21 June 2023

Synthesis v retrosynthesis: How to use both to optimise your experiments

In organic chemistry, synthesis techniques are - quite literally - the building blocks of discovery. Synthesis and retrosynthesis are both ways of exploring the chemical space around a particular target molecule, helping chemists to develop a greater understanding of the chemical make-up and, in turn, streamlining the route to novel molecule discovery.

But synthesis and retrosynthesis work in different ways, and offer different benefits to users. To get the most out of each technique, it’s important to understand how they differ - and how they can work together.

Want to find out more about ICSYNTH, the AI-powered retrosynthesis planning tool from deepmatter®? Get in touch.

Understanding synthesis and retrosynthesis

At their core, both synthesis and retrosynthesis are used in organic chemistry to create and analyse complex molecules. How they do this, however, involves different methods that may be better suited for specific situations.

In essence, synthesis is a forward process that combines the building blocks to create new molecules, whereas retrosynthesis is a backward process that breaks down the complex molecule to help chemists understand its origins.

Defining synthesis in chemistry

Synthesis refers to a chemical reaction that combines two or more compounds to create a new product - effectively developing a new molecule from simpler compounds. It is used in everything from therapeutic drug development to the creation of advanced materials for electronic devices.

An example of synthesis in use is the development of aspirin. It was created through the synthesis of salicylic acid with acetic anhydride, which forms acetylsalicylic acid - the active ingredient in aspirin.

Advantages of synthesis

The main advantage of synthesis is its potential to create new compounds that hadn’t previously existed, enabling the development of new solutions in a variety of fields including medicine, materials science and many more. When executed properly, it can introduce functional groups selectively, increase the purity of the desired compound, and enable the production of non-natural compounds.

Using synthesis, chemists can combine an endless variety of compounds, selected for their properties and estimated reactions to target specific diseases or offer specialised features.

Defining retrosynthesis in chemistry

In contrast to synthesis, which builds up to a complex molecule using simpler compounds, retrosynthesis involves breaking down a target molecule into simpler components which can be more easily managed. It is then easier to design an elegant pathway back to the target market, minimising the appearance of any unwanted properties.

Utilising retrosynthesis enables chemists to plan the synthetic route to complex molecules systematically, rather than working from scratch.

Advantages of retrosynthesis

While synthesis enables the development of new molecules, it can be difficult to know where to start. Retrosynthesis, on the other hand, begins at the target molecule and works backwards. It makes the starting materials more clear and helps chemists to find creative strategies for finding the most efficient routes to synthesis. Plus, once a complex molecule is broken down, it is simpler for a chemist to evaluate the feasibility of the synthesis plan - it’s easier to see an issue when the entire journey is laid out than when only the starting blocks are available.

Working in synergy

Although synthesis and retrosynthesis have distinctive benefits, combining both strategies can lead to even greater advantages. Approaching a synthetic challenge with both tools allows scientists to think creatively about the target molecule while using retrosynthesis to develop an optimal synthetic pathway. This provides a faster and more efficient process, where retrosynthesis helps to inform the building blocks that make up a more accurate synthetic process.

The combined process

Both synthesis and retrosynthesis require careful planning and execution, as well as an in-depth understanding of the way molecules are formed, their properties and their interactions. In order to optimise the molecule discovery process, a trajectory similar to the below might be followed.

Part 1: Retrosynthesis

a) Identifying key functional groups

The first step is identifying the key functional groups in your target molecule. Functional groups are groups of atoms within a molecule that are responsible for its chemical properties. Some common examples of functional groups include:

  • Alkane
  • Alkene
  • Alcohol
  • Ether
  • Nitrile
  • Aldehyde

By identifying which of these groups are applicable to the molecule, chemists can determine the best way to break it down into simpler building blocks. For example, if the target molecule contains an amine group, it might be broken down into an amide and an alcohol. The choice of which functional groups to target depends on the overall goal of the synthesis and the available reagents.

AI-based tools can support at this stage of the process, with technology such as ICSYNTH from deepmatter® offering suggestions for how similar target molecules have been broken down in the past. It can also make recommendations based on this information, such as providing information about the potential sustainability of the reagents or offering more inexpensive alternatives.

b) Dissecting complex molecules

Once your key functional groups have been identified, the target molecule needs to be broken down accordingly. It’s crucial at this stage for chemists to possess a deep understanding of the function groups and their capabilities, to ensure the stability of each building block and their reactivity with one another.

At this stage, it’s also possible to create protecting groups. These are molecular frameworks that block a certain functional group’s reactivity, and can be especially useful when reaction conditions are required to make alterations elsewhere within the molecule.

c) Evaluating synthetic routes

Once the target molecule has been broken into simpler compounds, the chemist is presented with all the information to develop a synthetic pathway. Are there any visible issues or inefficiencies with recreating the target molecule using this pathway? There are several considerations that need to be taken into account, including:

  • The stability of the different reagents
  • The safety of the reaction conditions
  • The estimated yield of the final product
  • The estimated purity of the final product

If there are any concerns around these parameters, this is the point at which chemists can reevaluate their strategy and make changes to improve the reliability of the pathway. This might involve returning to step b), and dissecting the target molecule in a different way to produce an alternative pathway.

Part 2: Synthesis

a) Selecting appropriate reagents

A reagent is any substance that is added to a system to either cause a chemical reaction, or test if one occurs. These can be chosen based on the building blocks uncovered in the retrosynthetic process, but there are a number of factors that also influence the choice of reagent. These can include:

  • The nature of the reagent
  • The desired reaction pathway
  • The availability of the reagent
  • The cost of the reagent

It’s possible that the reagent recommended through the process of retrosynthesis wouldn’t be practical in reality, and an alternative must be found and tested. In these situations, machine-learning techniques such as those found in ICSYNTH can be used to predict the behaviour of molecules and reactions. This is a fast, accurate and automated way to generate alternatives, saving time, money and resources for the lab.

b) Controlling reaction conditions

When you’re baking a cake, it isn’t just the ingredients that matter - bakers have to ensure the perfect oven temperature, baking time, cooling time and so on. Similarly, effective synthesis doesn’t occur simply by putting a few reagents together and letting them get to work. Chemists need to meticulously control the conditions surrounding the reactions and, in turn, monitor them closely to change them if necessary. This is to eliminate the production of unwanted side products, as well as ensuring the experiment is as sustainable as possible and not wasting materials.

Two examples of conditions that frequently impact a reaction are temperature and pH level. These can alter the yield of the experiment, or even the outcome of the reaction itself, so it’s crucial that they are carefully monitored throughout the experiment.

c) Monitoring reaction progress

Synthetic experiments are rarely immediate, and monitoring the reaction as it progresses is vital for ensuring that it remains on track and there are no problems occurring that could damage the test. Spectroscopic techniques and specialist probes are often used to monitor a range of conditions throughout the process, including temperature, pH, the presence of one or more compounds, and many others that may be relevant for the specific experiment.

While these probes are tracking the experiment, however, it can be difficult to ensure that chemists are accessing timely information - especially when experiments are operating overnight or during times when the laboratory is closed. Tools like DigitalGlassware® offer impressive solutions for real-time monitoring, collecting the data directly from the probes and inputting it into graphical representations on the cloud-based software. This means that chemists can access their experimental information from anywhere, at any time, without having to physically monitor the reaction themselves. Furthermore, the information is stored securely for future reference, can be compared against other similar reactions, and can even be used to help predict future experiments.

Part 3: Repeat?

The intention for synthesis and retrosynthesis may not be that repetition is required, but the nature of molecule discovery means that a level of trial-and-error is often needed. However, the techniques set out above help to streamline any repetition that occurs, as chemists can benefit from machine-learning tools that store data, recommend new methods and help them to analyse the nuances of the experiments - bringing chemists closer to a discovery with every stage.

A synergistic approach for a streamlined outcome

While both synthesis and retrosynthesis offer specific benefits on their own, it is clear that combining the two can lead to faster and more effective synthesis development. The careful and considered use of both in tandem provides an extra helping hand for chemists, but there are tools that have been specifically designed to optimise the synthesis of organic chemistry even further. Through the implementation of AI-based platforms such as ICSYNTH and DigitalGlassware®, both part of the deepmatter® family, chemists can access unparalleled control and information about their experiments.

Do you want to learn more about how our machine learning solutions can help optimise your chemical synthesis? Speak to a member of our expert team.