Click Chemistry!

[hypervalent_iodine]

There has been a depressing lack of good organic chemistry threads of late, so I thought I might start spark some conversation.

 

A topic I've always found rather amusing is that of Click chemistry. It seems to evoke so many conflicting emotions amongst the chemists that I know - some spit at it in disgust, some (I'm sure) have shrines dedicated to Barry Sharpless in their offices, while others question whether or not it exists at all. For those of you aren't aware of what it takes to be a Clickalicious reaction, or who have never heard the term in their life, some background:

 

Click chemistry is quoted in wikipedia as a 'chemical philosophy' - a term I rather agree with. It was first coined by Barry Sharpless of the Scripps institute and was used by Sharpless and his colleagues to describe a class of reactions that adhere to the following criteria:

 

- Have a wide scope (i.e. apply to a large variety of substrates)

- Be chemo and regioselective

- Be modular/have high atom economy (i.e. all of the atoms in the reagent should be incorporated into the product)

- Give high yields

- Generate only benign by-products

- Be performed in easy to handle solvents (ionic liquids are a big NO)

- Exhibit a large thermodynamic driving force towards the production of a single product)

- Be stable

- Starting materials should be easy to handle and easy to obtain

 

The poster child of this class of reaction is that of the super-clicky Huisgen cycloaddition:

 

 

(image from Huisgen Reaction (wikipedia))

 

Polymer chemists adore this reaction. In fact, if you ask most polymer chemists, the Huisgen reaction is all there is to Click chemistry. Indeed, many fledgling polymer chemists I know of wouldn't be able to tell you the first thing about what it really means to 'do the Click' and are thus understandably confused by all the commotion 90% of organic chemists make about it. There is some truth to their belief that Click = Huisgen, however. It is in fact one of maybe two reactions that truly apply to the Sharpless definition - the other one being a thiol-ene type reaction (source). There have been others cited as being Click-tastic, but I personally find them questionable. One such example I found while reading a blog, Carbon Based Curiosities:

 

 

 

The author of the blog questions the ease of synthesising the benzyne intermediate, which appears to violate the stipulation of Click reactions using only benign and easily accessible starting materials - and I would personally agree with their position. They also raise the point that making alkynes and azides isn't a very Clicky process either, which begs the question of whether the Huisgen is truly a Click reaction?

 

I think the wikipedia description of Click chemistry as a philosophy rather than a class of reactions is quite apt. As noted in the Carbon Based Curiosities blog:

 

it's the idea that's important, and a worthwhile goal to achieve.

 

I agree with this statement. However, I think it is silly to assume that organic chemists and the like wouldn't, didn't and don't aim to achieve clean, high-yielding reactions irrespective of the existence of Click chemistry. This is why many organic chemists find the idea so offensive - why would anyone assume that they need to be told that this is what they should be aiming for in developing a reaction? My opinion of the matter is that it is certainly a useful idea, but it's also an obvious one that doesn't really need its own name and one that most certainly existed before Sharpless decided to give it one.

 

So what does everyone else think?

[mississippichem]

I read that blog post on carbon based curiosities about this a while back as well. Many people blur the lines of what was originally defined as click chemistry but I don't think it matters. Yes, I agree that anything involving benzynes is not "click chemistry". But I think the point of click chemistry is still achieved wherever one can do reactions at mild "physiological-ish" conditions and at the same time have high atom economy and stereo-selectivity.

 

I've noticed there's this notion around that enzymatic catalysis doesn't work in non-aqueous solvents. I think its utter BS. You read a lot in the literature where people talk about potential enzymatic routes but then in the same sentence worry about having to use water as a solvent. Though, a quick Scifinder search reveals that many enzymatic reactions have been conducted in many organic solvents and with high selectivity. I think rational enzymatic catalysis design is the future of click chemistry. I really loved this recent article from JACS:Mapping the Reaction Coordinate of Enzymatic Defluorination, Chan et. al It's not a click chemistry article per se, but if we want click chemistry to become purely "click" we are going to need more work like this! Hydrolyzing C-F at room temperature in water...yes please. Enzymes can be cheap as well, it depends.

 

I also know a guy who has recently found that he can enatio-tune a certain esterase by playing with mixed solvent ratios; up to >90% ee S or R depending on the mixed solvent ratio!!!! I don't want to divulge too many details but its quite interesting. How much more "click" can you get?

[hypervalent_iodine]

You know, I never actually considered enzymatic reactions. It's an interesting addition, even if I do consider it cheating . The use of enzyme-catalysed reactions is generally precluded due to cost. Some are cheap, as you say, but most are extremely pricey, which makes them useless for large-scale preps.

 

I agree with you also on the point of the fuzzy line not mattering. As I said, I think that Click chemistry is more of a philosophy than anything. Knowing what a 'good' reaction is, which is really what Click chemistry tries to define, is perhaps not necessary (synthetic chemists should be aiming for it regardless), but at the same time it can serve as a handy reminder of where to make improvements and what to aim for. Another thing that came to mind a while ago was that it also appeals to the notion of convenience.

[mississippichem]

The use of enzyme-catalysed reactions is generally precluded due to cost. Some are cheap, as you say, but most are extremely pricey, which makes them useless for large-scale preps.

 

True many are expensive, but this guy_

 

also know a guy who has recently found that he can enatio-tune a certain esterase by playing with mixed solvent ratios; up to >90% ee S or R depending on the mixed solvent ratio!!!! I don't want to divulge too many details but its quite interesting. How much more "click" can you get?

 

_is using an enzyme from a livestock animal which brings the cost down to about $3 kg! I think the key is to find promiscuous enzymes (the ones that will allow many types of substrates to dock, ooh yeah sexy ), that come from the useless parts of animals we are already killing...pigs, cows, chickens. Then it's just literally a matter of a walk down to the meat plant followed by a nice grinding and a little extraction (if you don't mind a few isozymes in there).

 

Hypervalent_Iodine did you have a look at that de-fluorination paper above? Read it, the mechanism is beautiful.