Synthetic Routes

We will discuss many synthetic routes elaborating on how to make a chemical compound from another chemical compound. We will learn as well how to go about the chemical reactions, and what reagents and catalysts to use.

• In this article, you will learn what a synthetic route is.
• You will learn how to map a synthetic route when given a starting material and a target compound.
• You will look at the overview of synthetic routes for aliphatic compounds and aromatic compounds.
• The synthetic route overview will help map the steps to take when converting one organic compound into another - the reagents, catalysts, and conditions required for each reaction.
• We will discuss and map some examples of synthetic routes to help you understand how to use the information given in this article.

Synthetic routes in organic chemistry - aliphatic compounds

Let us start by listing out all the functional groups we know. We are familiar with:

• Alkanes
• Alkenes
• Halogenalkanes/haloalkanes
• Alcohols
• Carboxylic acids
• Aldehydes
• Ketones
• Esters
• Amines
• Amides
• Nitriles

That's quite a few! We can draw a flow chart of which functional groups can be converted into other groups. This will make it easier to understand and remember.

Organic synthesis routes, Olive [Odagbu] StudySmarter

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, Kanishk Singh, StudySmarter Originals

Looking at the flowchart, the easiest route to take from haloalkane to carboxylic acid is through an alcohol. Thus, we can convert 1-bromopropane into an alcohol and then into a carboxylic acid. Let's go through the steps of this reaction.

1. Haloalkanes can be converted to alcohols through hydrolysis. Hydrolysis of haloalkanes is a nucleophilic substitution reaction. In this reaction, the nucleophile is H₂O. Since H₂O alone is a weak nucleophile, this reaction is slow. Therefore, NaOH is added and the solution is heated under reflux. The halogen is replaced by the -OH group.
2. To convert alcohol to carboxylic acid, it needs to be oxidised. For this reaction, acidified Potassium Dichromate (K₂Cr₂O₇/H⁺) is added. K₂Cr₂O₇ is an orange-coloured substance which is a strong oxidising agent. The reaction needs to take place with heat under reflux.

The synthetic route of Propanoic acid from 1-bromopropane can be described like this -

Synthetic Route of 1-bromopropane to Propanoic acid, Kanishk Singh, StudySmarter Originals

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.

Ethene, Kanishk Singh StudySmarter Originals

Propylamine, Kanishk Singh, StudySmarter Originals

Look at the flowchart again. To get to an Amine from an Alkene, you can take the route of alkene → haloalkane → amine. But if we take this route, the end product will be ethylamine, which is a 2- carbon compound. Where do we get an extra carbon from? We will have to take a longer route through the nitrile. So, the final route would be alkene → haloalkane → nitrile → amine. The nitrile group (CN) will give us the extra carbon we need. Let us go through the steps of this synthesis route:

1. Alkenes can be converted to haloalkanes by adding a hydrogen halide at 20^oC. Thus, adding a Hydrogen halide (HBr for example) to ethene and holding the reaction at 20^oC will give us 1-bromoethane. The double bond of ethene is replaced by hydrogen on one side and bromine on the other side.
2. We will now replace the halogen with a nitrile group. Haloalkanes can be converted to nitrile by reacting them with a solution of sodium cyanide (NaCN) or potassium cyanide (KCN) in ethanol, and heating under reflux. With this reaction, 1-bromoethane will be converted to propanenitrile.
3. Next, we need to convert the nitrile group to an amine group. The nitrile group consists of a triple bond between carbon and nitrogen ( ). This can be reduced by catalytic hydrogenation (reaction with hydrogen in the presence of a catalyst). The catalyst used is usually a metal catalyst such as palladium, platinum, or nickel. Through this reaction, will give us .

This diagram summarises the reactions discussed above, and represents the synthetic route of ethene to propylamine.

Synthetic route of Ethene to Propylamine, Kanishk Singh, StudySmarter Originals

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.

Ethene, Kanishk Singh, StudySmarter Originals

Ethanol | Kanishk Singh, StudySmarter Originals

Looking at the flowchart, we can convert an alkene to an alcohol in a single step i.e. single reaction. This reaction is called hydration and is the direct, simpler method. In hydration, the alkene is treated with steam at high temperature and pressure, in the presence of a catalyst. The catalyst used in this process is phosphoric acid (H₃PO₄).

But there is also a two-step hydration process of alkenes. Let us see the reactions of the two-step hydration of ethene.

1. In the first step, ethene is treated with sulphuric acid (H₂SO₄). This reaction yields Ethyl Hydrogen Sulphate. It is also called the 'Ethyl Ester of Sulphuric Acid'.
2. Then, ethyl hydrogen sulphate is hydrolysed i.e. reacted with water. This reaction produces ethanol, and also regenerates the sulphuric acid.

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.

Synthetic Route Overview for Aliphatic Compounds | StuDocu

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.

Synthetic Routes Overview for Aromatic Compounds | StuDocu

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.

Benzene as the starting material, 4-bromo-3-nitroacetophenone as the target compound, Kanishk Singh, StudySmarter Originals

In the target compound, there are 3 functional groups attached to the parent compound (benzene). Looking at the overview of the synthetic routes, we can see that there is no direct route to get from our starting material to the target compound. So, this will be a 3-step route, in which each step will be a reaction to add 1 functional group to the parent compound. To map this route, we will employ the technique of retrosynthesis.

We look at the target compound, thinking about which reaction was done last to obtain this compound. To determine this, we have to look at the functional groups.

1. We know that Br is an ortho-, para-director because of the lone pairs of electrons on it.
2. We also know that the nitro group is a meta-director because of the +1 formal charge.
3. We also know that the acyl group is a meta-director because of the partial positive charge on the carbon double-bonded to oxygen.

Considering these points, it makes sense that the nitro group was added last because:

1. It is in the ortho position to the ortho-director bromine.
2. It is meta to the meta-director acyl group.

So, the precursor to the target compound was 4-bromoacetophenone, on which the nitration reaction was done. We can write the nitration reaction as below:

Nitration of 4-bromoacetophenone, Kanishk Singh, StudySmarter Originals

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.

Friedel-Crafts Acylationof Bromobenzene, Kanishk Singh, StudySmarter Originals

We have discussed the individual steps of the synthetic route of 4-bromo-3-nitroacetophenone from benzene. This diagram shows the complete synthetic route.