Synthesis The click concept To some, ‘click chemistry’ is simply a relabelling of standard organic chemistry practices. Others follow its principles almost religiously. Philip Ball reveals where click chemistry stands today
When chemistry is compared to Some even question whether added to the list almost daily? Why cookery, that’s not just because it In short it exists at all. ‘Click chemistry is has it become so protean, if not involves mixing the ingredients Nobel laureate Barry neither a concept nor a discovery,’ indeed misunderstood? and baking them, but also because Sharpless, Scripps said one organic chemist I you can’t always be sure what will Institite, US, coined the approached. ‘It is simply the Bowing to nature come out of the oven. Your chemical term click chemistry collection of reactions that emerges Sharpless, who was awarded his soufflé may have sunk, or gone black, Click chemistry upon cataloguing the available Nobel in 2001 for developing chiral or separated. Or more often than concerns finding synthetic reactions.’ And if all it catalysts for oxidation reactions not, you get a bit of soufflé mixed reactions with a large implies is that chemists should look in organic chemistry, is among the with a lot of other unappetising junk. thermodynamic driving for efficient reactions, he adds: ‘That many organic chemists who have Chemistry just isn’t as reliable as force that give almost is obvious and does not constitute an been struck by how cumbersome we’d like. complete conversion idea – it is merely common sense’. and tortuous our efforts at making That’s what led Nobel laureate of reagents to a single Others are even more dismissive, carbon-based molecules are in Barry Sharpless of the Scripps product suggesting that the notion of ‘click comparison with nature’s (see Research Institute in La Jolla, Some of click chemistry’ is positively misleading. Chemistry in Britain, November California, US, several years ago to chemistry’s proponents ‘Like many other chemists, I regret 2001, p26). Why do we find it so advocate a new approach to making dream that the the use of this meaningless verbiage difficult? molecules, called click chemistry. If philosophy could one in synthetic chemistry,’ said one. Well, for one thing, nature’s you prepare all your recipes using day help people in the ‘It is an unneeded and unwelcome chemists are enzymes that work at so-called ‘click’ reactions, say its developing world to make publicity stunt.’ the atomic scale – whereas we can’t. advocates, you’ll get perfect results pharmaceuticals on the ‘“Common sense” is indeed the ‘In the “unnatural” process it is our every time. spot best definition of click chemistry,’ hands controlling the tools,’ says But trying to define click counters Valery Fokin, Sharpless’s Sharpless. ‘Is it any wonder that chemistry brings to mind the blind colleague at Scripps. ‘Many of things rarely work as planned? No Indian sages trying to describe an us somehow forget common matter how clever the brain behind elephant. Since being coined by sense when we’re trying to make the hands, they remain ludicrously Sharpless, it now seems to mean something useful, so it is worth out of scale for the manipulations many different things to different reminding ourselves of what it can intended.’ people. Some will say it is a certain accomplish.’ But he thinks there are also type of copper-catalysed reaction So is click chemistry a useful problems with what we’re trying for making organic molecules, concept or not? What did Sharpless to make. Since organic molecules others a general new way of have in mind when he introduced generally have frameworks of carbon making polymers. Some think it the idea, and why did he consider it atoms, one of the biggest challenges has something to do with enzyme necessary? Why, if click chemistry in chemical synthesis is finding ways catalysis, others that it is a new is so roundly criticised by some to link two carbon atoms together approach to organic synthesis in chemists, does it now feature in at to make C–C bonds. In nature this general. least 600 papers, with more being often happens via a generic reaction 46 | Chemistry World | April 2007 www.chemistryworld.org
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called the aldol condensation, pharmaceutical chemists, because Many heteroatom can do well. Nature’s chemistry which involves carbonyl (C=O) every low-yield step in a multi-step reactions click together isn’t just about making C–C bonds, groups. Sharpless feels that organic synthesis of some biologically active in a predictable way he says; in fact, the small-molecule chemists have long made the error molecule slashes the final yield of building blocks of nature’s key of thinking that they should mimic product and makes the synthesis compounds – proteins, nucleic acids nature in finding ways of creating wasteful and costly. It also makes and polysaccharides – generally have new C–C bonds. But most synthetic the process of drug discovery slow, no more than six consecutive C–C reactions that exist to do this have because it is expensive in labour, bonds. They are full of heteroatom only a very modest thermodynamic time and materials to make new bonds, in which carbon is linked to driving force – which means that candidate drugs. atoms of a different element, mostly they happen inefficiently, giving low So Sharpless argues that, rather oxygen or nitrogen. The heteroatom yields. than slogging away at what we do X often bridges two carbons, That is a huge burden for badly, we should focus on what we creating C–X–C units.
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Linkages of this sort, he says, are much easier to make efficiently. So why not focus on them? In other words, we can start with molecules that have all the C–C bonds we need, and think about how to link up these reagents in the right way via heteroatom bonds made using efficient reactions. This, he says, turns the philosophy of drug development on its head. Rather than choosing some daunting molecular target and then slaving at the bench for years to try to make it, we should pay greater attention to molecules that we know how to make, using reliable and effective heteroatom chemistry.
Click sense What, though, are these ‘reliable reactions’? That’s where click chemistry comes in. Sharpless and other converts to the ‘click’ concept have concentrated on finding reactions with a large thermodynamic driving force, which give virtually complete conversion of reagents to a single product. Such reactions are ‘spring-loaded’ – they start with ‘high-energy’ compounds that will ‘click’ together in a predictable way with very little prompting. Ideally, such reactions should proceed under relatively mild reaction conditions – no intensive cooking, which runs the risk of breaking down some reagents or products into unwanted byproducts. And they should work in solvents that are benign, especially water. All of this potentially makes click chemistry both clean (it doesn’t produce anything you don’t want) and green. ‘The lack of byproducts and quantitative yields are the big advantages of click chemistry for
materials chemistry,’ says polymer CORBIS chemist Craig Hawker of the University of California in Santa criterion for evaluation.’ Barry Sharpless and the material useful properties. ‘I Barbara, US. ‘This allows multiple Hawker has no doubts that the his team are gradually have been searching for years for a functionalisation along a polymer ‘click’ perspective was valuable adding more reactions to reaction that allows me to couple backbone to be accomplished for his own efforts to make new, the click toolbox together high molecular weight with high efficiency, and the complex polymers. Among those polymers to give block copolymers,’ products isolated easily.’ M G Finn, he has aimed to make are block says Hawker. ‘With click chemistry a collaborator with Sharpless and copolymers, in which two or more this can now be achieved.’ Fokin at Scripps on the development chains of different polymers are Hawker and others have also and use of click reactions, says that stitched together. These materials used click reactions to put polymers materials scientists picked up on can combine the properties of together in architectures more the ideas of click chemistry much different polymers that, in pure complex than conventional chains, faster than many organic chemists. form, don’t mix readily. For example, such as the tree-like molecules ‘This is not surprising, since Barry the rubbery material used in some called dendrimers, which have and the rest of us had polymer training-shoe soles is a triblock uses ranging from catalysis and chemistry firmly in mind when we copolymer of polystyrene and adhesion to drug delivery. For were thinking about the subject,’ he polybutadiene. The chain segments example, his team has used click says. ‘It’s the one area of synthesis tend to segregate into different chemistry to make polymer in which function is always far domains at the microscopic scale, nanoparticles with chemically active more important than structure as a and this microstructure can give surfaces. They prepared polymer 48 | Chemistry World | April 2007 www.chemistryworld.org
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micelles (spherical aggregates) from Yet neither do some chemists chains primed for click chemistry, take kindly to the idea that they
PHOTODISC and then used small molecules should focus on what is easy to with the conjugate ‘click’ group make. To some, the challenge of simultaneously to crosslink difficult synthetic targets has always the chains and to introduce new been a driver for discovering new reactive ‘click’ groups where other synthetic techniques. ‘To suggest molecular substituents could be that the synthetic chemists should plugged into the particles (see figure rest on their laurels and restrict below). themselves to those reactions and those molecules that they know how Cross reactions to perform and synthesise is absurd,’ You can hardly expect to suggest says one. ‘Based on such philosophy that synthetic organic chemists we would neither have any progress have been barking up the wrong tree in the art of chemical synthesis nor or conducting sloppy, ineffectual would we have witnessed the last chemistry without making some two Nobel Prizes for the field [2001 of them cross. What some seem to and 2005].’ The former is Sharpless’s object to is Sharpless’s coining of a own award. new term to describe any reaction All the same, Sharpless and his that is efficient by virtue of its colleagues insist that synthetic thermodynamic impetus – and chemistry can only benefit from the concomitant implication that identifying the most powerful until now organic chemists have transformations that operate under neglected to select their reactions the simplest conditions, and seeing on such grounds. ‘Of course we use what can be made with them. One known and efficient reactions in our of the ‘click’ reactions they have work, just like everyone else,’ says cherished reactions on which we Barry Sharpless believes particularly championed is a form one critic. ‘But we don’t call them cut our teeth.’ He adds that ‘many that chemists thought of cycloaddition typified by the so- “click”.’ of the reactions that we all love are more in ‘click’ terms 50 called Huisgen reaction, in which Harvard chemist George not “click” reactions, not because years ago than today alkyne groups (carbon-carbon triple Whitesides, however, concurs they aren’t beautiful or useful or bonds) dangling from the end of a with the idea that today’s organic interesting, but just because they molecule are combined with azides synthesis is rarely a paradigm of cannot be applied to a wide range (N3 groups, containing two nitrogen- efficiency. Most of the reactions of substrates under a wide range of nitrogen double bonds) to make described in text books, he says, conditions’. heteroatoms called 1,2,3-triazoles are actually too messy to be of Sharpless says that in fact in a regioselective manner. In 2002, much practical value, and chemists chemists thought more in ‘click’ Sharpless and colleagues at Scripps, typically have to make do with only terms 100 to 50 years ago than and Morten Meldal and coworkers a small subset of them. He feels that they do now. This was a matter of at the Carlsberg Laboratory in click chemistry has the virtue of necessity – they had few catalysts, Denmark, independently showed making that shortcoming explicit. but had to rely instead only on heat that when the reaction is catalysed Finn recognises that not everyone to speed reactions up. And the with a copper(I) salt, it links the will be ready to abandon methods choice of solvents and of purification two carbons in the acetylene group that don’t reach the click chemistry techniques was much smaller. As a to different nitrogens in the azide, standards of reliability. ‘A strict result, they would have got nowhere generating a five-membered ring adherence to the “click” principle of at all with organic synthesis unless in an extremely efficient manner, using of the most reliable synthetic they selected those reactions that Click chemistry can give giving very high yields (see figure, techniques is harder than it sounds could be relied on to give a single polymer nanoparticles p51). ‘This improved version is a very for most of us,’ he says, ‘since it product in good yield that was easy chemically active useful reaction for joining chemical forces us to abandon many of those to isolate and purify. surfaces building blocks together to form
Polymer micelle Azide functionalised Functionalised shell cross linked shell cross linked nanoparticle nanoparticle
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CW.04.07.CLICK.indd 50 22/03/2007 09:23:56 larger assemblies and conjugates,’ ‘Click’ followers reaction has become so popular that more effectively in places that have says K C Nicolaou, a synthetic champion the Huisgen it is now almost synonymous with previously lacked the facilities for organic chemist also at Scripps. reaction which gives high click chemistry, and it has been put complex synthesis. ‘We nurture a The particular attraction of this yields of 1,2,3-triazoles to all kinds of uses. For example, fantasy that people in developing reaction is that, although both Benjamin Cravatt at Scripps, has countries could someday make acetylene and azide groups are used it to fish out of labelled proteins pharmaceuticals or pesticides on the ‘high-energy’, potentially reactive from complex mixtures produced by spot, not in the form of a kit but in a components, they aren’t recognised living cells. Hawker has welcomed real discovery mode,’ he says. ‘We as such by biological molecules. the azide–acetylene click too. ‘In also believe that a ready supply of So the reaction can be conducted my own work, it is the orthogonality click building blocks and coupling cleanly in the presence of, say, and efficiency of this reaction methods may be useful in emergency enzymes without reacting with which has allowed us to make well- situations such as the need for a everything in sight. That is one of defined, multifunctional materials new antiviral agent to respond to an the most desirable attributes of click with a precision approaching small outbreak of disease.’ chemistry (but one that is rarely molecule chemistry,’ he says. Others will no doubt continue achieved): the reactions should be Albert Eschenmoser, an organic to resist the idea. ‘Chemists have ‘orthogonal’ to a wide range of other chemist at the ETH in Zürich, always used their common sense to functional groups. The aim, says Switzerland, feels that the discovery choose the most efficient reactions Sharpless, is to create highly reactive was pivotal in persuading other to synthesise their favourite ‘sticky spots’ with the right target chemists to take click chemistry molecules,’ argues one organic groups while having them remain seriously. It was, he says, ‘an chemist. ‘We do not need to invent invisible to most other types of improvement in the efficiency a new name for such reactions. molecule. and scope of a known organic Rather, we need more of those This orthogonality meant that reaction that was so dramatic that reactions! Synthetic chemists Sharpless and his coworkers it clearly amounted to a discovery interested in providing a substance could use the reaction to assemble of the first order in the field of in the most economical and efficient molecules in situ inside an enzyme’s synthetic methodology, one whose way will always seek to apply the active site – a process that sounds applicability turned out to go far most efficient reactions, whether we rather like putting a firecracker in beyond organic chemistry.’ And he call them “click” or not.’ your mouth. Small molecules that admits that the discovery silenced Finn doesn’t disagree with that, inhibit enzymes by slotting into his own scepticism about the field. but he also sees the value of ‘click’ their ‘jaws’ and blocking access to ‘I stopped laughing at the term click as a way of sharpening the critical the enzyme’s usual target have many chemistry when I realised how the faculties of chemists when they pharmacological uses. Sharpless’s psychology and research attitude come to plan their syntheses. team has been using click chemistry standing behind this “joke of a ‘If click chemistry comes to be to make such inhibitors from term” can lead to a discovery of such recognised as a shorthand way of libraries of small building blocks importance.’ saying that you’re using one or a primed with acetylene and azide few particularly good reactions substituents, which will bind in Chemical tool box because they improve your chances the active site. The idea is that the But click chemistry needs more to achieve your target function, active site acts as a mould to create than a single trick. Sharpless and that’s fine. Also, if people start to molecules that make a good fit. In his colleagues have been gradually ask whether or not a reaction has 2001 the Scripps researchers used adding others to the list of reactions reached “click” status, that would this approach to construct molecules that fit the click criteria – among be great, since it would embody an that would fit into the active site of them, reactions that open ‘spring- awareness of what makes reactions acetylcholinesterase, an enzyme loaded’ small rings with a wide truly useful in a practical way.’ involved in neurotransmission. vareity of attacking groups. ‘My It’s obvious, but true nonetheless, Along with their colleague hope is that click chemistry develops to say that the concept either clicks Hartmuth Kolb, Sharpless and a large enough toolbox to allow a with you or it doesn’t. Fokin have used the same idea wide range of functional groups to to create inhibitors of carbonic be prepared,’ says Hawker. ‘Then a Philip Ball is a science writer based in anhydrase, an enzyme targeted multi-step synthesis would employ London for treating glaucoma, and HIV two or three click reactions as well as Further reading protease, an enzyme without which standard chemical transformations. C J Hawker and K L Wooley, Science, 2005,
ALFRED PASIEKA / SCIENCE PHOTO LIBRARY PHOTO SCIENCE / PASIEKA ALFRED HIV transmission can’t occur. The I see it as a major aid to synthesis 309, 1200 molecules they identified this way rather than a synthetic philosophy R K O’Reilly et al, Chem Soc Rev., 2006, 35, were at least as effective in binding Barry Sharpless unto itself.’ 1068 V V Rostovstev et al, Angew. Chem. Int. Ed., to the enzymes as those currently et al have used click Finn, meanwhile, hopes that 2002, 41, 2596 used as drugs. chemistry to make the click philosophy will enable H C Kolb et al, Angew. Chem. Int. Ed., 2001, 40, The copper-catalysed Huisgen enzyme inhibitors chemistry to be done faster and 2004
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