In this blog post, we'll be explaining how to make a chemical compound from another using something called synthetic routes. This includes different steps, reagents, and catalysts that you'll need to know to get the job done. If you've studied Organic Chemistry and Organic Synthesis, this will be a good refresher for you.

So, what is a synthetic route? It's basically a set of instructions that you follow to create a chemical compound from smaller and less complex chemicals. In this post, we'll show you how to map out a synthetic route when given a starting material and a target compound. We'll also cover the overview of synthetic routes for aliphatic compounds and aromatic compounds. First, let's list out all the functional groups you need to know about. These include alkanes, alkenes, halogen alkanes/haloalkanes, alcohols, carboxylic acids, aldehydes, ketones, esters, amines, amides, and nitriles. That's a lot to remember! To make it easier, we'll draw a flow chart to show you which functional groups can be converted into other groups. By the end of this post, you'll have a good understanding of synthetic routes and how to use them. We'll also give you some examples to help you apply what you've learned. So, let's get started!

‍

The arrows represent which groups can be synthesised from other groups using the right reagents, catalysts, and conditions.

Synthetic route: 1-bromopropane to propanoic acid

Let us consider the synthesis of propanoic acid from 1-bromopropane. Propanoic acid has a carboxylic acid functional group, while 1-bromopropane is a haloalkane.

Propanoic acid

‍

To make propanoic acid from 1-bromopropane, we need to follow a synthetic route. First, we'll convert 1-bromopropane into an alcohol using a process called hydrolysis. This reaction involves adding NaOH and heating the solution under reflux to replace the bromine with an -OH group.

Next, we'll convert the alcohol into a carboxylic acid through oxidation. Acidified Potassium Dichromate (K2Cr2O7/H+) is added to the solution and heated under reflux. K2Cr2O7 is an orange-coloured substance which is a strong oxidising agent.

Throughout this process, 1-bromopropane is the starting material, and propanoic acid is the target compound. The intermediate compound is propanol.

By following this synthetic route, we can convert 1-bromopropane into propanoic acid.

‍

‍

Synthetic route: ethene to propylamine

Let us consider another synthetic route. We can synthesise propylamine from ethene. Ethene is an alkene with a double bond between 2 carbon atoms. Propylamine has an amine group attached at the end of a 3-Carbon chain.

‍

‍

Let's explore how to create propylamine from ethene using a synthetic route. To start, we need to convert ethene into a haloalkane by adding a hydrogen halide, such as HBr, at 20°C. This reaction will replace one of the double bond carbons with a hydrogen atom and the other with a bromine atom, resulting in 1-bromoethane.

Next, we need to replace the bromine with a nitrile group to add an extra carbon atom. This can be done by reacting 1-bromoethane with a solution of sodium cyanide (NaCN) or potassium cyanide (KCN) in ethanol, and heating the mixture under reflux. This reaction will convert 1-bromoethane into propanenitrile, also known as ethyl cyanide or propionitrile.

To convert the nitrile group into an amine group, we need to reduce the triple bond between carbon and nitrogen (C≡N) using catalytic hydrogenation. This reaction involves adding hydrogen gas in the presence of a metal catalyst such as palladium, platinum, or nickel. The result of this reaction is propylamine. In summary, the synthetic route of ethene to propylamine involves the following steps: ethene → haloalkane → nitrile → amine.

By following this synthetic route, we can create propylamine from ethene.

2-step Synthetic route: ethene to ethanol (hydration of alkene)

Let us now consider a simple synthetic route. We shall synthesise ethanol from ethene. Ethene is an alkene with a double bond between 2 carbon atoms. Ethanol is an alcohol with an -OH group attached to a 2-carbon chain.

‍

Let's dive into the two-step hydration process of ethene to produce ethanol. In the first step, ethene is treated with sulphuric acid (H2SO4) to yield Ethyl Hydrogen Sulphate. This reaction is an electrophilic addition reaction where the double bond of the alkene is attacked by the hydrogen ion (H+) of H2SO4, adding a proton to one of the carbon atoms and forming a carbocation intermediate. The carbocation then reacts with a sulphate ion (SO4-2) to yield Ethyl Hydrogen Sulphate.

In the second step, Ethyl Hydrogen Sulphate is hydrolyzed by reacting it with water. This reaction produces ethanol and regenerates the sulphuric acid. The hydrolysis reaction is a nucleophilic substitution reaction, where water acts as a nucleophile and attacks the carbocationic carbon, breaking the C-O bond and forming an alcohol functional group. This two-step hydration process of alkenes is traditionally used in the industrial production of ethanol, but it is less commonly used now due to the more direct and simpler method of hydration where the alkene is treated with steam in the presence of a catalyst such as phosphoric acid (H3PO4).

Synthetic routes for all aliphatic compounds

The synthetic routes overview diagram given below shows all possible synthetic routes between functional groups found in aliphatic organic compounds. The diagram shows the reagents and conditions required for each conversion. You can map any synthetic route between any starting organic material to any target organic compound. To map a synthetic route between a starting material and a target compound, check for common intermediate functional groups from the flowchart below. Then, list the reactions required to be done, as well as the reagents, catalysts, and conditions required for each intermediate compound.

‍

Looking at the synthetic routes overview diagram, there are always multiple routes to get from a starting material to a target compound. You should always try to minimise the steps it takes to get from the starting material to the target compound, to maximise the product yield.

Synthetic routes in organic chemistry - aromatic compounds

Similar to the synthetic routes overview diagram for aliphatic compounds, we can draw a synthetic routes overview diagram for aromatic compounds. Thankfully, it is much smaller than for aliphatic compounds, and much easier to remember.

You know that the parent member of all aromatic compounds is benzene. All aromatic compounds can be synthesised from benzene, and that already makes it easier to remember. As an example, let us try to synthesise one aromatic compound from benzene.

Synthetic route: 4-bromo-3-nitroacetophenone from benzene

Let us draw the starting material and the target compound first.

‍

4-bromoacetophenone + HNO3/H2SO4 → 4-bromo-2-nitroacetophenone

The next step in the retrosynthesis process is to determine the precursor to 4-bromoacetophenone. To do this, we need to think about which functional group was added next in the synthetic route.

Looking at the target compound, we can see that there is an acyl group attached to the benzene ring, which means that the precursor to 4-bromoacetophenone must have been benzene with an acyl group attached. The reaction to add the acyl group is a Friedel-Crafts acylation reaction. So, the synthetic route for the second step can be written as:

Benzene + CH3COCl/AlCl3 → acetophenone
Acetophenone + Br2/PBr3 → 4-bromoacetophenone

Finally, we need to determine the precursor to benzene. In this case, it is simply the starting material - ethene. The synthetic route for the third step is:

Ethene + H2SO4 → ethyl hydrogen sulfate
Ethyl hydrogen sulfate + NaOH → benzene

Putting all of the steps together, the synthetic route for the target compound can be written as:

Ethene + H2SO4 → ethyl hydrogen sulfate
Ethyl hydrogen sulfate + NaOH → benzene
Benzene + CH3COCl/AlCl3 → acetophenone
Acetophenone + Br2/PBr3 → 4-bromoacetophenone
4-bromoacetophenone + HNO3/H2SO4 → 4-bromo-2-nitroacetophenone

This is the 3-step synthetic route to obtain the target compound.

‍

‍

Following the same procedure, we know that bromine is an ortho-, para-director and the acyl group is a meta-director. Therefore, it makes sense that the precursor to 4-bromoacetophenone was bromobenzene and the acyl group was added to the ortho position by the ortho-director bromine. The reaction to add an acyl group is called Friedel–Crafts acylation reaction.

‍

You might be wondering; since bromine is a deactivation group on the benzene ring, how can we add an acyl group? The answer to this is that bromine is only a weakly deactivating group. We can't do a Friedel-Crafts reaction when there is a moderately or highly deactivating group present on the ring.

Finally, the only group left is bromine. The reaction is a bromination reaction:We have discussed the individual steps of the synthetic route of 4-bromo-3-nitroacetophenone from benzene. This diagram shows the complete synthetic route.

For your exam, you are expected to know the synthetic route for any starting material to any target compound, and the reagents, catalysts, and conditions required. There are numerous possibilities! The easiest way is to remember the two synthetic route overview diagrams given in this article (one for aliphatic compounds and the other for aromatic compounds) and construct the route for any given starting and target compound. You'll need a lot of practice, but you can handle this!

Analyse the synthetic route described below.  For each step, identify the type of reaction and the reagents and catalysts used in the reaction. Also list the by-products of each reaction.

‍

The first step of the route is addition of an alkyl group onto a benzene ring. This is called Friedel‐Crafts alkylation reaction. It is an electrophilic aromatic substitution reaction. The reaction occurs in the presence of aluminium chloride (AlCl3), which is a Lewis acid and acts as a catalyst in this reaction. The by-product of this reaction is hydrogen chloride (HCl).

‍

The second step of the route is the addition of an acyl group to the product of the first reaction. This is the Friedel‐Crafts acylation reaction. This reaction also needs to occur under reflux and in the presence of AlCl3 catalyst. The by-product of this reaction is also hydrogen chloride (HCl).

‍

Synthetic Routes - Key takeaways A synthetic route is a series of steps to be followed in order to make a chemical compound from smaller and less complex chemicals. In a synthetic route, each step is a chemical reaction. The final chemical in the route i.e., the chemical compound to be made is called the target compound. The chemical from which you start the route is called the starting material. All chemical compounds formed between the starting material and the target compound are called intermediate compounds. While mapping synthetic routes, always try to minimise the number of steps to maximise the product yield. Retrosynthesis is the process of figuring out the synthetic route in the reverse direction - from target compound to the starting material. For your exam, you are expected to know the synthetic routes - reagents, catalysts, and the conditions required for each reaction - for any given starting and target compound.

Synthetic Routes

How do you make a synthetic route?

To make a synthetic route between a starting material and the target compound - List all the molecules that can be made from the starting material. List all the molecules from which the target molecule can be made. Check for common intermediate compounds between the starting material and the target compound.

What is a synthetic route?

A Synthetic Route is a series of steps to be followed in order to make a chemical compound from smaller and less complex chemicals. 

How do you remember synthetic routes?

The easiest way to map synthetic routes on your own is to remember the two synthetic route overview diagrams given in this article (one for aliphatic compounds and the other from aromatic compounds), and construct the route for any given starting and target compound from there.

Why is Synthetic organic chemistry important?

Synthetic organic chemistry allows the synthesis of chemicals that can be used to make polymers, or used in agriculture or cosmetics. It can also facilitate biology and medicine by allowing for synthesis of designer drugs.

Where is synthetic chemistry used? 

Synthetic chemistry is used in the pharmaceutical industry to make designer drugs, in the materials industry to synthesize new polymers and other materials; and in the energy industry to make new fuels.

‍