Let me start off by saying that I haven’t had the opportunity to meet Ian Baxendale, but in taking a look at his group at Durham University and reading one of his review articles on enabling technologies (The Integration of Flow Reactors into Synthetic Chemistry: J Chem Technol Biotechnol 2013), I would have to say that I hope to in the future, unless of course he is a Man U fan.
Information and technology have certainly changed the landscape of synthetic chemistry the way we know it today. I still remember using chem draw for the first time, lol! And now, microwave and flow technologies are the real ‘game changers’ with the days of being stuck in a round bottom flask can be thought of as fondly as the bunsen burner — it’s been over 150 years – what would Woodward do now?
The way it used to be, maybe old-school……
The general thinking in organic chemistry was to be as good with the mechanism, selectivity, reactivity and disconnection to remove the side-reactions and have a reactive intermediate survive to the product – but it was always counter to what I was used to hearing – heat it up some more – well that doesn’t add up, because reactivity and stability don’t often correlate – the hammer and tongs should be placed in the drawer – microwaves often satisfied, since a high percentage of reactions do benefit from heat and are robust enough to react quickly (and to be honest the inorganic community would second that notion and they get a tremendous boost). But we should strive on the organic side to gain something from emerging technologies which help us look deeper into the chemistry. The is often counter to many medicinal chemistry departments looking for a 1000 compounds out of each chemist – so they turn into good fisherman and poor synthetic chemists – what I mean is that a reaction can be poor but they can use improved HPLC techniques to obtain enough compound to test – yikes…..my experience is that this slows drug discovery because the cost of resynthesis is high compared to making enough compound to get through the testing cascade in the first place.
Ian helps us restep our tracks a bit and think about mixing and reactivity, but more importantly how to think about developing more efficient and optimized synthetic strategies. He mentions what we know — purification and backend characterization have been strong for many years and there is no reason why we should improve the frontend. That should make us feel a bit better at night after a long day in the lab.
At the risk of speaking for Ian, we need to be a bit more mindful in a positive way to the integration or marriage of chemical engineering and synthetic chemistry – and this has been done over the last 10 years in a fruitful way. Both disciplines have been doing their thing for a while now, with flow processes in place for over 20 years, but each in separate silo without a need to find the other.
Ian takes us out of our comfort zone and talks about the conceptual approach where reactions can be run in tandem through several reactors without the need for solvent switching – [cartoon of round bottom to round bottom to flow ]– he then brings us back and mentions that this is not an ideal world and we would be faced with quenches, and solvent changes and such due to the nature of reactivity in synthetic transformations. However, we can get close by combining the technology with solid-supported reagents and scavengers (and liquid separators) to maintain a continuous flowing sequence.
Solid-supported reagents and scavengers in flow chemistry
Solid supported reagents have been used extensively in multi- step organic syntheses in batch. Ideally, the use of such reagents should provide clean products without chromatography, crystallization, distillation or any traditional work-up procedures. Supported reagents are reactive species that are associated with a heterogeneous support material. They transform a solution resident substrate (or substrates) into a new chemical product (or products), with the excess or spent reagent remaining tethered to the solid matrix making separation a simple process. In a similar fashion, impurities can be removed from a flow stream using a scavenger species immobilized on a support. This scavenger creates either an electrostatic or covalent interact with the impurity, sequestering it from solution and binding it to the solid matrix thereby effecting purification of the reaction stream. By utilizing these supported components packed into simple columns or reactor cartridges it is immediately possible to perform multi-step organic sequences employing an orchestrated suite of supported reagents to effect all the chemical transformations and purifications.
An illustration of this concept is shown in the formation of 4,5-disubstituted oxazoles from an isocyanide and an acid chloride, facilitated by cyclizing the reactive imidoyl chloride with an immobilized PS-BEMP base. Any excess acid chloride was then trapped with a benzyl amine resin in-line column to provide the desired compounds in >95% purity in high yields. Comparing a traditional batch method where yields are greatly diminished. Running the system for ~12 hr provided 10-25 g of material if needed – showing that scaling-out will be an straightforward process.
Reactive intermediate flow methods need to have a solid foundation for chemists to use the technology and it is a must to be able to trap undesired materials in order for the reactive intermediate to flow through the sequence – an example used here utilizes a Curtius rearrangement with an acid or acid chloride to form the reactive acylazide which undergoes rearrangement to form the isocyanate and reacted with nucleophiles to form the desired product – alternatively, DPPA can be an effective alternative in large scale flow reactions where excess acid is used and the resultant coil performs the rearrangement with an immediate quench with the nucleophile on the backend of the flow sequence. In-line acid-base scavenger columns and an acyl-azide Merrifield resins have been utilized to facilitate the reactive intermediates moving forward and the undesired materials trapped from further participation.
OK – the review is exciting, but I don’t want to rewrite it. I will leave you with the thought that technologies can be combined in cleaver ways as added to value to each. Several examples of microwave flow examples can be done simply by building a coiled reactor that can be placed in a multi-mode microwave – there are two examples shown below, one with a glass coil with modified caps and the second with a Teflon reactor case with fluoropolymer tubing that can be exchanged in volume, diameter and length.
Ian goes on to additional configurations and multi-stage/step approaches with these concepts in mind including several different types of reactors with the ability to trap or react the way the chemistry needs. He then goes into great detail on the diagnostic end and the data handling and how we can scope and optimize the chemistry, and finally ends with several examples of the application of the technology in drug discovery – from library generation to optimizing a lead compound. I hope you enjoy the review as much as I did and it generates some thoughts and discussion within your research groups. Happy Reading!