Sunday, 8 September 2013

#chemclub Reviews: C-H Activation

This month's review is by Kat, aka the Grumpy Chemist, a PhD student working on Pd-catalysed reactions. You can find her on Twitter as @Chemistry_Kat.

Biaryls – what are they good for anyway?
Biaryls are those nice, flat little structures that are very common in natural products, pharmaceuticals, agrochemicals or even functional materials and make one forget that there’s such thing as stereoisomers.

Here is where I usually pull out the statistics: according to Novartis, one of their best-selling drugs ($4 billion in 2012!) is Valsartan, used to treat high blood pressure. Valsartan contains a biaryl group, and it is only one of many. Last month, Jess’article on fluorinated drugs featured Lipitor, a drug with several interconnected arenes.


The long road from cross coupling to C-H activation
Everybody loves palladium-catalysed cross couplings. And they have good reason to do so: it’s a straight-forward and versatile class of reactions. Cross-couplings can connect sp to sp2 carbons (e.g. Sonogoshira coupling), sp3 to sp2 carbons (e.g. Fukuyama coupling), or my personal favourite, sp2 to sp2 carbons (e.g. Suzuki, Stille, Negishi couplings).

Since their discovery in the 1970s people constantly refined and improved upon the cross coupling reaction conditions. In 2010 Heck, Negishi and Suzuki, three of the “big players” in the field of palladium-catalysed cross-coupling, received theNobel Prize for their discoveries made almost 40 years earlier.

Traditionally, cross couplings need pre-functionalisation of both coupling partners, usually one as a (pseudo)halide, one as a organometal (or metalloid). The Suzuki coupling, one of the most common cross-couplings, uses arylboronic acids for coupling with arylhalides or even a pseudohalides like aryltriflates. Making the functionalised arenes, such as the arylboronic acid and the arylhalide needed for a Suzuki coupling, of course means additional synthetic steps. Placing and then, in the process of cross-coupling, removing the functionalities (boronic acid & halide) also generates usually solid, sometimes toxic, waste products.

Click figures for a larger version!
With cross-couplings like these well developed the next logical step, realised mainly within the last two decades, was to replace one of the coupling partners with a non-pre-functionalised arene. This is exactly what C-H activation is all about. Most people chose to replace the organometallic, as it is generally the more difficult to make and less stable coupling partner, rather than the (pseudo)halide.1

Taking it one step further one could imagine coupling two arenes but not pre-functionalising any of them. This is called oxidative coupling. It is currently the most difficult and still least developed method because of the stability and ubiquity of C-H bonds.

The trouble with regioselectivity
The problem with C-H activation is that most arenes have so darn many C-H bonds that can potentially react with palladium. The reactivity of arenes in C-H activations is extremely dependant on their substitutents. Despite being a major research focus, we’re not at the point yet where we can take any given arene and react it specifically at a desired C-H bond. We have mostly got the reactivity figured out: there are tons of methodologies of Pd-catalysed C-H activation out there that can bring a certain substrate type to reaction, but oftentimes the regioselectivity in arenes with more than one C-H bond leaves a lot to be desired. Something like toluene, that has no particular electronic properties making it either very electron-rich or electron-poor, usually gives mixtures of regioisomers in C-H arylation (if it reacts at all).

Solution 1: A directing group
A common way around this problem is to use a directing group. These are able to coordinate and direct the Pd catalyst to a certain position on the ring to perform the C-H activation regioselectively, and usually come in form of a heteroatom. Most, like phenols, amides, ketones, aldehydes, imines, heterocycles like pyridines or quinolones and many others, direct the reaction ortho to the directing group. Meta and para C-H activations are a little more unusual.

An example for a meta-selective C-H activation uses a specially designed “template”-type directing group for meta-olefination. This directing group can not only override effects from other potential directing groups groups, it also can be removed fairly easily.2



Carboxylic acids are excellent directing groups for palladium. Coincidentally (and conveniently), they can also be removed through decarboxylation. Combine the two and you get the cunning way to meta-selective C-H activation by arylating an ortho-substituted benzoic acid and then in-situ removing the carboxylic acid group: voilĂ , meta-subsitution.3



Solution 2: The electronics of the substrate
Heteroarenes like thiophene, furan and many others are so electron-rich that they can react with palladium(II) in an SEAr type reaction, usually with great regiocontrol for the most nucleophilic position. A lot of them react preferentially next to the heteroatom. Indoles are a little special in that respect: depending on the group on the nitrogen, the electronic properties can be tweaked towards favouring either C2 or C3 arylation.4



On the other end of the spectrum there are the very electron-deficient arenes like pentafluorobenzene. Even though there are exceptions, a rule of thumb is: the lower the pKa of the aromatic proton, the better its reactivity. Being thought to be quite unreactive for a long time, polyfluoroarenes and other electron-poor arenes can indeed react beautifully in C-H activation reactions, even at room temperature, through a mechanism coined CMD (concerted-metallation-deprotonation). Initially only suggested by a handful of groups, it is now an accepted mechanism that has been studied intensively in the last couple of years.5


And then there are those arenes which don’t have strong intrinsic electronic features, benzene being the godfather of all of them. One thing the currently available arylation procedures all have in common is that they use the “unactivated arene” in a huge excess, usually as the solvent. It’s a good thing that benzene, toluene and others are fairly cheap and readily available.6



To be continued
Now you know that palladium is pretty good at the whole C-C bond formation thing. People have thought of are some ingenious and elegant solutions to the problems of reactivity and selectivity. There’s no “the one (palladium) ring” for all possible substrates out there yet, but judging by the substantial number of new Pd-catalysed syntheses that are published every week, people work hard to find it. I’m certain that people will come up with more ingenious directing group designs that can be easily attached and detached on a very wide range of substrates for convenient C-H activation. Another thing I hope will get developed further in the future is oxidative coupling. Wouldn’t it be great to take any two arenes and just “snip off” the C-H bonds and make them into a C-C bond instead? Just like crafting, only with a transition metal as the scissors and glue and atoms as the paper.

References 
1 A few reviews for further reading: Chem. Rev. 2007, 107, 174; Chem. Soc. Rev. 2011, 40, 4740; Acc. Chem. Res. 2009, 42, 1074; Chem. Soc. Rev. 2011, 40, 1885
2 Nature 2012, 468, 518
3 Angew. Chem. Int. Ed. 2011, 50, 9429
4 Chem. Rev. 2011, 111, PR215
5 Org. Lett. 2010, 12, 2116; J. Org. Chem. 2012, 77, 658

6 J. Am. Chem. Soc. 2006, 128, 16496

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