Retrosynthesis

Yilang Zheng

1,*

and Yilin Gong

North Cross School Shanghai, Shanghai, 200940, China

Department of Shanghai, Fairmont international school, Shanghai, 201100, China

Keywords: Bond, Synthon, Break, Pathway.

Abstract: This essay focuses on a very important part of organic chemistry, the retrosynthesis reactions. The essay goes

from the shallow to the deep, starting with the most basic organic synthesis and transitioning to the

retrosynthesis reactions. It is described in relatively simple and understandable terms, so that all readers can

gain an understanding and insight after reading the paper.

1 INTRODUCTION

1.1 Why We Choose Retrosynthesis as

Our Paper Topic?

At the very beginning we were all new to organic

chemistry and had no previous in-depth knowledge of

this area. It was with this enthusiasm and curiosity

that we joined Prof. Brian's research project and spent

almost a month and a half in lectures to learn more

about organic chemistry. During one of the lectures,

we heard the professor talk slowly about

retrosynthesis reactions, which immediately caught

our attention and curiosity. This was our first

introduction to the subject, and as we studied and

researched it, we became more and more curious

about the retrosynthesis reaction and wanted to

document it in writing.

1.2 Briefly Introduction

The full synthesis of complex molecules requires a

thorough understanding of the reactions that form

carbon-carbon bonds and the reactions that change

one functional group into another. The largest number

of chemical reactions used in synthesis involve the

manipulation of functional groups. Furthermore,

unless all aspects of chemical reactivity, functional

group interactions, conformation and stereochemistry

are fully understood, the synthesis of molecules is

rarely successful.

Today, the term organic synthesis encompasses a

large number of chemical reactions. The planning and

use of organic transformations to piece together a

molecule is of course an important aspect of organic

synthesis. In order to achieve this, a thorough

understanding of the many organic reactions, reagents

and chemical transformations that are now known is

required. As mentioned earlier, the practice of organic

synthesis requires an understanding of the chirality

and stereochemistry of molecules, both to develop

synthetic strategies and to select the reactions and

reagents to be used in the various chemical

transformations. (Corey, 1988) It is essential to

understand the conformational analysis of each

molecule, from the starting material to the final

product, as chemical reactivity and stereochemistry

are often influenced by conformation.

Perhaps the most important component of

planning an organic synthesis is a thorough and in-

depth knowledge of chemical reactions and reagents.

If one knows only one reagent that converts an

alcohol to a ketone, and if that reagent does not work

for a particular system, then there is no alternative.

On the other hand, if one knows of 30 different

reagents for such conversions, there are many

alternatives if one of them does not work. Perhaps

more importantly, knowing these 30 reagents allows

one to better plan the synthesis and use a certain

reagent to maximise the chances that the synthetic

sequence will go as planned. The same comments

apply to making carbon-carbon bonds. (Corey, 1991)

Presumably, a synthesis starts with a starting material

of a few carbon atoms and the reaction will add

carbon fragments to increase the complexity of the

molecule as it is transformed into the final target in

many steps. It is therefore essential to understand the

different reactions and reagents used to form different

128

Zheng, Y. and Gong, Y.

Retrosynthesis.

DOI: 10.5220/0012003500003625

In Proceedings of the 1st International Conference on Food Science and Biotechnology (FSB 2022), pages 128-133

ISBN: 978-989-758-638-5

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

types of carbon-carbon bonds. (Corey, 1995)

BACKGROUND

INFORMATION

Before I talk about retrosynthesis, I would like to start

with an introduction to having synthesis. Synthesis is

a subject that is usually introduced in organic

chemistry and is introduced after you have studied the

alkyne reaction. You will make use of it time and time

again as the number of reactions you learn builds up.

2.1

What Is Retrosynthesis in Organic

Chemistry？

The definition is in its name: organic synthesis simply

means making organic compounds from scratch in the

laboratory or in industry. (Leah4sci, 2016)

Well, organic synthesis is a field where the

principles of organic chemistry are applied.

Most organic compounds come from living

things. For example, ethanol comes from the

fermentation of biomass. Ethanol is a simple and rich

example of organic compounds, but there are some

more complex organic compounds that are important

but less common in nature.

One good example is the drug aspirin. Aspirin

originated from willow bark. However, extracting

aspirin from it is too time-consuming and wasteful

because willow bark contains very little aspirin.

Some scientists have developed steps to

synthesize aspirin from laboratory compounds such

as salicylic acid. In this way, aspirin can be produced

in a high-volume and low-cost manner (Dr. Pere

Romea., 2014).

2.2

What Is Retrosynthesis in Organic

Chemistry?

If you look at this word in its simplest form, retro

means backwards, and synthetic means synthetic. Put

them together, this is what we call a retrosynthetic

reaction. Take an example from the results of the

discoveries of E.J. Coe of Harvard University in the

20th century.

As shown in Figure 1, this simple example of a

reverse synthetic analysis, the target molecule is

envisaged to be produced by hydrolysis of 2-bromo-

2-methylpropane. 2-Bromo-2-methylpropane is in

turn envisaged to be produced from methyl propane

via radical bromination. (https://www.chem.

ucla.edu/~harding/IGOC/R/retrosynthesis.html#:~:te

xt=Inthissimpleexampleofretrosyntheticanalysis%2C

,toariseviahydrolysisof2-bromo-2-methylpropane).

2.3

Why Is It Important in Organic

Chemistry

Retrosynthetic analysis can be used to get a clear idea

about the structure of naturally available compounds.

Also, it is a powerful tool to prepare compounds in

order to analyze the mechanism of the reaction. There

is a good example, which is the labeled compound.

Furthermore, the novel problems present everyday

requires advanced solutions that trigger

developments of modern chemistry.

DISCONNECTION

As previously mentioned, retrosynthetic analysis is to

disconnect target molecule into less complex

structures. This procedure is repeated until form

simple, easily available starting material. To

accomplish this goal, it usually takes known or

reasonable reactions as the account for the

disconnections used in the analysis.

Figure 1: Simple example of retrosynthetic analysis.

Retrosynthesis

129

The overall synthesis of any complex organic

molecules requires a thorough knowledge of

reactions. In the synthesis reactions, there are two

main categories of reaction types. One is called

carbon-carbon bond forming reaction. The other one

changes one functional group into another, this is

functional group exchange reaction.

Disconnection means breaking the bonds of the

molecule to produce simpler fragments.

Disconnection is actually a mental activity (we don't

actually break bonds chemically), if we break a bond

we must have a chemical process in mind to make that

bond.

As a reverse reaction to synthesis, retrosynthesis

disconnects the bonds and simplifies the target

molecule.

3.1 Carbon-Carbon Bonds

Disconnections

First and perhaps the most important retrosynthetic

rule is related to the C–C bond, electronic structure

and electronic charges of synthons that are designed

by the disconnection of those C-C bond. This rule can

be revealed in the products of disconnections which

are ionic fragments or radicals. To be synthons, those

particles should exist and be seen as reagents or

synthetic equivalents.

Before considering the electronic structure and

properties of synthons, there is a general scheme of

retrosynthetic analysis.

In figure 2, the curving line and arrow on the C–

C bond indicate the site of disconnection. The broader

arrow indicates the disconnection from left (target

molecule) to right (charged species). Then,

disconnection process continues until simple,

commercially available compounds are reached.

(Vitomir Šunjić, 2016).

Now consider disconnections of the C–C bond in

cyclic system in Figure 3. By disconnection of one

bond in TM Ⅱ, the ring is detached. Although there is

only one synthon, it probably provides a new vision

on how to separate the molecule in-depth. Of course,

the complex open-chain structure requires further

retrosynthetic consideration. This is just a possible

path.

In the cyclic TM Ⅲ, we disconnect two C–C

bonds at the same time. Two synthons are obtained.

The same, if one or both of this second generation still

contains complex structures, retrosynthetic

consideration continues.

To be more specific, the disconnection in TM Ⅲ

is a very well-known reaction called Diels–Alder

reaction. With two simultaneously formed carbon-

carbon bonds, Diels-Alder reaction becomes an

reliable source to form plentiful required six-

membered rings. Figure 4 reveals the most common

Diels-Alder reactions.

Figure 2: Disconnection steps.

Figure 3: Common ways to break C-C bond in the cyclic system.

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Figure 4: An usual Diels-Alder reaction model.

Figure 5: Strategic bonds.

Figure 6: Electron transfer when breaking bond.

The reverse reaction of a Diels–Alder reaction

becomes favorable at a high temperature, although

this may not be significant to most of the Diels-Alder

products. However, it makes abundant disconnection

of carbon rings possible. This reverse reaction is

known as the retro-Diels–Alder reaction.

Besides, there is another principle used to discern

strategic bonds which is that the strategic bonds are

in the primary rings, and they are not shared by two

fused rings. Since Five-, Six-, Seven-membered rings

are easy to form, whereas larger rings would be

difficult to form using synthetic ways. As a result, any

disconnections that generate rings containing more

than 7 carbon atoms is not feasible. In figure 5, the

bonds a-i are all strategic bonds except bond k. It can

be seen more directly in molecule C. If the communal

bond in the middle of the fused ring system is broken,

a ten-membered ring will be built. (Michael, 2016).

3.2 Ionic Fragments or Radicals

In the process of retrosynthesis, there is movement of

electrons that needs to be considered instead of just

thinking about the framework of the target molecule.

The arrow shown in the Figure 6 indicates the flow of

electrons. Additionally, fragmented ions can be

positively charged or negatively charged. Therefore,

they can be replaced if required.

First, the electron-

withdrawing groups should be disconnected. Then,

the group they used to attach will be positively

charged and induce another group to form reaction.

Nevertheless, it does not always obtain stable ions. In

this circumstance, FGI can be used to get the desired

ions.

There is another way to separate bonds called

homolysis (Figure 7). It produces radicals.

Comparing to polar reactions, although radical

reactions is less frequently used, it is still regarded as

a distinct genre and sometimes provides a lot of

convenience (

Abhik, 2014).

Retrosynthesis

131

Figure 7: Homolysis - separate bond equally.

Figure 8: Difference between two synthesis types.

GUIDELINES

4.1

Make the Pathway Short If

Possible

In the laboratory, the ideal retrosynthesis pathway

would include the highest safety and efficiency.

Based on this principle, a short plan is favorable

because it results in more yield from a given amount

of reactant.

4.1.1 Convergence

Convergence is a strategy for multistep synthesis.

Different from linear synthesis (also called

consecutive synthesis), convergent synthesis apply

much less steps. Since reactions cannot reach 100%

yield, as steps increases, the percent yield of the

target molecule decreases. Based on this belief,

shortening the synthesis pathway leads to a higher

efficiency using given amount of starting material.

From Figure 8, we can see a clear difference between

linear synthesis and convergent synthesis.

To summarize, the first step in the inverse

synthesis of a complex target molecule is to analyse

the oxidation level of each carbon atom. By

analysing the oxidation levels, we can convert the

binding to electronegative atoms into binding to

oxygen. As a result, we can find possible dioxygen

dioxide patterns, which indicate the type of

disconnection carried out. The disconnection will

result in simpler molecules that can be further

disconnected. Furthermore, the dioxygen dioxide

pattern guides the synthetic pathway of the target

molecule, which is a purpose of retrosynthetic

analysis as it provides known reactions that can

produce the target molecule from the disconnected

part.

4.1.2 Exploit Any Symmetrical Structure

Exploiting the symmetrical structure in the target

molecule or its intermediate can dramatically

simplify retrosynthesis. In addition, it provides

significant chance to identify a convergent pathway.

4.2

Do the Retrosynthesis with Easily

Accessible Synthons

On the practical aspect, a good retrosynthesis

pathway should make its synthons easier to approach

by buying or making in the process.

4.3 Transfer the Less Reactive

Functional Groups into Reactive

Ones

If any substructures interfere with a key process, it

can be removed using transformation to other

functional groups.

CONCLUSION

Our research continued for several months, and at the

beginning, we studied abundant aspects of organic

chemistry in detail. Then, we started to inquire about

retrosynthesis in depth. In the process of research, we

find it is effective to use retrosynthetic ways to

analyze chemical substances. After the development,

we group basic ideology and guidelines.

We find it with great significance that to produce

more target from easier approached raw material.

This demands a solid foundation on known chemical

reactions. In organic chemistry, we may encounter

problems that are too difficult for us to solve.

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Learning reverse synthetic analysis allows us to think

critically about problems from different perspectives,

moving from forward to backward and then

backwards again. Having such chemical intuition

provides us a better understanding to more difficult

chemical problems in the future. This way of

thinking is not only applicable to our future

chemistry studies but also to our school life.

REFERENCES

Abhik Ghosh, Steffen Berg (2014), Arrow Pushing in

Inorganic Chemistry: A Logical Approach to the

Chemistry of the Main Group Elements, Wiley

Dr. Pere Romea. (2014). Intr. to Retrosynthetic Analysis.

Barcelona: universitat de barcelona.

E. J. Corey (1988). "Retrosynthetic Thinking - Essentials

and Examples". Chem. Soc. Rev. 17: 111-133. doi:

10.1039/CS9881700111.

E. J. Corey (1991). "The Logic of Chemical Synthesis:

Multistep Synthesis of Complex Carbogenic

Molecules (Nobel Lecture)" (Reprint). Angewandte

Chemie International Edition in English 30 (5): 455-

465. doi:10.1002/anie.199104553.

E. J. Corey, X-M. Cheng (1995). The Logic of Chemical

Synthesis. New York: Wiley. ISBN 0-471-11594-0.

https://www.chem.ucla.edu/~harding/IGOC/R/retrosynthe

sis.html#:~:text=Inthissimpleexampleofretrosynthetic

analysis%2C,toariseviahydrolysisof2-bromo-2-methyl

propane

Leah4sci. (2016.11.17). A Simple Approach to Retro-

synthesis in Organic Chemistry. America: https://

leah4sci.com/organic-chemistry-retrosynthesis/.

Michael B. Smith (2016), Organic Synthesis,4th Edition,

Academic Press

Vitomir Šunjić, Vesna Petrović Peroković (2016), Organic

Chemistry from retrosynthesis to Asymmetric

Synthesis, Springer

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