF).
Alkylation, Halogenation, and Aldol Reaction of Enolates obtained with
Lithium Diisopropylamide

Why is LDA useful? Well, enolates are extremely useful nucleophiles, able
to participate in S N 2 reactions with alkyl halides as well as the aldol reaction
(among many other things). If we used NaNH 2 to form an enolate like this, we’d
likely get a mixture of two enolates, which would lead to a mixture of products.
The selectivity of LDA in forming the less substituted enolate makes it extremely
useful.
Formation of Less-Substituted Alkenes in Elimination Reactions:

(“Non-Zaitsev (Saytzeff)” or “Hoffmann” Products)
Although less common, LDA can also be used for the formation of
“Hoffman” products in elimination reactions. The usual base for this is potassium
t-butoxide, but LDA can do it too:
Formation of Less Substituted Enolates with LDA: Mechanism

This diagram below shows the reaction between LDA and the ketone. Note
the bonds that are forming (N-H, C-C) and the bonds that are breaking (C–H, C–O).
The enolate that is formed has a resonance isomer where the negative charge is on
the carbon. This is, in some respects, the more “important” resonance form, as it is
the carbon that tends to be a better nucleophile than oxygen in reactions of
enolates.

Ireland–Claisen (silyl ketene acetal) rearrangement
Rearrangement of allyl trimethylsilyl ketene acetal, prepared by reaction of
allylic ester enolates with trimethylsilyl chloride, to yield γ, δ-unsaturated
carboxylic acids. The Ireland–Claisen rearrangement seems to be advantageous to
the other variants of the Claisen rearrangement in terms of E/Z geometry control
and mild conditions.
Example

Thia-Fries rearrangement
Meyers Oxazoline method

Chiral oxazolines employed as activating groups and/or chiral auxiliaries in
nucleophilic addition and substitution reactions that lead to the asymmetric
construction of carbon–carbon bonds.
Anion-accelerated Carroll Rearrangement:
SOLVED P ROBLEMS 01
29) Problem 01-01
Which type of enolate formation promotes LDA (Lithium diisopropylamide)?

A. more; B. less; C. thermodynamically
Solution: The correct option is B less.

LDA is bulky base thus, it will abstract proton from less hindrance side and majorly
formed less substituted enolate or kinetically stable enolate.

30) Problem: 01-02: Select the incorrect statements regarding the final product.
This question has multiple correct options

A. It gives iodoform test.
B. It undergoes Cannizzaro’s reaction.
C. It is lactone.
D. It is ketone
Solution: Correct options are A, B and C
SHORT A NSWER QUESTIONS 01
29) SAQ 01-01
Find out the major product Y.
Answer: This is the one type of selective reaction using an LDA or Lithium
diisopropylamide reagent in presence of THF solvent. We know that LDA is a good
selective type of reagent, using various sectors in the organic synthesis field for
required product making.

This reaction increases the nucleophilicity of the Alpha position of the given
compound. And step number two- which nucleophile is attacked in Benzyl halide on
electrophile electrophilic center and release the Br-.
30) SAQ 01-02: What product is formed when each compound is treated first with
LDA in THF solution at low temperature, followed by CH 3 CH 2 I?
Answer: The products formed when each starting material is treated with LDA are
shown below.
01-02: DICYCLOHEXYL CARBODIIMIDE (DCC)
DCC (N, N’-Dicyclohexyl carbodiimide) is a useful reagent for the

formation of amides from amines and carboxylic acids. Its most common
application is in the synthesis of peptides from amino acids. It sequesters one
molar equivalent of water, resulting in a dicylohexyl urea byproduct. It can also be
used for the formation of esters from carboxylic acids.
Amide Formation

Since the initial reports, DCC has become the most common reagent in
peptide synthesis and in other amide bond-forming reactions of primary and
secondary amines with carboxylic acids. The mechanism is considered to be well
understood.
Typically, DCC (1.1 equiv.) is added to a concentrated solution (0.1-1.0 M)
of the carboxylic acid (1.0 equiv.), amine (1.0 equiv.), and catalyst (when used) in
methylene chloride or acetonitrile at 0 °C. The hydrated DCC adduct,
dicyclohexylurea (DCU), quickly precipitates and the reaction is generally
complete within 1 h at rt. The solvents THF and DMF can be used, but are reported
to reduce reaction rates and encourage the formation of the N-acylurea side
product, as well as increasing racemization in chiral carboxylic acids. If the amine
is initially present as the salt (i.e., amine hydrochloride), it may be neutralized by
adding 1 equiv. of Diisopropylethylamine prior to adding DCC; however, the
addition of tertiary amines (particularly Triethylamine) can facilitate N-acylurea
formation and racemization. Racemization occurs via the formation of an oxazolone
intermediate. The addition of coupling agents (acylation catalysts) such as 1-
Hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-Hydroxy
succinimide (HOSu), and 3-Hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one can
generally ameliorate both problems. These additives are required for the coupling
of sterically hindered components, or when the amine is weakly nucleophilic.
Another potential problem with DCC is that at the completion of the reaction some
DCU remains in solution with the product, necessitating additional purification.
Water-soluble carbodiimide derivatives such as 1-Cyclohexyl-3-(2-
morpholinoethyl) carbodiimide Metho-p-toluenesulfonate and 1-Ethyl-3-(3´-
dimethylaminopropyl) carbodiimide Hydrochloride (EDCI)22 obviate this problem,
as they are removed by a simple extraction. Many newer coupling agents have been
developed for peptide synthesis and other acylation reactions. These include
Benzotriazol-1-yl-oxytris (dimethyl amino) phosphonium Hexafluorophosphate
(BOP), O-Benzotriazol-1-yl-N, N, N´, N´-tetramethyluronium Hexafluorophosphate
(HBTU), Bis (2-oxo-3-oxazolidinyl) phosphoric Chloride (BOP-Cl), and (1H-1,2,3-
benzotriazol-1-yl-oxytris (pyrrolidino)phosphonium hexafluorophosphate (PyBOP).
In addition to linear and polymeric amides, lactams of various ring sizes have been
synthesized using these methods (eq 1).
Ester and Thioester Formation

These reactions occur through the same O-acylurea or anhydride active
intermediate as in the amide coupling reactions, and the discussion of associated
problems applies here as well. In general, alkyl and (particularly) aryl thiols can be
efficiently coupled to carboxylic acids using DCC. Reactions of primary and
secondary alcohols proceed reliably, but require the presence of an acylation
catalyst. This is usually 4-Dimethylaminopyridine (DMAP), but others have been
used including 4-pyrrolidinopyridine31 and pyridine (solvent) with catalytic
p-Toluenesulfonic Acid. The acylation of more hindered alcohols often results in
reduced yields; however, even t-butanol can be acylated, providing a useful route to
t-butyl esters. Various other carbodiimide derivatives have also been used in the
preparation of esters. As with amides, which are not limited to intermolecular
reactions, a wide variety of lactones can also be synthesized.
Anhydride Formation
Among other anhydride-forming reagents, including Acetic Anhydride,
Trifluoroacetic Anhydride, and Phosphorus (V) Oxide, DCC is one of the simplest,
mildest, and most effective reagents for the preparation of symmetrical anhydrides,
including formic anhydride, which is useful in the preparation of formamides (eq
2).
Anhydride formation is associated with each of the reaction types involving

carboxylic acids. The anhydride is often the reactive species, to the extent that it
competes with the O-acylurea or covalent catalyst adduct.
Sulfinate and Phosphate Esters

Anhydrides of sulfinic and sulfonic acids and phosphate monoesters can be
prepared using DCC. Further reaction with alcohols or phenols gives the
corresponding sulfinates and phosphate diesters. Pyrophosphates can be prepared
from mono- and disubstituted phosphate esters. Reaction of activated sulfinates
with amines gives the corresponding sulfinamides.
Oxidation of Alcohols to Aldehydes and Ketones: Moffatt Oxidation

The oxidation of primary and secondary alcohols46 to aldehydes and
ketones, respectively, can be carried out by reaction with DMSO activated by DCC.
In comparison to the many metal-mediated oxidative reactions, the Moffatt
oxidation is carried out under very mild conditions, and has found widespread use
for reactions in the presence of sensitive functional groups (eq 3). In addition, over-

oxidation of aldehydes to form carboxylic acids is not observed. Under typical
reaction conditions, a solution of the alcohol (1 equiv), DCC (3 equiv), and a
proton source (pyridinium trifluoroacetate) (0.5 equiv) is stirred in DMSO or
DMSO/benzene overnight at rt. After quenching the reaction with aqueous acetic
acid and removing DCU by filtration, the product can be isolated by extraction. In
modifications of this reaction, DCC can be replaced by other DMSO-activating
agents including acetic anhydride trifluoroacetic anhydride and oxalyl chloride (see
Dimethyl Sulfoxide-Oxalyl Chloride).
Dehydrative-Type Couplings
Because of the power of DCC as a dehydrating agent, it has found many
uses in a variety of other dehydrative coupling reactions. These include the reaction
of primary amines with DCC and Carbon Dioxide or Carbon Disulfide to form urea
(eq 4) or isothiocyanates (eq 5), respectively.
Symmetrical peroxides can be synthesized from benzoic acid derivatives and

hydrogen peroxide (eq 6). Unsymmetrical peroxides can be synthesized from the
corresponding carboxylic acid and peroxy acid.
Aromatic and aliphatic alcohols and thiophenols can be coupled to form

ethers (eq 7) and thioethers (eq 8), respectively, using DCC.

In cases where sensitivity of the compound precludes the formation of an
acid chloride,  -diazo ketones can be synthesized by the DCC-mediated coupling
of diazomethane to carboxylic acids (eq 9).
Dehydration to Alkenes, Epoxides, Nitriles, and Ketenes

-Hydroxy ketones and -hydroxy esters can be dehydrated, using DCC, to
,-unsaturated ketones (eq 10 ) and esters (eq 11), respectively. Cyclopropanes can
be synthesized by the dehydration of -hydroxy ketones (eq 12 ).
Other dehydration reactions include the conversion of primary amides to

nitriles, aldehydes to nitriles (via the hydroxylamine) (eq 13) and carboxylic acids
to ketenes (eq 14).
Dehydroxylation of Alcohols

Alcohols and phenols can be dehydroxylated to the corresponding alkane by
hydrogenation of the O-acylurea adduct formed from the reaction of the alcohol
with DCC (eq 15).
Inversion of Secondary Alcohols

Secondary alcohols can be stereo chemically inverted by formylation (or
esterification) with DCC, followed by saponification (eq 16).
Heterocyclization Reactions
DCC has frequently been used both as a reagent and as a reactant in the
synthesis of heterocycles. For example, DCC mediated cyclodesulfurative
annulation reactions have been used to synthesize guanosine-type nucleotide
analogs (eq 17).

SOLVED PROBLEMS 02
31) Problem 01-03: Treatment of 5-aminopentanoic acid with DCC
(dicyclohexylcarbodiimide) yields a lactam. Show the structure of the product and
the mechanism of the reaction.
Solution:
Step 1: The goal required to accomplish the task is to draft a reaction mechanism
for the reaction of 5-aminopentanoic acid with DCC and derive the product of the
reaction.
Step 2: The reaction of 5-aminopentanoic acid with DCC is a nucleophilic acyl

substitution reaction. In this type of reaction, a substituent in the acyl group is
replaced by an incoming nucleophile. However, in this case, cyclization of a linear
chain is involved upon the formation of product.
Step 3: For the reaction mechanism, the O atom from the hydroxyl group of 5-
aminopentanoic acid attacks the C atom in DCC, initiating an electron push from
one of its C=N bond.
Step 4: Then, a proton is transfer from the positively charged O atom towards the
negatively charge N atom.
Step 5: The amino group of 5-aminopentanoic acid attacks the C atom in C=O
bond, resulting to the cyclization of the linear chain and initiating another electron
push from C=O bond, forming oxide anion.
Step 6: The oxide anion re-forms the C=O double bond through another electron
push. Consequently, the DCC is cleaved from the substrate compound.

Step 7: A proton abstraction occurs, and it results to the formation of the lactam.
32) Problem 01-04: Give the name of reaction for oxidation of alcohols using
DCC.
Solution: Oxidation of alcohols using DCC and DMSO, Moffatt oxidation and
“Pfitzner−Moffatt oxidation”.
Examples
SHORT ANSWER QUESTIONS 02

31) SAQ 01-03: DCC as a dehydrating agent, explain.

Answer: DCC as a dehydrating agent, it has found many uses in a variety of other
dehydrative coupling reactions. These include the reaction of primary amines with
DCC and Carbon Dioxide or Carbon Disulfide to form urea (eq 4) or
isothiocyanates (eq 5), respectively.
32) SAQ 01-04: Dehydroxylation of Alcohols, is it possible using DCC?
Answer: Alcohols and phenols can be dehydroxylated to the corresponding alkane

by hydrogenation of the O-acylurea adduct formed from the reaction of the alcohol
with DCC.
01-03: LEAD TETRA ACETATE

Lead Tetraacetate in Organic Synthesis
Lead tetraacetate (LTA), a versatile oxidizing agent for different functional
groups, has been widely used for oxidative decarboxylation of carboxylic acid,
cleavage of 1,2-diol, formation of the cyclic ether, acetoxylation, methylation,
dehydrogenation etc. The present micro review describes the utility of LTA in 1,2-
glycol-cleavage and decarboxylation of carboxylic acid.
The commercially available LTA is hygroscopic and turns brown due to the
formation of lead oxide. Therefore, LTA should be stored in absence of moisture,
kept tightly sealed and stored under 10oC in the dark and in the presence of about
5% glacial acetic acid. LTA is very toxic and may be absorbed through the skin.
Due to the high toxicity the reagent should be handled with care in chemical fume
hood. It is soluble in hot acetic acid, benzene, cyclohexane, chloroform, and carbon
tetrachloride.

Use of LTA in Organic Synthesis
1,2-glycol-cleavage
Scheme 1. Cleavage of diols.
LTA is one of the most frequently used reagents for the cleavage of glycols
and for the preparation’s carbonyl compounds. The reactions are performed either
in aprotic solvents (benzene, nitrobenzene,1,2-dichloroethane) or in protic solvents
such as acetic acid. The role of LTA in glycol cleavage is highly dependent on the
structure and stereochemistry of the substrate. The cleavage of diols proceeds via a
cyclic intermediate as shown in Scheme 1. The cleavage of cis diol occurs more
easily than the trans-diol which does not permit the easy formation of the cyclic
intermediate. Some examples are given in Scheme 2.
Scheme 2: Cleavage of diols 1, 3, 4 and 6 with LTA.
The diol 1 on treatment with LTA in benzene affords aldehyde 2 but the
diols 3 and 4 with LTA suffer4 cleavage and yield ketone 5. 1,2-Glycol cleavage by
LTA has been widely applied for the oxidation of carbohydrates and sugars. The

diol 6 on oxidation with LTA in acetic acid yields the aldehyde 7. The reactivity of
individual glycol units in sugar molecules is often different and thus the LTA
reaction is helpful tool for structural determination and for degradation studies in
carbohydrate chemistry. It has been observed that trans-1,2-diols which are cleaved
slowly with LTA in acetic acid are readily cleaved if pyridine is used as reaction
solvent.
The cyclopropene ester 9, prepared from the bromo derivative of cis-1,2-
hydrocatechol 8, on treatment with LTA produces the cyclopropane aldehyde 10
which is a potential intermediate for the cis-pyrethroid class of insecticides. The
trans-diol 12, obtained from D-mannitol 11, with LTA affords ketone 13 in
unspecified yield. Reduction of 13 with sodium borohydride produces the alcohol
14 which is utilized for the synthesis of mixed-acid phospholipids polyunsaturated
fatty acid as shown in Scheme 3.
Scheme 3:
Decarboxylation of carboxylic acid
Oxidative decarboxylation of carboxylic acids by LTA has been frequently
used in the synthesis of terpenoid compounds. Oxidative decarboxylation by LTA
depends on the conditions of reaction, core agents and structure of acids and hence
a variety of products such as acetate esters, alkanes, alkenes, and alkyl halides can
be obtained. The reactions are performed in nonpolar solvents (benzene, carbon
tetrachloride) or polar solvents (acetic acid, pyridine, HMPA). Decarboxylation of
primary and secondary carboxylic acids usually affords acetate esters as major
products. If a mixture of acetate and olefin is formed, it is recommended to perform
the reaction in presence of potassium acetate. The cyclohexane carboxylic acid 15
if heated under reflux with LTA in benzene furnishes a mixture of acetate 16 and
the olefin 17 but only the acetate 16 is produced in high yield when heated with
potassium acetate in acetic acid (Scheme 4).

Scheme 4: Decarboxylation of 15 with LTA.
The monocarboxylic acid on oxidation with LTA in presence of copper (II)

salts gives mainly alkenes (Scheme 5). The free radical mechanism is generally
accepted. Rosefuran 19 has been obtained in crude form (70%) by the oxidative
decarboxylation of 3-methyl-2-furoic acid 18 with LTA in boiling benzene in the
presence of copper acetate. Bisdecarboxylation of compounds containing carboxyl
groups on adjacent carbons can be achieved with LTA in the presence of oxygen
and pyridine. Thus, the dicarboxylic acid 20 on decarboxylation affords the
tetrahydrobenzene 21. Similarly, the acid 22 if subjected to bisdecarboxylation can
yield compound 23 (Scheme 6). The compounds containing germinal carboxyl
groups (malonic acid derivatives) 24 are decarboxylated with LTA to give gem
diacetate which can easily be hydrolyzed to ketone 25.
Scheme 5: Decarboxylation of 18 with LTA

Scheme 6: Decarboxylation of 20 22 and 24 with LTA.
The LTA decarboxylation of tertiary carboxylic acids gives a mixture of

alkenes and acetate esters. O-methylpodocarpic acid 26 on heating with LTA yields
a mixture of olefins 27, 28, 29, acetates 30 and 31. In addition a lactone 32 is
obtained (Scheme 7).
Scheme 7: Decarboxylation of tertiary carboxylic acid 26 with LTA.
Banerjee and collaborators have observed that the decarboxylation of the

acid 34, prepared from the cyclic ether 33, with LTA, pyridine and DMF affords a
mixture of olefins 35 (Scheme 8). The transformation of 35 into the ketone 36 is
affected in two steps: (a) demethoxylation with sodium iodide, boron tribromide,
15-crown ether-5, (b) oxidation with Jones Reagent. Bromination of 36 followed by
dehydrobromination and aromatization respectively yield tetraol 37 in 60% Yield.
The tetraol 37 is a potential intermediate for the synthesis of diterpenoid quinones
cryptotanshinone and tanshinone IIA.

Scheme 8: Decarboxylation of tertiary carboxylic acid 34 with LTA, to obtain 37.
Masamune and collaborators have also studied the decarboxylation of

tertiary carboxylic acid with LTA in relation of the studies on the synthesis of the
terpene glutinosone. The lactone 39, prepared from the ketoester 38, on alkaline
hydrolysis and acetylation respectively is converted to the acid 40 (Scheme 9). The
acid 40 on being heated with LTA and DMF undergoes decarboxylation and
produces a mixture of olefins 41. Treatment of 41 with methanolic potassium
hydroxide (5%) followed by the addition of triphenyl methyl fluoborite afford
glutinosone 42.
Scheme 9: Decarboxylation of tertiary carboxylic acid 40 with LTA.

Oxidative decarboxylation reaction has proved useful in the synthesis of
sesquiterpene furoventalene 46 as depicted in the scheme 10. m-Anisic ester 43 is
converted into the ester 44 in three steps (reductive alkylation, metalation, and
alkylation). Acidic hydrolysis and cyclization of the ester 44 yield dihydro
benzofuran 45. Alkaline hydrolysis and oxidative decarboxylation with LTA lead
the formation of furoventalene 46.

Scheme 10: Decarboxylation of 45 with LTA to obtain 46.
Banerjee and collaborators have utilized oxidative decarboxylation for the

synthesis of sesquiterpene (±) frullanalide the details are described in scheme 11.
The ketone acid 48, prepared from the cyclic ether 47, on heating with LTA and
copper (II) acetate undergoes oxidative decarboxylation yielding enone 49.
Alkylation of 49 with ethyl bromoacetate produces ketoester 50 which on reduction
with sodium borohydride in methanol followed by stirring with hydrochloric acid
afford the lactone 51. As the lactone 51, has already converted [24] into (±)
frullanalide 52 the present synthesis of 51 constitutes a formal total synthesis [25]
of frullanalide 52.
Scheme 11: Decarboxylation of 48 with LTA to obtain 52.

Another interesting use of oxidative decarboxylation with LTA is shown in
scheme 12. The acid 53 on decarboxylation with LTA gives a mixture of olefins 54.
Epoxidation followed by hydrolysis with Lewis’s acid produces aldehyde 55 which
on methylation and oxidation respectively afford Callitrisic acid 56. The above-
mentioned examples exhibit the importance of LTA in the synthesis of terpenoid
compounds.
Scheme 12: Decarboxylation of 53 with LTA and synthesis of Callitrisic acid 56.
LTA has also been utilized for acetoxylation of ketones in enol form, nuclear
methylation, and oxidation of phenols. Alkyl sulfides, alkyl hydroperoxides and
organometallic compounds are also oxidized by LTA. Several cyclic ethers have
been synthesized by LTA oxidation.
SOLVED PROBLEMS 03
33) Problem 01-05: What happens when glycol reacts with lead tetraacetate?
Solution: Lead tetraacetate is used cleave a carbon-carbon bond in a glycol. This

reaction is useful in the formation of ketones and aldehydes and involves a
favourable five membered cyclic intermediate.
34) Problem 01-06: What is the use of lead tetra acetate reagent?

Solution: Lead tetraacetate is used in solvents (e.g., acetic acid or benzene)
primarily for the oxidative cleavage of 1,2-diols, α-hydroxy ketones, 1,2-diketones
or α-hydroxy acids.
33) SAQ 01-05: What is lead tetraacetate in organic synthesis?
Answer: Lead tetraacetate (LTA), a versatile oxidizing agent for different
functional groups, has been widely used for oxidative decarboxylation of
carboxylic acid, cleavage of 1,2-diol, formation of the cyclic ether, acetoxylation,
methylation, dehydrogenation etc.
34) SAQ 01-06: What are the properties of lead tetraacetate?
Answer: Lead (IV) acetate or lead tetraacetate is an organometallic compound with

chemical formula Pb(C 2 H 3 O 2 ) 4 . It is a colourless solid that is soluble in nonpolar,
organic solvents, indicating that it is not a salt. It is degraded by moisture and is
typically stored with additional acetic acid.
01-04: POLYPHOSPHORIC ACID (PPA)

PPA as a reagent in organic chemistry
Polyphosphoric acid (PPA), a powerful dehydrating agent, has been widely

used to perform several important organic reactions and thus has played an
important role in the synthesis of organic compounds and natural products.
The use of PPA
i) In the cyclization of acids on the aromatic ring
ii) In acetylation and isopropylation on the aromatic ring,
iii) Hydrolysis of esters,

iv) Cleavage of epoxides and
v) Synthesis of heterocyclic compounds.
The commercially available PPA is hygroscopic, highly viscous, clear,
colorless, or light amber liquid. The acid is neither soluble nor reacts with nonpolar
organic solvents such as toluene or hexane. PPA is prepared by mixing phosphoric
acid (85%, d 1.7 g/mL) with phosphorous pentoxide (P 2 O 5 ) followed by heating at
200 0 C for 30 min. Due to high viscosity PPA is difficult to pour and stir at room
temperature but is much easier to work with a temperature above 60 0 C. The
addition of solvents, such as xylene, simplifies the difficult workup usually
associated with PPA. Ice is normally used during the work-up to moderate the
exothermic reaction that occurs with water. The commercially available PPA
contains 82-85 % P 2 O 5 . The powerful dehydrating properties, low nucleophilicity
and moderate acidity explain the reasons for the wide applications of PPA in
organic synthesis.
Cyclization of Acids
Several acids on the aromatic ring have been cyclized with PPA to obtain
cyclic ketones and some of these ketones have been utilized for the synthesis of
natural products. Some examples are given below.
The acid 1 in Scheme 1, obtained by Friedel-Crafts alkylation of p-xylene
with 5-chlorovaleric acid in presence of aluminum chloride, on cyclization with
PPA yields the cyclic ketone 2 (Banerjee etal. 2002) which on heating with 2,4-
pentanediol and p-toluenesulfonic acid (Vuligonda etal.1996) yields the alkene 3.
The transformation of the alkene 3 to the reported benzsuberone 4 (Ho & Lin,
1999) is achieved in four steps respectively: acetylation [manganese (III) acetate
dihydrate], alkaline hydrolysis (NaOH, MeOH), catalytic hydrogenation (H2, PtO 2 )
and oxidation with Jones reagent (Bowers etal., 1953). The Wittig reaction of 4
with ethoxy carbonyl methylene triphenyl phosphorene in the presence of a
catalytic quantity of benzoic acid in toluene gives the ester 5. The ester is not
obtained in good yield with cinnamic acid.

Scheme 1. Synthesis of tavacpallescenicine by cyclization of aromatic acid 1
Oxidative cyclization of the ester 5 with selenium dioxide in acetic acid

furnishes butenolide 6 whose transformation to tavacpallescenicine 7 has already
been accomplished by heating with DIBAL in THF (Ho & Lin, 1999). PPA
cyclization of the acid has also been used for the synthesis of sesquiterpene
lacinilene C methyl ether 14 (McCormick etal., 1978). The synthetic route is
depicted in Scheme 2.
Scheme 2. Synthesis of sesquiterpene lacinilene C methyl ether

Alkylation of the ketoester 8 with isopropyl magnesium chloride in THF at -
o
15 C affords pure lactone 9 whose conversion to the acid 10 is achieved by
reduction with zinc and acetic acid.

The transformation of the acid 10 to dihydronaphthalene 11 is accomplished
in two steps: (i) cyclization with PPA and (ii) treatment of the resulting tetralone
with methylmagnesium iodide. Oxidation of 11 with OsO 4 /NMMO.H 2 O in acetone
gives a mixture of diols 12 (Cocker & Sainsbury, 1965) which is oxidized (Bowers
etal., 1953) to yield a mixture of ketone 13 and lacinilene C methyl ether 14.
Treatment of the mixture with dicyano dichloro benzquinone (DDQ) provides the
natural product 14 in 27% yield.
The PPA cyclization has been utilized in the development of a two-step
synthesis of 1,2,3,4-tetrahydro-5,8-dimethyl-1- tetralone 16 in high yield (Banerjee
etal.,2004) whose transformation to sesquiterpene occidol 21 (Mane & Kadam,
1998) has been accomplished without any difficulty and the synthetic route is
presented in Scheme 3.
Friedel-Crafts alkylation of xylene with chlorobutyric yields acid 15 which
on cyclization with PPA affords the tetralone 16 in high yield. An alternative
approach of the tetralone 16 has also been published (Mane & Kadam, 1998) but
the yield is not high compared with the published procedure (Banerjee etal, .2004).
The alcohol 17, obtained by the metal hydride reduction of tetralone16, is
converted to the aldehyde 18 by Vilsmeier-Hack reagent (Smith, 1954). Metal
hydride reduction produces the alcohol 19 which on oxidation with Jones reagent
(Bowers etal., 1953) furnishes the acid 20 whose conversion to occidol 21 is
achieved in one step by reaction with an excess of methyllithium.
Scheme 3. Synthesis of occidol 21

PPA cyclization of acid has been sought (Giarruso & Ireland, 1968) to
achieve the synthesis of (±)-desoxypodocarpic acid 27 and (±) 13-
methoxydesoxypodocarpic acid 28. The synthetic route is depicted in Scheme 4.
The hydrindenone 23, prepared from 2-methyl-2-phenylcyclohexanone 22, on
oxidation with selenium dioxide yields dione 24 which is converted to acid 25 in
three steps (reduction, hydrogenation, oxidation respectively). The cyclization of
the acid 25 with PPA yields 7-keto-desoxypodocarpic acid 26 which on
hydrogenolysis yield desoxypodocarpic acid 27. Nitration of 26 followed by
hydrogenation and addition of isoamyl nitrate affords 13-methoxydesoxypodocarpic
acid 28.
Scheme 4. Synthesis of (±)-Desoxypodocarpic acid 27 and (±)-13-

Methoxydesoxypodocarpic acid 28
The use of PPA for the cyclization of acids has also been recorded during
synthesis of bicarbocyclic sesquiterpene (±) - Emmotin-H 33 (Reddy & Krishna
Rao, 1979) as has been described in Scheme 5. The cyclization of the acid 29 with
PPA affords ketone 30 in 63% yield. Esterification followed by oxidation with
selenium dioxide give the O-quinone 31 which is reduced and acetylated
respectively to obtain the diacetate 32. No yield is reported of this compound.
Treatment of the diacetate with excess methylmagnesium bromide followed by air
oxidation leads the formation of Emmotin-H 33.

Scheme 5. Synthesis of Emmotin H
The use of PPA cyclization can be observed in the synthesis (Nambudiry &
Krishna Rao, 1974) of Pterosin E, a norsesquiterpene isolated by Yoshihara and
others (Yoshihara etal., 1971). The synthetic route is exhibited in Scheme 6.
Alkylation of diethylmethylmalonate 34 with 3,5-dimethylbenzyl bromide 35
affords 36 which on chloromethylation yields 37. The crude product is converted to
the diacid 38 by hydrolysis with sodium cyanide in dimethylformamide. The
cyclization of the acid 38 with polyphosphoric acid (PPA) leads the formation of
sesquiterpene Pterosin E 39. It is worthwhile to go through the published works,
(Mason, 2008, Mason etal., 2008, Edwards etal., 2007, Dodd, 2001, Dodd, 1999,
Popp & McEwen, 1958) for more examples.
Scheme 6. Alkylation of diethylmethylmalonate 34 with 3,5-dimethylbenzyl

bromide 35

Acylation and Isopropylation on Aromatic Ring with PPA
Acylation reaction is one of the most important reactions which has been
frequently used for the synthesis of organic compounds. Several intermolecular
acylation reactions carried out with PPA have been reported (Popp & McEwen,
1958; Snyder & Werber, 1950). Acylation of 1,4-dimethyl-6-methoxytetralin 40
(Bachute & Mane, 1991) with acetic acid and PPA leads the formation of 7-acetyl-
6-methoxy-1,4-dimethyltetralin 41. Dehydrogenation with DDQ furnishes the
naphthalene 42 which is converted to the sesquiterpene Emmotin-G methyl ether 43
(Scheme 7) with the Grignard reagent.
Scheme 7. Synthesis of the sesquiterpene Emmotin-G methyl ether 43
The acylation of cycloheptene 44 with acetic acid (Rand & Dollinski, 1966)
and PPA produces a mixture of acetylated 45 (23%), 46 (0.6%), ester 47 (4.8%) and
the hydrocarbon (0.6%) respectively as shown in Scheme 8. The formations of
these products can be explained by assuming the generation of the carbocation 44A
which undergoes several intramolecular transformations leading the formation of
products 45, 46, 47 and 48.
Scheme 8. Acylation of cycloheptene 44 with acetic acid and PPA

The Friedel-Crafts acylation (Renault etal., 1999) of aromatic compounds
for example, toluene 49 with diethylmalonic acid in presence of PPA produces the
acylated product 51. Similar acylation of anisole 52 and thiophene 55 with phenyl

malonic acid 53 and methyl ethyl malonic acid 56 respectively with polyphosphoric
acid (84% minimum) provides the acylated products 54 and 57 respectively
(Scheme 9).
Scheme 9. Friedel-Crafts acylation
In the phenyl substituent series, the rings carrying an electron-donating

group (methyl, methoxy) afford the acylated product at p-position in very good
yield (82-92%). The absence of o-product may be explained as a steric effect of the
electrophilic agent. The selective acylation occurs at the α-position of thiophene, 2-
bromo-thiophene, thiophene-2- carboxylic acid, and furan whereas pyrrole gives
only degradation products and N-phenylpyrrole affords only 5% of the acylated
product. The acylation reaction fails if H 3 PO 4 or P 2 O 5 is used instead of
polyphosphoric acid. No acylation occurs with malonic acid ester derivatives and
cyanoacetic acid. The acylation reaction under this condition also fails with other
diacids such as succinic, glutaric, and adipic acids.
The isopropylation of ketone has been achieved with isopropanol in
presence of PPA (Wollinsky etal., 1972). The tricyclic ketone 58 on isopropylation
with isopropyl alcohol and PPA furnishes a mixture of the ketones 59 and 60 in
75% yield. Wolff-Kishnner reduction of the ketone 59 followed by demethylation
with HBr produce ferruginol 61. (Yield not specified). The ketone 60 on
demethylation and aerialoxidatin respectively affords xanthoperol 62 (yield not
reported) which is characterized as its acetate (Scheme 10).

Scheme 10. Isopropylation of ketone 40 with isopropanol
PPA in isopropanol has been utilized for the isopropylation of 7-methoxy-1-

tetralone 63 (Cabrera etal. 2014). The resulting tetralone 64 (Scheme 11) obtained
in 85% yield, is converted to the tetraline 65 by heating with 2,4-pentanediol and a
catalytic amount of p-toluenesulfonic acid. Epoxidation of 65 followed by heating
with sulfuric acid affords the tetralone 66. The tetralones 64 and 66 are the
potential intermediates for the diterpenes miltirone and carnosic acid respectively.
Scheme 11. Isopropylation of ketone 63 with isopropanol

Hydrolysis of Esters into Acids
PPA has been used for the hydrolysis of esters (67-70) into the acids (71-74)
respectively (Scheme12) (He etal. 2002). The use of PPA is particularly useful for
the hydrolysis of chromone ester 70 to prevent the formation of the products 75 and
76.
Scheme 12. Hydrolysis of esters into acids
It is worthwhile to mention that exist many reagents that can be utilized for
the hydrolysis of esters into acids in mild condition. The use of PPA for the
hydrolysis of esters into acid is hardly observed.
Cleavage of Aliphatic and Aromatic Epoxides

PPA in 30 mol % is used as promoter for the cleavage of aliphatic and
aromatic epoxides to alkenes in excellent yield under neat condition (Pathe &
Ahmed, 2015) at 50 0 C. The present method has several advantages such as use of
inexpensive reagent, acquisition of the desired product in high yield and the
formation of stereoselective product in short reaction time under ecofriendly
reaction conditions. The yield of the alkene gets reduced if the solvent is used to
perform the reaction. The following epoxides (77-80) have been cleaved to olefins
(81-84) in high yield (Scheme 13) by the present method.

Scheme 13. Cleavage of aliphatic and aromatic epoxides
The above mentioned procedure has also been utilized for the cleavage of
several chalcones epoxides to obtain chalcones. The method has proved useful for
the transformation of the following chalcones epoxides, e. g. 85-87 to chalcones
88-90 respectively in excellent yield. (Scheme 14)
Scheme 14. Cleavage of several chalcones epoxides to obtain chalcones

Scheme 15. Deoxygenation of nitrostyrene epoxides, and nitrochromene epoxides
chalcones
Several nitrostyrene oxides, e. g. 91-93 and nitrochromeepoxides e. g. 94-96

suffer cleavage to alkenes 97-102 respectively when heated with PPA at 15oC under
neat condition (Scheme 15).
Besides PPA, other acids like sulfuric acid have been used frequently to
perform the cleavage of epoxides to obtain olefin (Banerjee etal. 2022).
Synthesis of Heterocyclic Compounds with PPA

Synthesis of isoquinoline and xylopinine
The use of PPA has been observed during the synthesis of heterocyclic
compounds. The Bischler-Napieralski (BN) reaction is one of the most effective
methods (Whaley & Govindachari, 1951) for the preparation of 3,4-
dihydroisoquinoline derivative and in the synthesis of a variety of isoquinoline
derivatives and analogs of pharmacological interest. Venkov and Ivanov (Venkov&
Ivanov, 1996) have reported a new method for the synthesis of a variety of
isoquinolines which involves the reactions of carboxylic acids or their anhydrides

and esters with a variety of amines such as homoveratrylamine, 1, 2-
diphenylethylamines, N-acyl-2-phenylethylamines in non-aqueous acidic media as
polyphosphoric acid (PPA). The reaction with anhydrides proceeds faster than the
corresponding carboxylic acids or their ester. It has been observed that the
homoveratrylamine 103 reacts with the acid 104 in PPA to yield the isoquinoline
105. The reaction probably proceeds first with acylation of the activated aromatic
ring of the ammonium salt of 103 to 103 (i) and then occurs spontaneous
cyclization between the carbonyl group and the amine group to form the
isoquinoline 105 via the intermediate 103 (ii) (Scheme 16).
Scheme16. Preparation of isoquinoline by Bischler-Napieralski reaction in presence of

PPA
The acylation of the aromatic ring of homoveratrylamine 106 with

carboxylic acid 107 in PPA leads to the formation of enamines of isoquinoline 109
(a-d) via the adduct 108 (Scheme 17). The 1H NMR spectra clearly shows that 109
is obtained as a mixture of E and Z isomers. Reduction with NaBH 4 in MeOH
affords the corresponding tetrahydroisoquinolines 110 (unspecific yield) while the
oxidation with KMnO 4 in CHCl 3 in the presence of 18-crown-6 gives
dihydroisoquinolones 111(unreported yield).

Scheme17. Acylation of the aromatic ring of homoveratrylamine 106 with carboxylic acid
107
These results have provided a convenient procedure for the synthesis of

isoquinoline enamides as important intermediates in alkaloid synthesis. This
method has been applied for the synthesis of the alkaloid xylopinine 115 in two
steps (Scheme 18). The amine 112 is made to react with homoveratric acid 113 in
PPA at 80 0 C for 5 h to obtain 2,3,10,11-tetramethoxy- 8-oxoprotoberberine 114
which on treatment with POCl 3 followed by reduction with NaBH 4 in methanol
affords the alkaloid xylopinine (2,3,10,11-tetramethoxyberberine) 115.
Scheme 18. Synthesis of the alkaloid xylopinine 115
PPA suffers from several drawbacks. As 10 to 50 fold excess of acid is

generally employed, it is difficult to pour and stir at room temperature, it is
necessary to neutralize the reaction mixture very before the product extraction.
PPA/SiO 2 has been used as an efficient heterogeneous catalyst for many organic
transformations. Recently it has been shown (Manolov et al., 2013) the use of

silica-supported polyphosphoric acid in the synthesis of tetrahydroisoquinoline
derivatives as depicted in Scheme 19. The amine 116, obtained from the amino
acetaldehyde dimethylacetal and 1,2-dimethoxybenzene, on acetylation with acid
chlorides or sulfochlorides affords the amides 117 which on cyclization with
PPA/SiO 2 yield substituted isoquinolines 118. The catalyst is recovered
quantitatively without significant loss of activity the cyclization is also obtained
with MeCOOH: CF3COOH (4:1) but the yields are lower, and the reaction times are
larger. The catalyst is recovered quantitatively without significant loss of activity.
Scheme 19. Synthesis of tetrahydroisoquinoline

PPA has been utilized for the construction of a new tricyclic ring system
containing 1,5-benzooxazepine fused with an imidazolone ring (Stainisheva etal.,
2017). The synthetic details are given below (Scheme 20). The transformation of
benzoxazolone derivative 119 to the imidazolone derivative 120 is achieved two
steps (alkylation with chloroacetate and treatment with methylamine in n-propanol).
Alkylation of 120 with ethylbromoacetate affords 121 which on alkaline hydrolysis
yields acid 122 in quantitative yield. The intramolecular cyclization of 122 with
PPA furnishes oxazepinedione 123. Many oxazepinediones have been prepared by
changing the substituents e.g.: R 2 = Cl, R 1 =Cl, N-Bz etc.
Scheme 20. The intramolecular cyclization of 122 to obtain the oxazepinedione 123
One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Polyphosphoric acid as a catalyst has proved useful for a one-pot synthesis
(Zhao etal.,2015) of 3,4-dihydropyrimidin- 2(1H)-one (DHPMS) 130-133 in good
yield by grinding a mixture of aromatic aldehydes 124-127, ethyl acetoacetate 128
(R= Et, Me) and urea 129 under solvent-free condition (Scheme 21). The reactions
are carried out at room temperature. Many DHPM S have been prepared by using
different aldehydes. Scheme 21 shows the synthesis of some DHPM S by using
different aldehydes and different esters. Many important procedures are known for
the synthesis of DHPMs (Whaley & Govindachari, 1951). The present method is a
simple, time saving, and high yielding process. It has been observed that the
different moles ratio of the substrate has some effect on the reaction system. When
the mole ratio of aldehyde, β-ketoester, and urea is 1:1:1.5 the yield of DHPMs is
highest. The influence of the amount of catalyst on the reaction yield has also been
studied. The presence of 0.1 mmol of PPA as a reaction mediator per mmol of
reactions provides a higher yield; a higher amount of PPA does not improve the
result to a great extent. DHPM S and their derivatives exhibit a wide range of
therapeutical and pharmacological properties such as calcium channel blockers,
anti-tumor, anti-bacterial and anti-inflammatory behavior (Yang etal., 2021; Yang
etal., 2020).
Scheme 21. One pot synthesis of 3,4-dihydropyrimidin-2(1H)-one (DHPMs)
Synthesis of Carbonyl Containing Dihydrobenzofurans and Dihydrobenzopyrans

The carbonyl containing O-allyl phenols and O-prenyl phenols undergo
cyclization activated by PPA to yield dihydrobenzofurans and dihydrobenzopyrans
respectively (Yang etal. 2021). Dihydrobenzofuran and dihydrobenzopyran systems
are found in a variety of biologically active compounds and exhibit significant
biological activities such as antigen toxic, antiproliferative, anticancer etc. The
optimized reaction condition consists in heating the O-allyl and O-prenyl phenols
(1 equiv.), and PPA (5 equiv.) in DMF at 130 0 C for 10 hrs. Under a normal
atmosphere. In some cases, the reaction conditions are changed. The allyl phenols
134-136 undergo cyclization with PPA providing dihydrobenzofurans 137-139

respectively (Scheme 22). The possible mechanism of the cyclization is depicted in
Scheme 23.
Scheme 22. Cyclization of O-allyl phenols 134-136 to dihydrobenzofurans 137-139 respectively
Scheme 23. Mechanism of the cyclization of O-allyl phenol 134 to dihydrobenzofuran

137
Firstly, phosphorylate adduct 134A is formed from the allyl phenol 134 on
heating with PPA. Electron delocalization within π-π conjugated 134A due to more
polarized the O-H and better stabilization of the negative charge on the oxygen
atom form the intermediate 134 B. Finally, the nucleophilic attack leads to the
desired product dihydro furane 137. Similarly, the prenyl phenols 140-142 undergo
cyclization with PPA to yield dihydrobenzopyrans 143-145 respectively (Scheme
24).

Scheme 24. Cyclization of prenyl phenols 140-142 to dihydrobenzopyrans 143-145 respectively
Exist methods for the cyclization of carbonyl-containing ortho-allyl and
ortho-prenyl phenols with sulfuric acid, hydrochloric acid, p-toluenesulfonic acid,
trifluoroacetic acid, aluminium chloride and zirconium tetrachloride (Yang
etal.,2020). However, these reported methods suffer several disadvantages such as
the formation of unsatisfactory products, require long reaction time. The optimized
condition exists in the use of carbonyl product (1 equiv.), PPA (5 equiv.) in
dimethylformamide at 130 0 C for 10 hrs. under a normal atmosphere.
Synthesis of Coumarins
The formations of 3,4-disubstituted coumarins 151-152 have been reported
(yang etal., 2021) on heating the substituted salicylaldehydes 146-148 and acetic
anhydrides 149 respectively with PPA.
Scheme 25. Synthesis of substituted coumarins
These coumarins have also been formed by employing well-known reactions

e. g. Pechmann reaction, Knoevenagel condensation, Wittig reaction etc. (Yang etal.
2020). Most of these methods suffer from some drawbacks including limited
substrate scope and sometimes necessity of multistep reactions. The method (Yang

etal., 2021) promoted by PPA is convenient than the published procedures for the
synthesis of coumarins. The reaction performed in EtOH, THF, 1,4- dioxane or
DMSO does not give the desired product. The optimized reaction condition consists
in the use of substituted salicylaldehydes (1 equiv.), acetic anhydride (2 equiv. in
DMF) at 145 0 C for 3 hrs. under nitrogen atmosphere. The natural and synthetic
products which contain coumarin ring system exhibit diverse bioactivities such as
anti-oxidant, anti-inflammatory, anti-cancer, anti-tuberculosis, anti-coagulant etc.
Synthesis of Benzofuro [2,3-b] and 6H-Indolo [2,3-b] quinoline Cores

Several indoles (153-155) can be made to react with 1-methoxy-2-(2-
nitrovinyl)-benzene (156-158) using PPA at 80-110 o C (Aksenov etal., 2021) to
yield benzofuro [2,3-b] quinolines. In Scheme 26, the reaction of indoles (153-155)
with only nitrovinyl benzene 156 has been discussed. To the resulting complex is
added pyridine and heated at 320 o C to yield Benzofuro [2,3-b] quinolines 159A-
159C (Scheme 26). Although the method does not provide good yield, it allows all
synthetic operations to be carried out in a single operation instead of multiple step
sequence. Similarly, many other benzofuro quinolines have been obtained by the
reaction of the indoles (153- 155) with nitrovinyl benzene (154 and 156).
Scheme 26. Synthesis of benzofuro [2,3-b] quinolones
The mentioned method has also been applied for the synthesis of the indole
alkaloid neocryptolepine 163. The synthetic route is described in Scheme 27. A
mixture of the indole 160 and the nitrostyrene 161, if heated with PPA at 110-130 0 C
and Sn foil (3 equiv) followed by further heating for 2 hrs. at 180 0 C, yields
norcryptolepine 162 which on methylation affords neocryptolepine 163.
Scheme 27. Synthesis of norcryptolepine and neocryptolepine
In conclusion a novel approach has been developed for the synthesis of

benzofuro [2,3-b] quinolines and 6H-indole [2,3-b] quinolines by PPA assisted

cyclization. This unusual process involves the alkylation of indoles with
nitroalkenes, subsequent rearrangement into 3-aryl-2-quinolines and annulation of
five-membered ring (furan or pyrrole) to give the tetracyclic core. The
transformation is quite efficient if one considers the number of steps performed in a
single step. In addition, it offers an alternative to the known multi-step process.
Synthesis of Pyrrolo [1,2-a] Quinoxalines from Chalcones

PPA has been extensively used for the synthesis of several pyrrolo [1,2-a]
quinoxalines (Togiti etal., 2021). These compounds exhibit antitumor properties as
well as central dopamine antagonists.
The method consists in the treatment of chalcones e. g. 164-167 with Tosmic (p-
toluenesulfonyl methyl isocyanide) and potassium t-butoxide in DMSO at 25 0 C to
obtain 2,3-disubstituted pyrroles 168-171 respectively (Scheme 28). The resulting
pyrroles suffer rearrangement with PPA at 110oC to yield 2,4-disubstituted pyrroles
172-175 which are subjected to SNAr reaction using 1-fluro-2-nitrobenzene 176,
potassium t-butoxide (as base) and DMSO (as solvent) to obtain [1- (2-
nitrophenyl)-4-phenyl-1H-pyrrol-2-2yl(phenyl) methanone 177-180. These
methanones undergo cyclization with Fe (5 equiv), MeCOOH at 110 0 C to yield 2,4-
disubstituted pyrrol [1,2-a] quinoxalines 181-184 respectively. The cyclization tried
with sodium borohydride and nickel chloride and sodium dithionate does not afford
satisfactory yield.
Scheme 28. Synthesis of pyrrol [1,2-a] quinoxalines from chalcones
Synthesis of Benzonaphtho Naphthyridines

The use of PPA has been recorded (Prabha etal. 2021) during the synthesis
of benzonaphtho naphthyridines from 2,4- dichloroquinolines. The synthetic route
is depicted in Scheme 29.
Amination of 2,4-dichloroquinolines (185-187) with 1-naphthylamine 188
using CuI as catalyst leads the formation monosubstituted (189-191) and
disubstituted (192-194) naphthylamino quinolines respectively. The
aminoquinolines (189- 191) are converted into the linear benzo [g]naphtho [1,2-
b][1,8]naphthyridines (195-200) respectively by heating with PPA and acetic acid.
P-toluic can also be used instead of acetic acid. On similar treatment disubstituted
(192-194) aminoquinolines yield angular benzo [b]naphtho [2,1-
h][1,8]naphthyridines (201-206) respectively. The naphthyridines,
benzonaphthyridines and dibenzonaphthyridines display notable biological
activities such as CB2 selective agonists, anti- HIV, anticancer, selective 3-
phosphoinositide-dependent kinase-1 inhibitors.
Scheme 29. Synthesis of benzonaphtho naphthyridines
Synthesis of Benzo [H]carbazole [3,2-b] [1,6]Naphthyridines

PPA has been utilized in the development of an efficient synthesis
(Ezhumalai etal. 2022) of benzo [h]carbazole [3,2-b] 1,6] naphthyridines which are
useful for the synthesis of heterocyclic drugs. In order to achieve the desired
product, the 3-amino-9-ethylcarbazole 207 in DMF is made to react with 2-methyl-
4-chloroquinoline 208 using CUI as promoter to obtain 3-(N-(2-methylquinoline-4-
yl)amino)-9-ethyl-9H-carbazole 209 (R 1 =Me, R 2 = H) (Scheme 30). The resulting
carbazole is cyclized by heating with benzoic acid in presence of catalytic amount

of PPA to obtain only linear1,6- naphthyridine 210. By similar procedure the
naphthyridines 211 and 212 can be prepared. No angular naphthyridine is obtained.
The cyclization carried out without benzoic acid affords no desired result. The
benzoic acid can be replaced by p-toluic acid. The reaction time should be
significantly reliant on benzoic acid substituent. The presence of a methyl group at
para position of the phenyl ring aids reaction rate and increases product yield
significantly.
Scheme 30. Synthesis of 12-Aryl-9-ethyl-6-methyl-7.phenyl-9H-benzo[h]carlazol[3,2-

b][1,6]naphthyridines(4,5)
Synthesis of Benzimidazoles with Naphthalene Moiety

The utility of PPA as catalyst has been recorded in relation to the synthesis
(Ersan etal., 2020) of naphthyl-substituted benzimidazole under microwave
irradiation and conventional synthetic methods. These compounds show
antimicrobial activity. In order to develop the synthesis of benzimidazole
derivative, a mixture of the diamine 213, naphthalene carboxylic acid 214 and PPA
is stirred and irradiated (100-150 W) to obtain the naphthalene substituted
benzimidazole 215. Similarly, the diamines (216-219) are mixed with hydroxy
diacid 220 in presence of PPA and irradiated to obtain the naphthalene substituted
imidazoles (221-224) respectively (Scheme 31).

Scheme 31. Synthesis of benzimidazoles with naphthalene moiety compounds
The condensation carried out by conventional heating affords low yield and
requires more time. The structures of the products have been established on the
basis of spectral data. The compounds also have been screened for their
antimicrobial activity.
Synthesis of 2-arylquinolines
The importance of quinoline derivatives in the development of new
pharmaceuticals is well known. Several alkaloids contain the quinoline fragment
and most of these structures exhibit varied biological activity. Many approaches
have been developed for the synthesis of quinoline ring. It has been observed
(Grishin etal. 2022 that direct acylamination of arenes with nitro alkenes in PPA
followed by acylation leads the formation of 2-arylquinolines. Under this condition
the disubstituted arene 225 (Scheme 32) reacts with nitroalkene 226 (R=Et or Me)
in PPA and yield the acetanilide 227 which with acetic acid in PPA medium
furnishes quinoline 228. The formation of the quinoline 229 has not been detected.
Following the similar procedure, the transformations of the arenes 230 and 232 to
the quinolines 231 and 233respectively have been achieved. The O-

acetylacetanilides generated in situ undergo a series of cascade transformations
leading the formations of 2-(2-acylaminoaryl) quinolines.
Scheme 32. Synthesis of 2-aryl-quinolines

SOLVED PROBLEMS 04
35) Problem 01-07: Give the reaction for preparation of isoquinoline by the
Bischler-Napieralski reaction in presence of PPA.
Solution:
36) Problem 01-08: Demonstrate synthesis of cyclohexenone ring from following

alkenyl acids.
Solution:

35) SAQ 01-07: Choose the correct option for the Product obtained in the following
transformation.
O
PPA
?
Ph
O O
A) B) C) D) O
Ph
Ph Ph
Answer: Correct option is A
36) SAQ 01-08: The powerful dehydrating properties of PPA, low nucleophilicity
of the phosphoric acid media, and moderate acidity explain why this reagent is so
widely used.
Answer: Unlike Sulfuric Acid, PPA has a low propensity to cause oxidation of the
substrate and is also able to dissolve organic compounds. PPA has demonstrated
rates of dehydration equal to that of 100% sulfuric acid even though it is a much
weaker acid.
CHECK POINT 02-01

1) Diphenylfurans are formed in higher yields with PPA than with
…….,………or…………..as the dehydrating/cyclization agent
2) LDA can also be used for the formation of “……….” products in elimination
reactions.
3) DCC has frequently been used both as a……….. and as a …………..in the
synthesis of heterocycles.
4) LTA is one of the most frequently used reagents for the cleavage of ……….and
for the preparation’s ………compounds.
SUMMARY
 Lithium diisopropylamide can be used for the generation of carbanion or enolate
anions from carbonyl group-containing compounds.
 It can also be used as a base in:
 The direct alkylation and acylation of ketones.
 The aldol condensation reaction.
 α-Selenation reaction.
 Synthesis of α, β- unsaturated carbonyl compounds from carbonyl
compounds.
 The alkylation of acids, esters, amides, and nitriles.

 The initiation of anionic polymerization.
 DCC (N, N’-Dicyclohexylcarbodiimide) is a useful reagent for the formation of
amides from amines and carboxylic acids. Its most common application is in
the synthesis of peptides from amino acids. It sequesters one molar equivalent
of water, resulting in a dicylohexyl urea byproduct. It can also be used for the
formation of esters from carboxylic acids.
 Lead tetraacetate (LTA), a versatile oxidizing agent for different functional
groups, has been widely used for oxidative decarboxylation of carboxylic acid,
cleavage of 1,2-diol, formation of the cyclic ether, acetoxylation, methylation,
dehydrogenation etc. The present micro review describes the utility of LTA in
1,2-glycol-cleavage and decarboxylation of carboxylic acid.
 The commercially available LTA is hygroscopic and turns brown due to the
formation of lead oxide. Therefore, LTA should be stored in absence of moisture,
kept tightly sealed and stored under 10 0 C in the dark and in the presence of
about 5% glacial acetic acid. LTA is very toxic and may be absorbed through the
skin. Due to the high toxicity the reagent should be handled with care in
chemical fume hood. It is soluble in hot acetic acid, benzene, cyclohexane,
chloroform, etc.
 Polyphosphoric acid (PPA), a powerful dehydrating agent, has been widely used
to perform several important organic reactions and thus has played an important
role in the synthesis of organic compounds and natural products. The PPA is
used:
i) In the cyclization of acids on the aromatic ring
ii) In acetylation and isopropylation on the aromatic ring,
iii) Hydrolysis of esters,
iv) Cleavage of epoxides and
v) Synthesis of heterocyclic compounds.
KEY WORDS:
LDA, DCC, LTA, PPA

1) sulfuric acid, Acetic Anhydride, or phosphorus pentoxide
2) Hoffman
3) reagent; reactant
4) glycols; carbonyl
REFERENCES

YOUTUBE VIDEOS
https://www.youtube.com/watch?v=vBtXxjuY3sA
https://www.youtube.com/watch?v=4Eestb4V4ro
https://www.youtube.com/watch?v=yDe-kSES0pM
https://www.youtube.com/watch?v=7E1_c852Cqc
WIKIPEDIA
https://en.wikipedia.org/wiki/Lithium_diisopropylamide
https://en.wikipedia.org/wiki/N,N%27-Dicyclohexylcarbodiimide
https://en.wikipedia.org/wiki/Lead(IV)_acetate
https://en.wikipedia.org/wiki/Phosphoric_acids_and_phosphates
REFERENCE BOOKS
1. Encyclopedia of reagents for organic synthesis
2. Reagent in organic synthesis. Fieser & Fieser [Unit II, III]
3. Principle of organic synthesis. R.O.C. Norman [Unit II, III]
4. Organic reactions. R. Admas Advances in organometallic Chemistry. Stone
& West [Unit III]

CREDIT02-UNIT 02: REAGENTS AND REACTION IN SYNTHESIS-2
LEARNING OBJECTIVES
 Evaluate skilled in reaction mechanism of different synthetic reagents and

metals.
 Discuss the use of transition metal based and other catalysts for different organic
reactions.
 Describe the use of reagents for different reaction transformations.
INTRODUCTION
To learn how to use reactions in synthesis, instructors’ various types of

question. Some, such as “give the reagent” help the student to learn what is needed to
turn A into B. Others, like “predict the product,” help the student to use their knowledge
of mechanism and reaction specificity to work out which product will form, with what
stereochemistry, etc.
The last type, the open-ended synthesis question, is the hardest for beginners,
even though there may be now several correct answers. To answer such questions, you
need to be able to work back from the product, something that is hard at first but which
becomes easy with practice.

02-01: DIAZOMETHANE
Methylation of Heteroatoms
The most widely used feature of the chemistry of diazomethane is the
methylation of carboxylic acids. Carboxylic acids are good substrates for reaction
with diazomethane because the acid is capable of protonating the diazomethane on
carbon to form a diazonium carboxylate. The carboxylate can then attack the
diazonium salt in what is most likely an S N 2 reaction to provide the ester. Species
which are not acidic enough to protonate diazomethane, such as alcohols, require an
additional catalyst, such as Boron Trifluoride Etherate, to increase their acidity
and facilitate the reaction. The methylation reaction proceeds under mild conditions
and is highly reliable and very selective for carboxylic acids. A typical procedure is
to add a yellow solution of diazomethane to the carboxylic acid in portions. When
the yellow color persists and no more gas is evolved, the reaction is deemed
complete. Excess reagent can be destroyed by the addition of a few drops of acetic
acid and the entire solution concentrated to provide the methyl ester.
Esterification of Carboxylic Acids and Other Acidic Functional Groups

A variety of functional groups will tolerate the esterification of acids with
diazomethane. Thus α, β-unsaturated carboxylic acids and alcohols survive the
reaction (eq 1), as do ketones (eq 2), isolated alkenes (eq 3), and amines (eq 4).

Other acidic functional groups will also undergo reaction with
diazomethane. Thus, phosphonic acids (eq 5) and phenols (eq 6) are methylated in
high yields, as are hydroxy tropolones (eq 7) and vinylogous carboxylic acids (eq
8). The origin of the selectivity in eq 6 is due to the greater acidity of the A-ring
phenol.
Selective monomethylation of dicarboxylic acids has been reported using

Alumina as an additive (eq 9). It is thought that one of the two carboxylic acid
groups is bound to the surface of the alumina and is therefore not available for
reaction. Carboxylic acids that are engaged as lactols will also undergo methylation
with diazomethane to provide the methyl ester and aldehyde (eq 10).

Methylation of Alcohols and Other Less Acidic Functional Groups.
As previously mentioned, alcohols require the addition of a catalyst in order to

react with diazomethane. The most commonly used is boron trifluoride etherate (eq
11), but Tetrafluoroboric Acid has been used as well (eq 12). Mineral acids are not
effective since they rapidly react with diazomethane to provide the corresponding
methyl halides. Acids as mild as silica gel have also been found to be effective (eq
13). Monomethylation of 1,2-diols with diazomethane has been reported using
various Lewis acids as promoters, the most effective of which is Tin (II) Chloride
(eq 14).
An interesting case of an alcohol reacting with diazomethane at a rate

competitive with a carboxylic acid has been reported (eq 15). In this case, the
tertiary structure of the molecule is thought to place the alcohol and the carboxylic
acid in proximity to each other. Protonation of the diazomethane by the carboxylic
acid leads to a diazonium ion in proximity to the alcohol as well as the carboxylate.
These species then attack the diazonium ion at competitive rates to provide the

methyl ether and ester. No reaction is observed upon treatment of the corresponding
hydroxy ester with diazomethane, indicating that the acid is required to activate the
diazomethane.
Amides can also be methylated with diazomethane in the presence of silica gel;
however, the reaction requires a large excess of diazomethane (25-60 equiv, eq 16).
The reaction primarily provides O-methylated material; however, in one case a
mixture of O- and N-methylation was reported. Thioamides are also effectively
methylated with this procedure to provide S-methylated compounds. Finally,
amines have been methylated with diazomethane in the presence of BF 3 etherate,
fluoroboric acid, or copper (I) salts; however, the yields are low to moderate, and
the method is not widely used.
The Arndt-Eistert Synthesis.

Diazomethane is a useful reagent for the one-carbon homologation of acid
chlorides via a sequence of reactions known as the Arndt-Eistert synthesis. The first
step of this sequence takes advantage of the nucleophilicity of diazomethane in its
addition to an active ester, typically an acid chloride, to give an isolable a-diazo
ketone and HCl. The HCl that is liberated from this step can react with
diazomethane to produce methyl chloride and nitrogen, and therefore at least 2
equiv of diazomethane are typically used. The a-diazo ketone is then induced to
undergo loss of the diazo group and insertion into the adjacent carbon-carbon bond
of the ketone to provide a ketene. The ketene is finally attacked by water or an
alcohol (or some other nucleophile) to provide the homologated carboxylic acid or
ester. This insertion step of the sequence is known as the Wolff rearrangement and
can be accomplished either thermally (eq 17) or, more commonly, by treatment with
a metal ion (usually silver salts, eq 18), or photochemically (eq 19). It has been
suggested that the photochemical method is the most efficient of the three. As eq 18
and 19 illustrate, retention of stereochemistry is observed in the migrating group.
The obvious limitations of this reaction are that there must not be functional groups
present in the molecule which will react with diazomethane more rapidly than it
will attack the acid chloride. Thus, carboxylic acids will be methylated under these

conditions. Furthermore, electron-deficient alkenes will undergo [2,3] dipolar
cycloaddition with diazomethane more rapidly than addition to the acid chloride.
Thus, when the Arndt-Eistert synthesis is attempted on α, β-unsaturated acid
chlorides, cycloaddition to the alkene is observed in the product. In order to prevent
this, the alkene must first be protected by addition of HBr and then the reaction
carried out in the normal way (eq 20). Cycloaddition to isolated alkenes, however,
is not competitive with addition to acid chlorides.
Other Reactions of a-Diazo Ketones Derived from Diazomethane.

Depending on the conditions employed, the Wolff rearrangement may
proceed via a carbene or carbenoid intermediate, or it may proceed by a concerted
mechanism where the insertion is concomitant with loss of N 2 and no intermediate
is formed. In the case where a carbene or carbenoid is involved, other reactions
which are characteristic of these species can occur, such as intramolecular
cyclopropanation of alkenes. In fact, the reaction conditions can be adjusted to
favor cyclopropanation or homologation depending on which is desired. Thus,
treatment of the dienoic acid chloride shown in eq 21 with diazomethane followed
by decomposition of the a-diazo ketone with silver benzoate in the presence of
methanol and base provides the homologated methyl ester. However, treatment of
the same diazoketone intermediate with Cu (II) salts provides the cyclopropanation
products selectively. This trend is generally observed; that is, silver salts as well as
photochemical conditions (eq 18 and 19) favor the homologation pathway while
copper or rhodium salts favor cyclopropanation. Using copper salts to decompose
the diazo compounds, hindered alkenes as well as electron-rich aromatics can be
cyclopropanated as illustrated in eq 22 and 23respectively.

SOLVED PROBLEMS 01
37) Problem 02-01: Explain the mechanism of the reaction of carboxylic acid and
diazomethane (CH 2 N 2 ). And other reactions carried out using diazomethane
Solution:
38) Problem 02-02: Explain the Wolff Rearrangement

Solution:
37) SAQ 02-01: Draw a proper Lewis structure for diazomethane, CH 2 N 2 .

Answer: Lewis structure for diazomethane, CH 2 N 2 .

38) SAQ 02-02: How carboxylic acids can be made into methyl esters by treating
them with the reagent diazomethane, CH 2 N 2 ?
Answer:
02-02: OZONE
Ozone (O 3 ) is a Powerful Oxidant for Cleaving Alkenes to Carbonyl
Compounds.
Ozone does more than absorb UV radiation in the upper atmosphere and
cause breathing problems in traffic-clogged cities. It’s a powerful oxidant, and
since its discovery in the mid 1800’s by (Schönbein) has found use in the cleavage
of carbon-carbon multiple bonds.
Here’s the pattern for the reaction of alkenes with ozone:
Note that the carbon-carbon double bond is broken and we are forming a
carbon-oxygen double bond on each of the two carbons that originally composed
the alkene. The second step in ozonolysis is called the “workup”. There are two
different types of workups and the most common is referred to as “reductive
workup” In this step, we add a reducing agent (commonly zinc metal or dimethyl

sulfide) that decomposes the intermediate formed at the end of the ozonolysis
reaction (called an “ozonide” by the way).
Ozonolysis with “Reductive Workup” – All C–H Bonds Are Preserved
Using “reductive workup” preserves all other aspects of the molecule except
for the double bond. So, if we start with, say, a trisubstituted alkene, as in the
example below, we will end up with a ketone and an aldehyde.
[What happens if the alkene carbon is attached to two hydrogens? It becomes
formaldehyde H 2 C=O, which is then further converted to carbon dioxide CO 2 ]
Note that here written although (CH 3 ) 2 S as the reductant here, it’s
essentially interchangeable with Zn for our purposes.
Ozonolysis of a Ring results in a Chain with Two Carbonyls:

An interesting consequence of ozonolysis is that if the alkene is within a
ring, you end up with a chain containing two carbonyls:
Each of the carbons in the alkene have formed C=O bonds.

Note that the numbering here is not IUPAC – it’s just for keeping track of the
atoms.
Ozonolysis of a Compound with Multiple Bonds results in Several Fragments:

If your molecule has multiple alkenes, then you will end up with more than
two fragments. For many years ozonolysis was used as a method for the structure
determination of unknown molecules.
By analyzing the fragments, it is then possible to deduce what the original structure
was, through “stitching” together the fragments. Here’s one example:

Ozonolysis with Oxidative Workup converts Aldehydes to Carboxylic Acids:
There is a second type of workup that can be used, referred to as oxidative
workup. Instead of using Zn or S(CH 3 ) 2 , if we use the oxidant hydrogen peroxide
[H 2 O 2 ], any aldehydes that form will be oxidized to give carboxylic acids.
The C-H bond is oxidized to C-OH, but all the other bonds remain intact.
SOLVED PROBLEMS 02
39) Problem 02-03: Write the products of ozonolysis
Solution: This is ozonolysis with reductive workup. The reaction breaks the C=C
bond and results in two new carbonyls (C=O)
40) Problem 02-04: Write the products of following reaction

CH3
O3
CH3 C CH CH3 ?
Zn/H2O
Solution: This is ozonolysis with reductive workup. The reaction breaks the C=C
bond and results in two new carbonyls (C=O)

CH3 CH3
O3
CH3 C CH CH3 CH3 C O O C CH3
Zn/H2O
H

39) SAQ 02-03: Complete the following reaction
Answer: Ozonolysis breaks the C=C bond and results in two new carbonyls (C=O) .
40) SAQ 02-04: Draw the reactant for this ozonolysis reaction
Answer: Knowing that ozonolysis breaks C=C bond and forms two new C=O, we
can just apply these rules in reverse to get back the initial product.
02-03: PHASE TRANSFER CATALYST

Since its introduction around 1965, phase transfer catalysis (PTC) has
become a firmly established technique in synthetic organic chemistry. Many
reviews on synthetic methods using phase transfer catalysts have been published
(Brandstrom, 1977; Dehmlow and Dehmlow, 1993; Weber and Gokel, 1977; Starks,
1994; Freedman, 1986). One of the major concerns in using a phase transfer
catalyst (PTC) in soluble form is its separation from the reaction mixture. For
efficient use of the catalyst and to meet product purity requirements, synthetic
techniques using PTCs involve an additional separation for catalyst isolation and
product purification.
There are many desirable reactions which cannot be brought about because
of the reactants are inaccessible to each other. The crucial difficulty of bringing
together a water soluble nucleophilic reagent and an organic water insoluble
electrophilic reagent has been traditionally solved by the addition of a solvent that

is both water-like and organic-like (such as ethanol, which derives its hydrophilic
nature from its hydroxyl group and its lipophilicity from the ethyl group). The
transfer rate is very high by increasing the area of the interface. Phase-Transfer
Catalysis (PTC) is a well-known method of promoting reactions between reagents
with opposite solubility preferences. In such systems each reactant is dissolved in
the appropriate solvent. Commonly, the two solvents are immiscible to one another,
and then a phase-transfer catalyst is added to facilitate the transport of one reactant
into the other phase. By means of the catalytic step, the enhanced reactivity
between the ionic species leads to increase of the rate of the desired reaction. The
foundations of PTC were laid in the late 1960s and early 1970s from the studies of
Makosza (1975), Starks (1971), and Brandstrom (1977). Starks is believed to have
coined the phrase phase transfer catalysis, and although some would tend to
disagree with calling the PT cycle a catalytic process in the true sense of the word
catalysis, the terminology has been well established and stays, especially since only
catalytic amounts of the phase-transfer agents are required for effective phase-
transfer action.
TYPES OF PHASE-TRANSFER CATALYSTS

There are many types of phase transfer catalysts, such as quaternary
ammonium and phosphonium salts, crown ethers, cryptands, etc. Among these, the
quaternary ammonium salts are the cheapest and hence the most widely used in the
industry.
PRINCIPLE OF PHASE-TRANSFER CATALYSIS

The principle of phase transfer catalysis (PTC) is brought forth well by
Reuben and Sjoberg (1981). The principle of PTC is based on the ability of certain
phase-transfer agents. (PT catalysts) to facilitate the transport of one reagent from
one phase into another (immiscible) phase wherein the other reagent exists. Thus,
reaction is made possible by bringing together the reagents which are originally in
different phases. However, it is also necessary that the transferred species is in an
active state for effective PT catalytic action, and that it is regenerated during the
organic reaction.

MECHANISMS OF PTC
The mechanism of PTC reaction was first proposed in 1971. According to
Starks’ original work, a quaternary ammonium halide dissolved in the aqueous
phase (Q+X-) undergoes anion exchange with the anion of the reactant dissolved in
the aqueous solution. The ion-pair formed (Q+X-) can cross the liquid-liquid
interface due to its lipophilic nature and diffuses from the interface into the organic
phase, this step being the ‘phase-transfer’. In the organic phase, the anion of the
ion-pair being quite nucleophilic undergoes a nucleophilic substitution reaction
with the organic reagent forming the desired product (RY). The catalyst
subsequently returns to the aqueous phase and the cycle continue. An overview of
PTC reactions is given in the scheme bellow:
PTC of uncharged species: Complexation and transfer of uncharged protic species

or metal salts into the organic medium as complexes of the phase –transfer
agent.
Electron-transfer catalysis: For Redox systems
Metal ion-transfer: From aqueous solutions into water immiscible ionic liquids
containing neutral complexing agents.
Pyrolytic alkylation process: For thermal decomposition of a quaternary
ammonium salt yields a volatile alkyl derivative in the heated injector of a
gas chromatography.
Example:
If the primary chloride is used, only the S N 2 reaction normally occurs so
that once again we get nucleophilic attack at the primary centre and the more stable
product with the more highly substituted alkene.
This example is interesting because the starting material contains an acetal

as well as a primary alcohol group. Acetals are very easily destroyed by acid so the
conditions must be kept strictly alkaline. NaOH does this, but it is insoluble in

organic solvents. The method shown here uses a two-phase system of water and
dichloromethane (DCM or CH 2 Cl 2 ). The organic molecules are in the DCM layer
and the NaOH is in the water layer.
The tetra alkyl ammonium salt has a polar group (N+) and hydrocarbon side
chains (butyl groups). The ammonium salt allows a low concentration of hydroxide
ions to pass into the DCM layer where they act as a base catalyst for the reaction.
This method is called PTC because the tetra alkyl ammonium salt acts as a PT
agent, allowing ions to pass into the organic phase. The ether product is, of course,
soluble in the organic phase and the work-up is very simple-separation of the
phases removes unchanged NaOH and the inorganic by-product, NaCl.
Inorganic Base-Promoted Activation of Acidic Organic Compounds:

The representative reaction system applied in asymmetric PTC is the
biphasic system composed of an organic phase containing an acidic methylene or
methine compound and an electrophile, and an aqueous or solid phase of inorganic
base such as alkaline metal (Na, K, Cs) hydroxide or carbonate. The key reactive
intermediate in this type of reaction is the onium carbanion species, mostly onium
enolate or nitronate, which reacts with the electrophile in the organic phase to
afford the product.
Generation of Reactive Onium Carbanion Species:

The exact pathway for generating the reactive onium carbanion species
remains the subject of controversy, typically among Starks extraction mechanism
and the Makosza interfacial mechanism. In the Starks extraction mechanism, the
PTC moves back and forth across the organic and aqueous phases. The onium salt
equilibrates with the inorganic base in the aqueous phase, and extracts hydroxide
into the organic phase. The onium hydroxide then abstracts hydrogen from the
acidic organic compound to give the reactive intermediate Q + R – . The advocated
pathway of the interfacial mechanism is the first formation of metal carbanion at
the interface of organic and aqueous phase in the absence of PTC, followed by the
extraction of the formed metal carbanion species from the interface into the organic
phase by the action of PTC. Since asymmetric PTC’s normally contain highly
lipophilic chiral organic frameworks, and are reluctant to enter the aqueous phase,

the Makosza interfacial mechanism seems possible. Clearly, the area of the
interface and the basicity of the inorganic salt affect the amount of available onium
carbanion. It should be also noted that an excessively lipophilic PTC would hardly
access the interface, and consequently the use of such a catalyst would result in an
insufficient reaction.
Starks Extraction Mechanism:
Makosza Interfacial Mechanism:
Stability of the Onium Carbanion:

The onium carbanion formed under PT conditions is unstable depending on
the anion source, and in the absence of an electrophilic reaction partner,
degradation of the accumulated onium carbanion in the organic phase may be
observed. This is known to proceed via Hoffman elimination, nucleophilic
substitution and/or Stevens’s rearrangement. The direct decomposition of onium
salt, as influenced by the strong inorganic base at the interface, may be also
operative.
Stevens Rearrangement

Reactivity of the Onium Carbanion:
Cation exchange from the metal cation to the onium carbanion improves the
intrinsic reactivity of the latter due to formation of the naked anion. At the same
time, the onium carbanion in the organic phase is less hydrated compared to the
metal carbanion at the interface, which functions as another factor for an enhanced
reactivity of the onium carbanion.
Hoffman Elimination:
Nucleophilic Substitution:
Nucleophilic Substitution Reaction:

The fate of the onium carbanion Q + R – incorporated into the organic phase
depends on the electrophilic reaction partner. The most studied area in the
asymmetric phase transfer catalysis is that of asymmetric alkylation of active
methylene or methane compounds with alkyl halides, in an irreversible manner. The
reaction mechanism illustrated above is exemplified by the asymmetric alkylation
of glycine Schiff base.
Asymmetric Alkylation of Glycine Schiff Base:

Mechanism:
In the first step, glycine Schiff base 2 reacts with the inorganic base 1 at the
interface of two phases to give the metal enolate 3, which remains at the interface
due to its highly polar character. The metal enolate 3 then exchanges the cation to
provide onium enolate 4. The sufficiently lipophilic 4 then moves into the organic
phase to react with alkyl halide. After the reaction, onium halide is regenerated and
enters the next catalytic cycle. The key issue to be considered here is the possibility
of product racemization and dialkylation. In this example, the basicity of the
inorganic base and acidity of the substrate and product, as well as other reaction
conditions, are carefully adjusted to circumvent this problem. It should be also
noted that control of the E/Z geometry of the enolate is apparently critical to the
asymmetric induction, although there is no clear evidence about which isomer is the
actual reacting species in this case. An asymmetric SN 2 reaction and S N Ar reaction
are included as other examples of this category.
Nucleophilic Addition to Electrophilic C=X Double Bonds:

Unlike the nucleophilic substitution reactions which generate stable onium
halide after the reaction, nucleophilic additions to electrophilic C=X (X=N or O)
provide rather basic onium anion species as an initial product. If the anion is
sufficiently stable under the reaction conditions, onium anion will then exchange
the counter ion for the other metal carbanion at the interface to regenerate the
reactive onium carbanion Q + R – . In another scenario, the basic onium anion may
abstract the acidic H-atom of the other substrate to provide Q + R – directly. Such a
reaction system ideally requires only a catalytic amount of the base although, in
general, a sub stoichiometric or excess amount of the base is used to lead the
reaction to completion. An additional feature of this system is the substantial
possibility of a retro-process at the crucial asymmetric induction step, which might

be problematic in some cases. The direct asymmetric aldol reaction under PT
conditions is a representative example of this class of PT reaction, which is known
to proceed with a catalytic amount of base and to include an undesired retro-
process. The PT-catalyzed asymmetric Michael addition and the Mannich reaction
are other typical examples which fall into this category.
Alkylations are the most common application of PTC
Reactions of organic anions with electrophiles:

PTC has found wide applications in organometallic chemistry. PTC offers
convenient conditions for carbonylations
Other PTC applications in organometallic chemistry includes reductions,

hydrogenations and Heck reactions.
Generation and reactions of carbenes

Solid-liquid PTC:
Asymmetric PTC:

SOLVED PROBLEMS 03
41) Problem 02-05: Selection of appropriate reaction conditions using PTC matrix
and variable diagram, explain.
Solution:
42) Problem 02-06: Explain Darzens Reaction?

Solution:

41) SAQ 02-05: What are the advantages that PTC offers over homogeneous
alternatives?
Answer: There are number advantages that PTC offers over homogeneous
alternatives:
 The reactions are relatively easy to perform and are highly scalable. "
 PTC is "green chemistry", for this reason industrial applications are
expanding
 Usually involves inexpensive reagents (NaOH, KOH, K 2 CO 3 etc. instead
of NaH, KHMDS t-BuOK, etc.)
42) SAQ 02-06: What is the use of Crown Ether as Phase-Transfer Catalyst?
Answer: Crown ether is the other important class of PTC which critically differs
from the onium salt, in that the whole inorganic salt is transferred into the organic
phase. The reaction modes described above can generally be accommodated in such
crown ether-catalyzed reactions, simply by replacing the onium cation by a metal
cation complex of crown ether.
02-04: WOODWARD-PREVOST HYDROXYLATION
Woodward Hydroxylation reaction is the modification of the Prevost

hydroxylation reaction that involves the treatment of alkenes with iodine and
silver acetate in presence of water to form Cis-diols or cis-glycols. American
organic chemist Robert Burns Woodward was the first to report on this reaction in
1954. If you find Woodward Prevost hydroxylation in the literature, it indicates the
same Woodward hydroxylation reaction.
Woodward hydroxylation
Woodward hydroxylation vs Prevost hydroxylation

The main difference between Woodward and Prevost hydroxylation is that
Woodward hydroxylation gives Cis-diol (Syn-diol) whereas Prevost hydroxylation
gives trans-diol (anti-diol).
Mechanistically, the first step of both reactions involves the addition of
iodine to the carbon-carbon double bond of alkene to form an iodonium
intermediate followed by an attack of acetate ion (or benzoate ions), thus α-
iodoacetate is formed in both cases. This further undergoes a substitution reaction
to form a five-membered cyclic intermediate.
Now, the main difference appears here. In the case of the Woodward
reaction, water acts as a nucleophile and adds to the partially positive carbon atom
of the five-membered intermediate so that ring is opened. Whereas in the Prevost
reaction, acetate ion or benzoate ions open the five-membered ring intermediate as
shown below.
Application of Woodward hydroxylation

As stated above, the major synthetic utility of this reaction is the production
of cis-diols from alkenes. Moreover, this reaction is a stereoselective reaction
hence it can be used in the synthesis of natural products, dyes, pharmaceuticals, etc.
SOLVED PROBLEMS 04
43) Problem 02-07
Depict the mechanism of the Woodward Reaction
Solution: Similar to the Prévost Reaction, initial addition of iodine leads to a

cyclic iodonium ion, that is opened through nucleophilic substitution by acetate
anion:

A cyclic acetoxonium ion is then formed:
44) Problem 02-08

Write the reaction NaIO 4 /LiBr-mediated Diastereoselective Dihydroxylation of
Olefins: A Catalytic Approach to the Prevost-Woodward Reaction.
Solution: NaIO 4 /LiBr-mediated Diastereoselective Dihydroxylation of Olefins: A

catalytic approach to the Prevost-Woodward Reaction is shown below:

43) SAQ 02-07: Prevost Reagent, Explain.
Answer:
 Prevost reagent is a solution of iodine in carbon tetra chloride together with
an equivalent amount of dry silver acetate or dry silver benzoate
 Under anhydrous conditions this reagent converts the alkene into the
diacetyl or dibenzoyl derivatives of the trans glycol, which on hydrolysis
gives trans-diol
 This reaction is known as Prevost Reaction.
 The olefin is reacted with iodine in the presence of silver acetate or silver
benzoate.

44) SAQ 02-08: Woodward Reagent, Explain.
Answer:
 A solution of iodine and silver acetate or silver benzoate (in equimolar
amount) in moist acetic acid is known as Woodward reagent.
 It converts the alkenes into cis-1,2 diols
 In this reaction, olefin reacts with iodine in the presence of silver acetate
to give an iodonium ion which undergoes displacement by acetate ion in
the S N 2 type reaction giving trans-iodoacetate
 Anchimeric assistance by the acetate group, together with the powerful
bonding capacity of silver ion for iodine, gives a cyclic acetoxonium
ion.
 The acetoxonium ion under wet conditions traps water and reacts to
yield a cis-hydroxyacetate which on saponification yields Cis-diols.
CHECK POINT 02-02

(True or False)
1) A variety of functional groups will tolerate the esterification of acids with

diazomethane.
2) Diazomethane is a useful reagent for the one -carbon homologation of acid

chlorides via a sequence of reactions known as the Arndt -Eistert synthesis.
3) Ozone does more than absorb UV radiation in the upper atmosphere and cause
breathing problems in traffic-clogged cities.
4) The onium carbanion formed under PT conditions is unstable depending on the

anion source, and in the absence of an electrophilic reaction partner,
degradation of the accumulated onium carbanion in the organic phase may be
observed.
SUMMARY
 Diazomethane has its uses. In introductory organic chemistry, these are
primarily:
 Formation of methyl esters from carboxylic acids
 In the formation of diazo ketones, and subsequent Wolff rearrangement
 Cyclopropanation

 It is, extremely toxic and potentially explosive. In the event that you are in the
position of having to carry out a procedure with CH 2 N 2 , it should be done with
the utmost care and only with proper training and equipment.
 Ozonolysis An alternative to using ozone for oxidative workup is to use the
reagent KMnO 4 , especially in the presence of hot acid; this will lead to the same
result.
 Phase Transfer Catalyst
 Applications involving the use of a co-catalyst include co-catalysis by
surfactants, alcohols and other weak acids in hydroxide transfer reactions,
use of iodide (traditionally considered a catalyst poison has been also
reported.
 In nucleophilic substitution reactions and in reactions in the presence of
bases involving the deprotonation of moderately and weakly acidic organic
compounds.
 PTC has made possible the use of cheaper and easily available alternative
raw materials like potassium carbonate and aqueous NaOH solution, thereby
obviating the need of severe anhydrous conditions, expensive solvents, and
dangerous bases such as metal hydrides and organometallic reagents.
 When any kind of chemical reactions are carried out in the presence of a
PTC in biphasic systems, simple, cheap and mild bases like NaOH and
K2CO3 can be used instead of toxic alkali metal alkoxides, amides, and
hydrides.
 PTC can also be used for the synthesis process for fine chemicals
manufacture (agrochemicals, pharmaceutical, dyes, paper etc.). It also used
in perfumery and fragrance industry like synthesis of phenylacetic acid, an
intermediate in the perfumery industry.
 In the field of pharmaceuticals like synthesis of various drugs like
dicyclomine, phenoperidine, oxaladine, ritaline, etc.
 However, the main disadvantages of PTC, especially in commercial
applications, are the need to separate the catalyst from the product organic
phase.
 Woodward-Prevost hydroxylation
Woodward reaction and Prevost reaction are important in producing a diol from
an alkene. These two reaction types are different from each other, according to
the reagents used during the reaction process. The key difference between
Woodward and Prevost reaction is that Woodward reaction proceeds in the
presence of iodine and silver acetate whereas Prevost reaction proceeds in the
presence of the silver salt of benzoic acid.

KEY WORDS
Diazomethane; Ozonolysis; Phase Transfer Catalyst; Woodward-Prevost
hydroxylation
REFERENCES
1. T RUE
2. True
3. T RUE
4. True
YOUTUBE VIDEOS
https://www.youtube.com/watch?v=X89Z3TRnYxw
https://www.youtube.com/watch?v=3MdaUCGiOHE
https://www.youtube.com/watch?v=t5OIfKDaDIY
https://www.youtube.com/watch?v=zOK_MnwhnJc
WIKIPEDIA
https://en.wikipedia.org/wiki/Diazomethane
https://en.wikipedia.org/wiki/Ozonolysis
https://en.wikipedia.org/wiki/Phase-transfer_catalyst
https://en.wikipedia.org/wiki/Woodward_cis-hydroxylation
REFERENCE BOOKS
1. Shioiri, Takayuki; Aoyama, Toyohiko; Snowden, Timothy (2001).

"Trimethylsilyl diazomethane". Encyclopedia of Reagents for Organic Synthesis.
e-EROS Encyclopedia of Reagents for Organic Synthesis.
doi:10.1002/047084289X.rt298.pub2. ISBN 0471936235.
2. Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience,
p. 1036, ISBN 978-0-471-72091-1
3. Marc Halpern "Phase-Transfer Catalysis" in Ullmann's Encyclopedia of
Industrial Chemistry 2002, Wiley-VCH, Weinheim.
doi:10.1002/14356007.a19_293
4. Carey, Francis A.; Sundberg, Richard J. Advanced Organic Chemistry Part B:
Reactions and Synthesis (5th ed.). Springer
5. Woodward, R. B.; Brutcher, F. V., Jr. J. Am. Chem. Soc. 1958, 80, 209−211.

6. Mergott, D. J. Woodward cis-dihydroxylation. In Name Reactions for Functional
Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons:
Hoboken, NJ, 2007, pp 327−332. (Review).

CREDIT02-UNIT 03: NAME REACTION-1
LEARNING OBJECTIVES
 Describe the widely used name reactions and rearrangements for the
synthesis of industrially and pharmaceutically important compounds.
 Identify the design reactions with the help of name reactions and
rearrangements and use of suitable reagents
INTRODUCTION
A name reaction is a chemical reaction named after its discoverers or

developers. Among the tens of thousands of organic reactions that are known,
hundreds of such reactions are well-known enough to be named after people. Well-
known examples include the Grignard reaction, the Sabatier reaction, the Wittig
reaction, the Claisen condensation, the Friedel-Crafts acylation, and the Diels-
Alder reaction. Books have been published devoted exclusively to name reactions;
the Merck Index, a chemical encyclopedia, also includes an appendix on name
reactions.
As organic chemistry developed during the 20 th century, chemists started
associating synthetically useful reactions with the names of the discoverers or
developers; in many cases, the name is merely a mnemonic. Some cases of
reactions that were not really discovered by their namesakes are known. Examples
include the Pummerer rearrangement, the Pinnick oxidation and the Birch
reduction.
Although systematic approaches for naming reactions based on the reaction
mechanism or the overall transformation exist (such as the IUPAC Nomenclature
for Transformations), the more descriptive names are often unwieldy or not specific
enough, so people names are often more practical for efficient communication.

03-01: BARTON AND SHAPIRO REACTION
Barton Reaction
Barton reaction is a photochemical conversion of nitrite ester into δ-nitroso

alcohol upon exposure to ultraviolet radiation. The reaction involves homolytic
cleavage of RO–NO followed by δ-hydrogen abstraction, and takes place in a liquid
phase. This reaction is popularly called as Barton nitrite ester reaction. The
geometry of the 6-membered radical intermediate accounts for the selectivity of the
δ-hydrogen.
Only starting materials with the proper structure and geometry exhibit the
Barton reaction, and photolysis of nitrite esters generally results in unproductive
fragmentation, disproportionation, or unselective intermolecular hydrogen
abstraction.
Some of the examples of Barton reaction are:
Barton Reaction Mechanism: The nitrous acid ester decomposes upon

irradiation, releasing nitrous oxide and alkoxy radical species. The further reaction
produces an intermediate carbon radical species, which subsequently undergoes
intramolecular hydrogen abstraction via a cyclic six -membered transition state to
produce the δ-nitroso alcohol. The formed nitroso molecule can fu rther undergo
tautomerization resulting in the formation of oxime derivative, which can then
hydrolyze into an aldehyde or be oxidized into nitrile. This mechanism is similar to
Hofmann–Löffler reaction.

The Barton reaction mechanism, thus can be illustrated as:
Applications of Barton Reaction
This reaction is useful in the conversion of the angular methyl group in

steroids into the carbonyl group. Some other useful applications are:
 In the preparation of 1-dethia-3-aza-1-carba-2-oxacephem
 Synthesis of a new carbacephem antibiotic, and so on.
The photolysis of 1-octyl nitrite 6 yields 4-nitroso-1-octanol 8 in 45% yield, via
cyclic transition state 7, the formation of regioisomeric nitroso alcohols is not
observed:
The most important application for the Barton is its use for the transformation of a
non-activated C-H group into a functional group. This has for example been applied
for the functionalization of the non-activated methyl groups C-18 and C-19 in the
synthesis of certain steroids.

SHAPIRO REACTION
The Shapiro reaction is a variant of the Bamford−Stevens reaction. The former uses
bases such as alkyl lithium and Grignard reagents whereas the latter employs bases
such as Na, NaOMe, LiH, NaH, NaNH 2 , etc. Consequently, the Shapiro reaction
generally affords the less-substituted olefins (the kinetic products), while the
Bamford−Stevens reaction delivers the more-substituted olefins (the
thermodynamic products).
Example 1
Example 2
Example 3

Example 4
SOLVED P ROBLEMS 01
45) Problem 03-01: What is the Barton ester mechanism?
Solution: The Barton reductive radical decarboxylation is a sequence of reactions
in which a carboxylic acid is first converted into a thio- hydroxamate ester and then
heated in the presence of a suitable hydrogen donor such as TBTH, TTMSS or t-
BuSH.
46) Problem 03-02: What are the applications of Barton reaction?

Solution: Applications of Barton Reaction
This reaction is useful in the conversion of the angular methyl group in
steroids into the carbonyl group. Some other useful applications are: In the
preparation of 1-dethia-3-aza-1-carba-2-oxacephem. Synthesis of a new
carbacephem antibiotic, and so on.

45) SAQ 03-01: What is Barton reaction in synthesis?
Answer: The Barton nitrite ester photolysis (Barton reaction) is generally
considered a landmark in the development of remote functionalizations. The
reaction involves the photolytic homolysis of a nitrite ester to generate an oxygen-
centered radical that abstracts hydrogen, usually from the δ-position
46) SAQ 03-02: What are the products in Barton reaction?

Answer: Barton reaction is the reaction used to carry out the conversion of nitrous
acid esters to γ nitroso alcohols. The reaction occurs in presence of ultraviolet light
and leads to the production of an alkoxy radical species and nitrous oxide.
03-02: HOFFMANN – LOFFLER-FREYTAG REACTION

The Hoffman–Löffler reaction (also referred to as Hofmann–Löffler–Freytag
reaction is an organic reaction in which a cyclic amine (pyrrolidine or, in some
cases, piperidine) is generated by thermal or photochemical decomposition of N-
halogenated amine in the presence of a strong acid (typically concentrated sulfuric
acid or concentrated TFA). The HLF reaction proceeds via an intramolecular 1,5-
hydrogen atom transfer to a nitrogen-centered radical and is an early example of a
remote intramolecular free radical C–H functionalization.
In the late 1870’s A. W. Hofmann performed a series of experiments
designed to determine the then unknown structure of piperidine. In the course of
these studies a series of N-haloamines and N-haloamides was synthesized and
Hofmann investigated the reaction of these species under acidic and basic
conditions. He reported that the treatment of these molecules with hot sulfuric acid
followed by basic workup furnished the corresponding tertiary amines. While this
was an interesting result the power of this reaction was unrecognized for nearly 25
years.
In 1909 Löffler and Freytag extended the scope of this transformation and
set the scene for it to become a general and straightforward method for the
formation of pyrrolidines by demonstrating that the reaction was possible with
simple secondary amines, showcased by the synthesis of nicotine.
General Reaction:

Initial Discovery:
First Application:
Initial Discovery: (a) Hofmann, A. W. (1879). Ber. Dtsch. Chem. Ges. 12 (1): 984–
990 (b) Hofmann, A. W. (1881). Ber. Dtsch. Chem. Ges. 14 (2): 2725–2736. (c)
Hofmann, A. W. (1883). Ber. Dtsch. Chem. Ges. 16 (1): 558–560. (d) Hofmann, A.
W. (1885). Ber. Dtsch. Chem. Ges. 18 (1): 5–23. (e) Hofmann, A. W. (1885). Ber.
Dtsch. Chem. Ges. 18 (1): 109–131.
First Application: (a) Löffler, K.; Freytag, C. (1909). Ber. Dtsch. Chem. Ges. 42
(3): 3427–3431. (b) Löffler, K.; Kober, S. (1909). Ber. Dtsch. Chem. Ges. 42 (3):
3431–3438.
Mechanistic Investigations of the HLF Reaction

Stereochemistry:
Isotopic Effect: K H /K D = 3.42-3.54
Determination of Intermediates:
Selectivity of Hydrogen Transfer:
Generally Accepted Mechanism of the HLF Reaction

Modifications of the HLF Reaction
The Suárez modification:
• Reaction can be performed under very mild neutral conditions
• Compatible with many functional and protecting groups
• Unstable iodoamine intermediates are generated in-situ
• Iodoamine homolysis proceeds thermally at low temperature (20-40 oC) or

by irradiation with visible (Not UV) light.

Applications of the Classical HLF Reaction
Applications of the Suárez Modification of the HLF Reaction

HLF Variant for the synthesis of 1,3-diols
The so-called Hofmann-Loeffler- Freytag reaction of N-chloroamines 9

proceeds by a similar mechanism, and is for example used for the synthesis of
pyrrolidines 11:
Upon heating or irradiation with uv-light of a solution of an N-chloroamine

9 in strong acid (conc. Sulfuric acid or trifluoroacetic acid) a δ-chloroamine 10 is
formed, which however is usually not isolated, but rather reacts during workup with
aqueous sodium hydroxide to yield a pyrrolidine 11. A radical mechanism is
presumed, since the transformation of the N-chloroamine does not takes place in the
dark and not at room temperature, but rather requires light, heat or the presence of
Fe-(II) ions, while on the other hand the presence of oxygen inhibits the reaction.
The highly specific hydrogen abstraction from the delta carbon further suggests an
intramolecular reaction via a cyclic, six-membered transition state. A mechanism is
formulated above is supported by the fact, that in certain cases the intermediate δ-
chloroamines 10 can be isolated.
The required N-chloroamines 9 can be prepared from corresponding amine
by treatment with sodium hypochlorite or N-chlorosuccinamide.
The Hofmann-Loeffler- Freytag reaction has been described with N-chloro-
as well as N-bromoamines the formed however usually give better yields. N-

chlorinated primary amines react well in the presence of Fe -(II) ions. Just like a
Barton reaction, the Hofmann-Loeffler- Freytag reaction has been applied mainly in
steroid chemistry. An interesting example from alkaloid chemistry is the synthesis
of nicotine by Loeffler.
SOLVED P ROBLEMS 02
47) Problem 03-03: What is the Hofmann Loffler Freytag reaction mechanism?
Solution: The Hofmann–Löffler–Freytag reaction proceeds via an intramolecular
hydrogen atom transfer to a nitrogen-centered radical and is an example of a remote
intramolecular free radical C–H functionalization.
48) Problem 03-04: What is Hofmann Löffler - Freytag reaction example?

Solution: One such example is the Hofmann–Loffler–Freytag reaction, which
provides a method for the synthesis of pyrrolidines from N-halogenated amines.

The reaction is affected by warming a solution of the halogenated amine in strong
acid (e. g. H 2 SO 4 or CF 3 COOH), or by irradiation of the acid solution with ultra-
violet light.

47) SAQ 03-03: Which is Hoffman's reagent?
Answer: The Hoffmann reagent, also known as the Hofmann reagent, has the
chemical formula Cl 2 CNLi. It is a potent and versatile reagent used in organic
chemistry for various transformations, particularly in the Hofmann degradation
reaction.
48) SAQ 03-04: As with other radical reactions, secondary hydrogen atoms react
more readily than primary as the resulting secondary radical is more stable.
(True/False)
Answer: True
03-03: PETERSON SYNTHESIS

The Peterson olefination (also called the Peterson reaction) is the chemical
reaction of α-silyl carbanions (1 in diagram below) with ketones (or aldehydes) to form a
β-hydroxysilane (2) which eliminates to form alkenes (3).

Reaction mechanism
One attractive feature of the Peterson olefination is that it can be used to prepare
either cis- or trans-alkenes from the same β-hydroxysilane. Treatment of the β-
hydroxysilane with acid will yield one alkene, while treatment of the same β-
hydroxysilane with base will yield the alkene of opposite stereochemistry.
Basic elimination
The action of base upon a β-hydroxysilane (1) results in a concerted syn
elimination of (2) or (3) to form the desired alkene. The penta-coordinate silicate
intermediate (3) is postulated, but no proof exists to date.
Potassium alkoxides eliminate quickly, while sodium alkoxides generally require

heating. Magnesium alkoxides only eliminate in extreme conditions. The order of
reactivity of alkoxides, K > Na >> Mg, is consistent with higher electron density on
oxygen, hence increasing the alkoxide nucleophilicity.
Acidic elimination
The treatment of the β-hydroxysilane (1) with acid results in protonation and an
anti-elimination to form the desired alkene.
Alkyl substituents
When the α-silyl carbanion contains only alkyl, hydrogen, or electron-donating
substituents, the stereo-chemical outcome of the Peterson olefination can be controlled,
because at low temperature the elimination is slow and the intermediate β-hydroxysilane
can be isolated. Once isolated, the diastereomeric β-hydroxysilanes are separated. One

diastereomer is treated with acid, while the other is treated with base, thus converted the
material to an alkene with the required stereochemistry.
Electron-withdrawing substituents
When the α-silyl carbanion contains electron-withdrawing substituents, the
Peterson olefination directly forms the alkene. The intermediate β-hydroxysilane cannot
be isolated as it eliminates in-situ. The basic elimination pathway has been postulated in
these cases.
SOLVED P ROBLEMS 03
49) Problem 03-05: What is Peterson's synthesis?

Solution: Trimethylsilyl group acts like a proton and is readily removed by hard
nucleophiles particularly F- and RO- and promote elimination. This reaction is
known as Peterson Reaction.
50) Problem 03-06: What is the product of Peterson olefination?
Solution: In the Peterson olefination, a β-hydroxy silane decomposes to form an
olefin and a silanol under the influence of acid or base.

49) SAQ 03-05: What is the use of Peterson olefination?
Answer: One attractive feature of the Peterson olefination is that it can be used to
prepare either cis- or trans-alkenes from the same β-hydroxysilane. Treatment of
the β-hydroxysilane with acid will yield one alkene, while treatment of the same β-
hydroxysilane with base will yield the alkene of opposite stereochemistry.
50) SAQ 03-06: What is the Peterson chain olefination reaction?

Answer: The Peterson Reaction allows the preparation of alkenes from α-silyl
carbanions. The intermediate β-hydroxy silane may be isolated, and the elimination
step can be performed later.
03-04: SELENIUM DIOXIDE AND DESS-MARTIN PERIODINANE

Selenium (IV) Oxide: Allylic Hydroxylation.
Selenium (IV) oxide is known primarily for hydroxylation of activated
carbon-bearing positions, particularly at allylic (or propargylic) sites. Studies by
Guillemonat and others have led to the following hydroxylation selectivity rules:
1) Hydroxylation occurs as to the more substituted end of the double bond.
2) The order of facility of oxidation is CH 2 > CH 3 > CH.
3) When the double bond is in a ring, oxidation occurs within the ring when
possible, and a to the more substituted end of the double bond.
4) Oxidation of a terminal double bond affords a primary alcohol with
allylic migration of the double bond.
An example of rules (1) and (2) is shown in the oxidation of 3-methyl-3-
butene, where the allylic methylene position is oxidized in preference to the methyl
or methine positions (eq 1). Alkene-selective oxidation of 5,6-dihydroergosterol in
ethanol, an example of rule (3), occurs at C-14 and is followed by allylic
rearrangement to give a 7a-ethoxy product (eq 2). The mechanism of the allylic
oxidation reaction is proposed to be initiated by ene addition, followed by
dehydration and [2,3]-sigmatropic rearrangement of the resultant allyl selenic acid.
In a key step of the synthesis of α-Onocerin, α -oxidation in acetic acid leads to an
unsaturated g-lactone product in good yield (eq 3). The milbemycins have been
hydroxylated in the 13 β-position by selenium dioxide. Because selenium dioxide

forms selenious acid (H 2 SeO 3 ) in the presence of water, hydroxylations of alkenes
containing acid-labile groups (e. g. acetals) have been run in pyridine.
Higher-Order Oxidations.
Oxidative Cleavage.
Miscellaneous Transformations

DESS-MARTIN PERIODINANE
Structure:
Dess-Martin Periodinane (DMP) is an acylated variant of the oxidizing

agent IBX. The acyl groups provide DMP more solubility in organic solvents than
IBX. DMP is a relatively mild reagent that can be used under neutral conditions
providing a high degree of selectivity and functional group compatibility. Other
benefits include the fact that DMP is much less toxic than chromium based
alternatives and the work-up is relatively easy. One of the main drawbacks is the
potential explosive capacity of DMP. The cost of DMP is also relatively high and
its high molecular weight often necessitates using quite a lot of reagents.
Reagent for the oxidation of alcohols to ketones
Reagent for the oxidation of alcohols to aldehydes
Partial hydrolysis of DMP or incomplete acetylation gives a more effective

oxidant, explaining why impure samples of DMP in many cases provide better
results than the pure reagent. When reliable and convenient rate enhancement is
desired, pure DMP may be decomposed with an equivalent of water immediately
before or during its use.

Alcohols are oxidized to the corresponding carbonyl compounds with
iodoxybenzoic acid (IBX) or with Dess-Martin-Periodinane (DMP) in [bmim] BF4
and [bmim] PF6 ionic liquids at room temperature in excellent yields with high
selectivity. These oxidations are faster in ionic liquids as compared to con ventional
solvents. The byproduct iodosobenzoic acid (IBA) and the ionic liquid are readily
recovered.
A mimic of the Wacker process initiated by a combination of Pd(II) and

Dess-Martin periodinane provides methyl ketones from terminal olefins. This
operationally simple and scalable method offers Markovnikov selectivity, has good
functional group compatibility, and is mild and high yielding.
Versatile trichloromethyl carbinols can be prepared in one pot from primary

alcohols by treatment with Dess-Martin periodinane in CHCl 3 followed by 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD).
Among the reported examples of new reactivity of the hypervalent iodine

reagent DMP (Dess-Martin periodinane) are the one-step oxidation of secondary
amides to imides and N-acyl vinylogous carbamates or urea’s and the direct
oxidation of benzylic and related primary amines to the corresponding nitriles.

SOLVED PROBLEMS 04
51) Problem 03-07: Is selenium dioxide acidic?
Solution: SeO 2 is considered an acidic oxide: it dissolves in water to form selenous
(selenious) acid. Often the term selenous (selenious) acid and selenium dioxide are
used interchangeably.
52) Problem 03-08: What is the Dess-Martin periodinane reaction?
Solution: The reaction uses a hypervalent iodine reagent similar to 2-
iodoxybenzoic acid to selectively and mildly oxidize alcohols to aldehydes or
ketones. The reaction is commonly conducted in chlorinated solvents such as
dichloromethane or chloroform. The reaction can be done at room temperature and
is quickly complete.

51) SAQ 03-07: What is selenium dioxide used for?
Answer: It is used as an oxidizing agent, an antioxidant in lubricating oils, a
catalyst, and a reagent.
52) SAQ 03-08: What reagent is DMP?
Answer: Dess-Martin Periodinane (DMP) is a widely used reagent for the mild
oxidation of alcohols to aldehydes and ketones.
CHECK POINT 02-03
FILL IN THE BLANKS
1) Barton reaction is a photochemical conversion of ……….into…….. Upon

exposure to ultraviolet radiation.
2) The Hoffman–Löffler reaction (also referred to as Hofmann–Löffler–Freytag

reaction is an organic reaction in which a …………(pyrrolidine or, in some
cases, piperidine) is generated by thermal or photochemical decomposition of
………….in the presence of a strong acid
3) The Peterson olefination (also called the Peterson reaction) is the chemical
reaction of α-silyl carbanions with ketones (or aldehydes) to form a
…………..which eliminates to form alkenes.
4) Selenium (IV) oxide is known primarily for hydroxylation of activated carbon-

bearing positions, particularly at ……….(or propargylic) sites.

SUMMARY
 The Barton reaction, also known as the Barton nitrite ester reaction, is a
photochemical reaction that involves the photolysis of an alkyl nitrite to form a
δ-nitroso alcohol.
 The Shapiro reaction utilizes the reaction of hydrazones with 2 equivalents of a
strong base, typically an organolithium to prepare the alkene via an elimination
and provides an intermediate vinyl lithium intermediate. Protonation,
deuteration, or tritration of this intermediate is then possible delivering the
alkene.
 The Hofmann–Löffler reaction (also referred to as Hofmann–Löffler–Freytag
reaction, Löffler–Freytag reaction, Löffler–Hofmann reaction, as well as
Löffler's method) is an organic reaction in which a cyclic amine 2 (pyrrolidine
or, in some cases, piperidine) is generated by thermal or photochemical
decomposition of N-halogenated amine 1 in the presence of a strong acid.
 The Peterson olefination is the chemical reaction of α-silyl carbanions with
ketones (or aldehydes) to form a β-hydroxysilane which eliminates to form
alkenes.
 Selenium dioxide, for instance, is one of the most remembered reagents in allylic
oxidations, having been applied in the synthesis of several naturally occurring
products. The main goal of this review is to show the recent advances in the use
of classical and new selenium reagents in organic synthesis.
 DMP a commercially accessible chemical, is often used as a mild oxidative agent
for the selective oxidation of primary and secondary alcohols to their
corresponding aldehydes and ketones, respectively.
KEY WORDS
Barton and Shapiro reaction, Hoffmann – Loffler-Freytag, Peterson synthesis,
Selenium dioxide, Dess-Martin periodinane,
REFERENCES
---

1) nitrite ester, δ-nitroso alcohol
2) cyclic amine, N-halogenated amine
3) β-hydroxysilane
4) allylic

MOOCS
https://ugcmoocs.inflibnet.ac.in/index.php/courses/view_ug/270
YOUTUBE VIDEOS
https://www.youtube.com/@NROChemistry?app=desktop
WIKIPEDIA
https://en.wikipedia.org/wiki/Name_reaction#:~:text=Among%20the%20tens%20of
%20thousands,and%20the%20Diels%2DAlder%20reaction .
OER
---
R EFERENCE B OOKS
1. Name Reactions: A Collection of Detailed Mechanisms and Synthetic

Applications book by Jie Jack Li, Springer Nature Switzerland AG 2021, eBook
ISBN 978-3-030-50865-4 Published: 28 January 2021
https://doi.org/10.1007/978-3-030-50865-4

CREDIT02-UNIT 04: NAME REACTION-2
LEARNING OBJECTIVES
 Know the widely used name reactions and rearrangements for the synthesis
of industrially and pharmaceutically important compounds.
 Know the design reactions with the help of name reactions and
rearrangements and use of suitable reagents
INTRODUCTION
A name reaction is a chemical reaction named after its discoverers or
developers. Among the tens of thousands of organic reactions that are known,
hundreds of such reactions are well-known enough to be named after people. In this
unit we will discuss the applications of the reagents like Periodic acid, Iodo
benzene diacetate, olefin metathesis using Grubb’s catalysts in organic reactions.
04-01: PERIODIC ACID

Periodic acid is the highest oxoacid of iodine, in which the iodine exists in
oxidation state VII. Like all periodates it can exist in two forms: orthoperiodic acid,
with the chemical formula H 5 IO 6 and metaperiodic acid, which has the formula
HIO 4 . Periodic acid was discovered by Heinrich Gustav Magnus and C. F.
Ammermüller in 1833.
Orthoperiodic Acid and Metaperiodic Acid
Like all periodates, periodic acid can be used to cleave various 1,2-
difunctional compounds. Most notably, periodic acid will cleave vicinal diols into
two aldehyde or ketone fragments.
This can be useful in determining the structure of carbohydrates as periodic

acid can be used to open saccharide rings. This process is often used in labeling
saccharides with fluorescent molecules or other tags such as biotin. Because the

process requires vicinal diols, periodate oxidation is often used to selectively label
the 3′-termini of RNA (ribose has vicinal diols) instead of DNA as deoxyribose
does not have vicinal diols.
Periodic acid is also used in as an oxidizing agent of moderate strength.
Examples
Benzyl alcohols and benzyl TBDMS ethers were efficiently oxidized to the
corresponding carbonyl compounds in high yield with periodic acid catalyzed by
CrO3 at low temperature (-78 °C). The oxidation procedure was highly functional
group tolerant and very selective for the TBDMS group over the TBDPS group.
Oxidation of primary and secondary alcohols, using catalytic amounts of

TEMPO and tetra-n-butylammonium bromide in combination with periodic acid and
wet alumina in dichloromethane is compatible with a broad range of functional
groups and acid-sensitive protecting groups. The system also enables a chemo
selective oxidation of secondary alcohols in the presence of primary alcohols.
CrO 3 is an efficient catalyst for benzylic oxidation with periodic acid as the
terminal oxidant in acetonitrile. Substituted e lectron-poor toluenes and
diarylmethanes were oxidized to the corresponding substituted benzoic acids and

ketones in excellent yields. Benzyl ethers such as isochroman and phthalan were
converted to 3,4-dihydroisocoumarin and phthalide in quantitative yiel ds.
A CrO 3 -catalyzed oxidation of primary alcohols to carboxylic acids

proceeds smoothly with only 1-2 mol % of CrO 3 and 2.5 equivalents of H 5 IO 6 in
wet MeCN to give the carboxylic acids in excellent yield. No significant
racemization is observed for alcohols with adjacent chiral centers. Secondary
alcohols are cleanly oxidized to ketones.
A facile and quantitative preparation of carboxylic acids by a pyridinium

chlorochromate (PCC) catalyzed (2 mol %) oxidation of primary alcohols and
aldehydes using 2.2 equivalents and 1.1 equivalents of H5IO6, respectively, in
acetonitrile is described here.
Cp*Ir complexes bearing a chiral N-(2-picolyl) sulfonamidato catalyze a

convenient asymmetric reductive amination of benzylic ketones using readily
available β-amino alcohols as chiral aminating agents. The amino alcohol -derived
chiral auxiliary was easily removed by mild periodic oxidants, leading to optically
active primary β-arylamines without erosion of the optical purity.
CrO 3 is an efficient catalyst for benzylic oxidation with periodic acid as the
terminal oxidant in acetonitrile. Substituted electron -poor toluenes and
diarylmethanes were oxidized to the corresponding substituted benzoic acids and

ketones in excellent yields. Benzyl ethers such as isochro man and phthalan were
converted to 3,4-dihydroisocoumarin and phthalide in quantitative yields.
SOLVED PROBLEMS 01
53) Problem 04-01: Why is it called periodic acid?
a) Solution: Periodic acid is HIO 4 or H 5 IO 6 . The name is not derived from

"period", but from "iodine": per-iodic acid (compare iodic acid, perchloric
acid), and it should thus be pronounced per-iodic and not as in the usual
meaning of periodic.
54) Problem 04-02: Is periodic acid a strong acid?
a) Solution: Periodic acid is a moderately strong oxidizing agent and the

highest oxoacid of iodine.

53) SAQ 04-01: What is the periodic acid cleavage?
Answer: Periodic acid (HIO 4 ) is a reagent that cleaves the carbon-carbon bonds in
a sugar through oxidation. Periodic acid attacks the vicinal diols in carbohydrates
and oxidizes these groups to form carbonyl compounds.
54) SAQ 04-02: What is periodate oxidation?
Answer: Periodate oxidation is a classic reaction in carbohydrate chemistry used to

split bonds between vicinal carbons bearing unsubstituted hydroxyl or amino
groups (17). As shown in Fig. 1, heparin bonds cleavable by periodate are those of
non-sulfated uronic acid residues, i.e., GlcA and IdoA.

04-02: IODOBENZENE DIACETATE
Iodobenzene diacetate/ (Diacetoxyiodo) benzene, also known as phenyl
iodine (III) diacetate (PIDA) is a hypervalent iodine chemical reagent with formula
C 6 H 5 I (OCOCH 3 ) 2 .
Diacetoxyiodobenzene / Iodobenzene diacetate is used as an oxidizing agent

in several reactions. Iodobenzene diacetate is a useful reagent in the synthesis of a
large variety of heterocyclic compounds. Iodobenzene diacetate (PhI (OAc) 2 has
Hypervalent iodine (III) compounds, are attractive oxidizing agents because of their
stability and selectivity. In the presence of enolizable carbonyl compounds, they are
able to accomplish oxidative functionalization of the α position. A key iodine (III)
enolate intermediate forms, which then undergoes either nucleophilic substitution
(α-functionalization), elimination (dehydrogenation), or rearrangement (Carbonyl
oxidation with hypervalent iodine reagents).
Structure of phenyl iodine (III) diacetate (PIDA)
 C-H Functionalization and Hetero-Hetero Bond Formations:

 C-Alkylation reaction
Due to the importance of alkyl groups in the life and material sciences,
alkylation reactions to create alkylated heterocycles have garnered the attention of
chemists as a key area of research. On the other hand, quinoxalin-2(1H)-ones are
widely present in a variety of pharmacologically active molecules and naturally
occurring chemicals, making them a valuable class of heterocycles. The
decarboxylative alkylation of quinoxalin-2(1H)-ones (2) with phenyl iodine (III)
dicarboxylates under visible light was established by He and co-workers, as an
effective and sustainable method for producing 3-alkylquinoxalin-2(1H)- ones (3
and 4) in the presence of PIDA (1) and PEG-200 as solvent (Scheme 1)

 C-C bond formation reaction on alkenes
Fluorinated substances have a significant role in the creation of
pharmaceuticals. The difluoro-methyl group (CF 2 H) stands out among them as a
physiologically stable lipophilic bioisostere of weak hydrogen bond donors such as
alcohols, anilines, amines, or thiophenols and has been used in a variety of
medicinal compounds as a result. Terminal alkenes (9) were
hydrodifluoromethylated (11) regioselectively in the presence of PIDA, in
accordance with a protocol devised by Gouverneur and his group (Scheme 2)

SOLVED P ROBLEMS 02
55) Problem 04-03: What is the use of Iodobenzene diacetate?
a) Solution: (Diacetoxyiodo) benzene is used in wide range of medicals
industrial applications as well as in human and animal nutrition products such
as antiseptics and disinfectants, pharmaceutical intermediates, polarizing films
for liquid crystal display [LCD] chemicals.
56) Problem 04-04: What is the role of PhI OAc 2 ?

a) Solution: The use of PhI(OAc) 2 in dichloromethane enables a clean
oxidative cleavage of 1,2-diols to aldehydes. In the presence of OsO 4 as
catalyst, NMO and 2,6-lutidine, olefinic bonds can be cleaved in acetone/water
to yield the corresponding carbonyl compounds.
55) SAQ 04-03: What is the property of Iodobenzene diacetate?
Answer: Iodobenzene diacetate (PhI (OAc) 2 has Hypervalent iodine (III)
compounds, are attractive oxidizing agents because of their stability and selectivity.
56) SAQ 04-04: What is the molecular formula for Iodobenzene diacetate?
Answer: Iodobenzene diacetate/(Diacetoxyiodo)benzene, also known as phenyl
iodine (III) diacetate (PIDA) is a hypervalent iodine chemical reagent with formula
C 6 H 5 I(OCOCH 3 ) 2 .
04-03: OLEFIN METATHESIS USING GRUBB’S CATALYSTS
Treatment of alkenes with Grubbs’ catalyst (pictured; “Ru” is ruthenium)
results in a “swapping” of the terminal carbons of alkenes, a reaction known as
olefin metathesis.
Note: The most effective version of this reaction is “ring-closing metathesis”,

where two terminal alkenes are joined together to form a new ring.

Examples:
Notes: The first and second examples show typical “ring-closing” metathesis
reactions (an intramolecular reaction) where the interior carbons on each alkene
form a ring, and the terminal CH 2 groups on each alkene come together to form
CH 2 =CH 2 . The third and fourth reactions join together two alkenes in
“intermolecular” fashion, a variant called “cross-metathesis”. The reaction works
best when one of the alkenes is present in excess.
Instead of drawing out Grubbs’ catalyst, just writing “Grubbs catalyst” or
“Ru catalyst” is commonly done.
Mechanism:
The first step is a cycloaddition between the alkene and the ruthenium
carbene to form a 4-membered ring (Step 1, arrows A and B). After this occurs, the
second step is a reverse cycloaddition (Step 2, arrows C and D) to give a new
ruthenium carbene and a new alkene (olefin).
Note that to keep things simple the other groups attached to the Grubbs’
catalyst (“ligands”) are omitted, and “Ru” is drawn.
The process is catalytic. Here is the catalytic cycle.

Step 1: Shows the initial cycloaddition (arrows A and B) between the ruthenium
carbene and the alkene.
Step 2: The reverse cycloaddition (arrows C and D) results in a new alkene as well
as a new ruthenium carbene.
Step 3: The carbene can then combine with a new equivalent of alkene (arrows E
and F) Step 4: Followed by another reverse cycloaddition (arrows G and H).
Notes: The geometry of the alkene is not very well-controlled in the intermolecular
version of this reaction (“cross-metathesis”), so a mixture of E and Z alkenes will
usually be obtained.
SOLVED P ROBLEMS 03
57) Problem 04-05: Why is it called periodic acid?
Solution: Periodic acid is HIO 4 or H 5 IO 6 . The name is not derived from "period",
but from "iodine": per-iodic acid (compare iodic acid, perchloric acid), and it
should thus be pronounced per-iodic and not as in the usual meaning of periodic.
58) Problem 04-06: What is the mechanism for olefin metathesis with the Grubbs
catalyst?
Solution: Mechanism: The first step is a cycloaddition between the alkene and the
ruthenium carbene to form a 4-membered ring (Step 1, arrows A and B). After this
occurs, the second step is a reverse cycloaddition (Step 2, arrows C and D) to give
a new ruthenium carbene and a new alkene (olefin).

57) SAQ 04-05: What catalyst is used in olefin metathesis?
Answer: Currently, the active phase in heterogeneous olefin metathesis catalysts is
usually a d-block metal complex such as molybdenum (Mo), tungsten (W), titanium
(Ti), rhenium (Re), or ruthenium (Ru). Among the most popular catalysts used in
heterogeneous systems are Schrock, Grubbs, etc. complexes.
58) SAQ 04-06: What is the process of olefin metathesis?

Answer: Olefin Metathesis is an organic chemical reaction that uses a metal
catalyst for the transfer of substituents between olefins, or alkenes by a 4-
membered ring intermediate, also known as a Chauvin Mechanism.
C HECK POINT 02-04
1. Periodic acid is a moderately strong oxidizing agent and the highest oxoacid of
iodine. (True/False)
2. Which of the following is true about the use of the Grubbs catalyst?
A) The Grubbs catalyst is used in carbon-carbon coupling reactions.
B) The Grubbs catalyst is used in alkene metathesis.
C) The Grubbs catalyst is used in carbene formation.
D) The Grubbs catalyst is used with palladium as a co-catalyst.
3. In an olefin metathesis reaction, two __________ react in the presence of a
transition metal catalyst that contains a carbon-metal __________ bond. The
reaction produces ________ new alkenes
SUMMARY
 The Grubbs Metathesis Reaction: The Grubbs reaction exchanges the groups
attached to the double bond of alkenes. The two alkenes exchange partners to
give two new products in which neither one is oxidized or reduced. This process
is a metathesis reaction.
 Periodic acid is the highest oxoacid of iodine, in which the iodine exists in
oxidation state VII. Like all periodates it can exist in two forms: orthoperiodic
acid, with the chemical formula H 5 IO 6 and metaperiodic acid, which has the

formula HIO 4 . Periodic acid was discovered by Heinrich Gustav Magnus and C.
F.
 Benzene undergoes electrophilic aromatic substitution with iodine in presence
of anhydrous FeCl 3 catalyst to formed iodobenzene. The byproduct HI can
reverse the reaction. To prevent this, HgO is used which consumes HI. When
ICl and AlCl 3 are used, iodination competes with chlorination.
KEY WORDS
Periodic acid, iodo isobenzyl diacetate, Olefin metathesis using Grub’s Catalyst
REFERENCES
A NSWER TO CHECK POINT 02-04
1. True
2. B
3. Alkenes, double, 2
Y OU T UBE V IDEOS
https://www.youtube.com/watch?v=d8n_AREnHRw
https://www.youtube.com/watch?v=1S29grjAoyA
W IKIPEDIA
https://en.wikipedia.org/wiki/Periodic_acid
R EFERENCE B OOKS
1. Aylett, founded by A.F. Holleman; continued by Egon Wiberg; translated by
Mary Eagleson, William Brewer; revised by Bernhard J. (2001). Inorganic
chemistry (1st English ed., [edited] by Nils Wiberg. ed.). San Diego, Calif.:
Berlin: Academic Press, W. de Gruyter. p. 453. ISBN 0123526515.
2. Handbook of Metathesis: Catalyst Development Editor: Professor Robert H.
Grubbs
First published: 26 August 2003, Print ISBN: 9783527306169;
Online ISBN: 9783527619481 |DOI:10.1002/9783527619481
Copyright © 2003 WILEY‐VCH Verlag GmbH & Co. KGaA

School of Architecture Science and Technology
Yashwantrao Chavan Maharashtra Open University, Nashik – 422222
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YASHWANTRAO CHAVAN MAHARASHTRA OPEN UNIVERSITY

V154: M.Sc. Chemistry

Maharashtra Open Advanced Synthetic

Foreword By The Director ......................................................................... 4

Credit 02...................................................................................................... 122

Feedback Sheet for the Student ............................................................ 234

CHE603: Advanced Synthetic Methods Page 1

Dr. Amol Haridas Kategaonkar Dr. Bharat More

This work by YCMOU is licensed under a Creative Commons Attribution-

CHE603: Advanced Synthetic Methods Page 2

CHE603: Advanced Synthetic Methods Page 3

- Dr. Chetana Kamlaskar

CHE603: Advanced Synthetic Methods Page 4

CHE603: Advanced Synthetic Methods Page 5

This retrosynthetic approach is about making molecules or rather it is to

CHE603: Advanced Synthetic Methods Page 6

CHE603: Advanced Synthetic Methods Page 7

The benzene ring is a very stable structural unit. Making aromatic

The sign for a disconnection on a molecule is some sort of wiggly line

CHE603: Advanced Synthetic Methods Page 8

Introduction to Retro-synthetic Analysis and Synthetic planning:

Examples of Linear Synthesis

2. Linear Synthesis of Musk Ambrette (perfume)

CHE603: Advanced Synthetic Methods Page 9

How Overall Yield in a Synthesis is affected by the number and yield of

CHE603: Advanced Synthetic Methods Page 10

Linear synthesis versus Convergent synthesis

A divergent synthesis is a strategy with the aim to improve the efficiency of

CHE603: Advanced Synthetic Methods Page 11

Solution: Synthetic equivalent: A reagent carrying out the function of a

Synthon: A generalized fragment, usually an ion, produced by a

2) Problem 01-02: What are the different types of synthons?

Solution: Synthons are classified as donor and acceptor synthons.

(a) Donor Synthons: These are negatively polarized synthons denoted by

(b) Acceptor Synthons: These are positively polarized synthons denoted by

SHORT ANSWER QUESTIONS WITH MODEL ANSWER 01

CHE603: Advanced Synthetic Methods Page 12

01-02: DISCONNECTION APPROACH

During the retrosynthetic analysis of compound 2 the retrosynthetic

Retro-Synthetic design involves two distinct steps:

CHE603: Advanced Synthetic Methods Page 13

Terms used in retro-synthesis:

CHE603: Advanced Synthetic Methods Page 14

 FGA (Functional group Addition)- addition of Functional group during a

 FGI (Functional Group Interchange)-Changing of one functional to

 Functional group Removal (FGR): Deletion of functional group in the

 Ring Disconnection (RGD): Cyclic ring structure is disconnected to form

 Chain Disconnection (CHD): Acyclic structure or appendage in the ring

Guidelines for Retrosynthesis:

1. Recognize the functional group in the TM.

CHE603: Advanced Synthetic Methods Page 15

Synthons and Synthetic equivalent:

Heterolytic retrosynthetic disconnection of a carbon-carbon bond in a

CHE603: Advanced Synthetic Methods Page 16

Synthon Derived reagent Synthetic equivalent

CHE603: Advanced Synthetic Methods Page 17

Synthon Synthetic equivalent

CHE603: Advanced Synthetic Methods Page 18

Alternating polarity disconnections:

CHE603: Advanced Synthetic Methods Page 19