A Level Chemistry A Topic Exploration Pack – Organic Synthesis Two-step synthesis

To begin… The easiest way to begin thinking about synthesis is to start with one-step reactions. Identify the functional groups in the reactants and products. Find them on the synthesis map. Find the easiest route between them.

In the reactant the functional group is a haloalkane. In the product the functional group is a nitrile group. Find them both on the synthesis map. The only route is to react the haloalkane with CN– in ethanol. Haloalkane Nitrile CN–/ethanol

In the reactant the functional group is an acyl chloride. In the product the functional group is a 2o amide. Find them both on the synthesis map. The only route is to react the acyl chloride with a primary amine, but now determine which! Acyl chloride 2o Amide primary amine

The chain highlighted in green is in both the reactant and product. The functional group in red is the amide. The chain highlighted in blue is new and must be part of the primary amine. It contains two carbons. It must be ethlyamine:

Try these

The first reaction changes a secondary alcohol into a ketone. Haloalkane Alcohol 1° 2° Alkene Ketone H2O (steam)/H3PO4 NaOH(aq) sodium halide / H2SO4 H3PO4 or H2SO4, heat K2Cr2O7/H2SO4, reflux NaBH4 The first reaction changes a secondary alcohol into a ketone. K2Cr2O7 with H2SO4 under reflux is the only option.

The second reaction changes an ester into a carboxylic acid. Alcohol Carboxylic acid Acyl chloride Ester alcohol/conc. H2SO4 dilute acid, heat OH– heat alcohol carboxylic acid/ conc. H2SO4 OR acid anhydride The second reaction changes an ester into a carboxylic acid. Refluxing with dilute acid is the only option. The alcohol propanol will also be formed. Carboxylate

Refluxing with an acid catalyst will cause this dehydration. Haloalkane Alcohol 1° 2° Alkene Ketone H2O (steam)/H3PO4 NaOH(aq) sodium halide / H2SO4 H3PO4 or H2SO4, heat K2Cr2O7/H2SO4, reflux NaBH4 The last reaction changes an alcohol to an alkene. While there is a benzene ring, it is unchanged from reactant to product. Refluxing with an acid catalyst will cause this dehydration.

Two-step synthesis This gets a lot more complicated as the number of possible functional groups available increase. E.g. starting with a haloalkane:

Two-step synthesis In one step a haloalkane can change to three other functional groups. In two steps this increases to eight.

Two-step synthesis To help reduce the number of options you can remove certain possibilities quickly with the following questions. Are there any benzene rings or phenol groups which change? - See the aromatic / phenol reaction pathways map. Is there the same number of carbon atoms in reactant and product? - This suggests addition of a nitrile or formation of an ester/amide. Are there other elements in the main chain which change? - Look for esters/amides.

Two-step synthesis Try this one

The reactant has an alkene The product has a carboxylic acid.

The easiest route is through primary alcohol to carboxylic acid.

Add H2O across the double bond. This requires steam and acid catalyst, e.g. H3PO4. This step produces two products: hexan-1-ol and hexan-2-ol. Hexan-2-ol is the major product (Markownikoff’s rule). Use the minor product (1° alcohol) to form the carboxylic acid. This step requires K2Cr2O7/H2SO4 under reflux.

Is this a useful way to synthesise hexanoic acid? Think about yield / atom economy.

Two-step synthesis Try this one.

The reactant has a benzene ring and a ketone group. The product has a benzene ring with a chlorine attached and an alcohol group. This is two separate functional groups requiring two different syntheses!

The two reactions are straightforward: NaBH4 to reduce the ketone Cl2 and a halogen carrier to add chlorine to the benzene ring. In a question like this it is important to think about which reaction to do first.

Which to do first? You can do this reaction in either order. Does the reduction in step 2 affect the chlorine in the intermediate? In this case no. Does the alcohol affect the position of the chlorine? The ketone and alcohol both direct the Cl toward position 3. So no. or You can do this reaction in either order. (See directing group rules.)

Next Steps The best way improve is to practise. The process becomes more difficult when you do not have the synthesis map in front of you. Like in the exam. As you improve try to do more without using the map, or use the blank map which does not show the reagents needed. Have a go at the two-step synthesis sheet. Then, start thinking about multi-step syntheses.

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