Organic synthesis: Multi-step reactions

Organic synthesis: Multi-step reactions

Lessons

In this lesson, we will learn:

  • How to “think” about organic synthesis involving multiple steps to a target product.
  • How to plan multi-step reactions in organic synthesis.

Notes:

  • Chemists do chemical reactions to get products that are of some medicinal or commercial use. Unfortunately, our target compounds are often very complicated and require more than one simple chemical change (such as reducing a ketone to an alcohol).

  • Multi step synthesis is about planning reactions with more than one individual step to get the intended product. Before looking at examples or talking about exam questions, remember a few things:
    • Yield losses are multiplied in every step of a reaction. If you only get 50% yield in your first step and 50% of the second step, your final yield is only 25%. You lost 75% of what you started with! This has not only cut out the benefit of your intended product, but also added a lot of waste to deal with.
    • Side products/waste actively costs money to store and dispose. It is not only a matter of you getting less product; your side-products may have to be disposed of in a certain way which can cost a lot of money.
    • The starting materials for reactions all need to be bought from an industrial supplier. Many chemical feedstocks are products of crude oil, and the more they’re processed/changed into more sophisticated molecules, the more they will cost to a chemist and their group.

    So while we want simple reactions with few steps to save money and the environment, most of the time we have to do multiple steps.

  • ‘Multi-step synthesis’ is not a topic, it’s a skill that needs practice: seeing how functional groups relate to one another. Train yourself to look at molecules and think:
    • How could this bond or functional group have been made?
    • What can this bond or functional group be converted into?
    Think of functional groups as if they are places on a map – how can we get from our current location to our destination?

  • The best preparation for multi-step synthesis questions in your exam is trying to map out the functional groups. An example of a functional group ‘map’ is below:

  • There are lots of these reaction maps online and in chemistry textbooks. They look complicated at first but they’re all saying the same thing – most of these functional groups are related to each other by a reaction or two.
    Think of multi-step synthesis like map directions, getting from one place to another and learn the routes you need to take what you need to get there.

  • Some common features of synthesis exam questions are:
    • Questions can use compounds that are unfamiliar. For example, the alkyl chain branching might be unusual or the compound goes by a unique name. Don’t panic. A ketone with a strange name is still a ketone and will react like it!
    • Exam questions can use any functional group in the syllabus; any others will have the necessary information given in the question.
    • The question could require a mechanism or conditions but usually not both. The mechanism is details like the structural formula with dipoles, and curly arrows to show electrons moving and making new bonds. Conditions are things like practical methods (e.g. reflux), solvent (e.g. ether) and any reducing/oxidising agents (e.g. LiAlH4) used.
    • Synthesis questions are sometimes combined with the practical techniques and/or analysis questions. The question might talk about a chemical reaction and:
      • Show you the practical setup with some mistakes in the apparatus, or missing labels on some key parts of it. Our lesson Practical methods and procedures looks in detail at the practical techniques used in synthesis at this level.
      • Show you some of the analytical results when the reaction is finished. It might give you the IR or mass spectra and expect you to spot the evidence that a product has been made. Our lessons Mass spectrometry and IR spectroscopy and our lessons on NMR spectroscopy look at the variety of analytical methods used at this level.
    • They can be ‘wordy’ questions. The steps might be written out in sentences instead of using chemical equations. Just read it carefully and look for buzzwords:
      • “…x is collected…” means the reaction is finished and x is a product.
      • A sample of x is added to…” means x is probably a reactant and whatever it’s being added to is also probably a reactant.
    • There can be up to four steps in the synthesis. There is a set number of marks on the paper so there can only be a certain amount for each question – the less steps, the more details expected in them!

  • As you can see there is a lot of variety to these questions, so just begin the question with the obvious parts:
    • Compare the reactants and products if you have the structure of both. What are the differences between them? Those differences are because reactions took place.
    • Look at reactants and their functional groups. Ask yourself what reactions can be done to those functional groups.
    • Look at products and their functional groups. Ask yourself what reactions make those functional groups.

  • Worked example: Suggest a multi-step synthesis.

  • Suggest a synthesis from benzene to aminobenzene (aniline), showing any conditions and reagents required.

    What are the differences between the reactant and product? An amino group is there that wasn’t there before. So the synthesis needs to replace a C-H and end with C-NH2 group.
    Remember though that benzene has the delocalised ring which makes it electron rich and unreactive. It especially won’t react with another electron rich species like an amino group. So what reactions will it do?
    We know two reactions of benzene so far:
    • Friedel-Crafts alkylation or acylation, using AlCl3 and an acyl chloride/haloalkane.
    • Nitration using H2SO4/HNO3.

    If you want alkyl branching of any sort, you’ll need to start with Friedel-Crafts. If you want nitrogen groups, you’ll need to start with nitration to get the -NO2 group on. Let’s suggest nitration for the first step:

    So in one step we now have nitrobenzene, by adding concentrated HNO3 and H2SO4 under reflux.
    Now we need to get from -NO2 to -NH2. This is a reduction! Aromatic nitro groups can be reduced to amino groups by adding concentrated HCl and tin.

    So in summary we have a two step synthesis: nitration of benzene followed by reduction of the nitro group.
  • Introduction
    Multi-step organic synthesis
    a)
    Why is multi-step synthesis important?

    b)
    Planning chemical reactions.

    c)
    Synthesis exam tips.

    d)
    Worked example: multi-step synthesis.


  • 1.
    Plan multi-step syntheses of compounds showing necessary reagents and conditions.
    The compound 1-aminopentan-2-ol can be made starting with butanal.

    CH3CH2CH2CHO \, \, (multi-step synthesis) \, \, CH3CH2CH2CH(OH)CH2NH2


    Suggest a synthesis of 1-aminopentan-2-ol starting from butanal, giving any reagents and conditions necessary in the steps.

  • 2.
    Suggest reagents and/or conditions for steps in a multi-step synthesis.
    a)
    The compound 3-methyl-2-butanone can react in several ways. Two are below:
    1. Suggest reagents for reactions 1 and 2.
    2. Identify the chiral centre in the product of reaction 1.
    3. Suggest the structure of compound C.

    b)
    Outline a mechanism for reaction 2 showing curly arrows and any dipoles.