Welcome to the lecture on Catalytic Organometallics Part 24. Today again CH activation processes are, or will be, in focus. Well, first of all, methanol.

Methanol, a very important solvent, and the production of methanol is about 50 million tons a year.

That's a lot. Most of that methanol is produced from syngas or synthesis gas. So, how do you produce that syngas?

You need, for instance, methane or other alkanes and you treat that with water at high temperature. So, we can think of producing methanol from methane going through the process of syngas formation first.

As I said, high temperature, several hundred degrees.

Of course, then, high pressure. And stoichiometrically we produce one equivalent, carbon monoxide, and three equivalents of hydrogen in the syngas production.

Several applications for syngas. Please remember the Fischer-Tropsch process, also a catalytic process forming various alkanes from syngas.

If you just take out one equivalent of hydrogen from that mixture, you would have this stoichiometry, carbon monoxide, and two equivalents of hydrogen.

And with the appropriate heterogeneous catalysts, copper or platinum surfaces, again high temperature and pressure, you can then produce methanol.

The production of methanol from methane is highly interesting for industrial purposes since.

Well, with methane as a gas, you have a relatively low energy density.

In comparison with methanol, you can easily handle, you can easily store that, and you have a high energy density.

Unfortunately, especially this first step for the synthesis of syngas is a highly endothermic process. And the overall efficiency of the transformation of CH4 methane to methanol is about 10% at best.

It would be much nicer if you could make that transformation directly,

CH4, inserting one oxygen atom, preferable from molecular oxygen, and getting to methanol.

Well, the problem in artificial processes is that it is difficult to stop at that oxidation state.

You normally just burn that. So, are there artificial processes that can do that? Well, in principle, yes.

There is the so-called Periana catalyst, a platinum complex with a rather robust ligand, of course,

which indeed catalyses the oxidation of methane in diluted sulfuric acid to give methanol plus SO2 plus water.

Well, the turnover number is somewhat above 300.

This is certainly interesting, but not sufficient for industrial purposes. So, we can say still naturally occurring.

Catalysts are much better, and of course I'm talking about enzymes.

Microorganisms which grow, are able to grow on alkanes, they feed from alkanes. They are able to oxidize alkanes, and those who can use even methane have then an enzyme called methane monooxygenase.

Actually, this is a class of enzymes. On the other hand, there is an enzyme cytochrome P450, which is abundant in all life forms.

This enzyme, for instance, helps to get rid of substances in your body which are less soluble in water just by oxidizing them.

By introducing a hydroxyl group, they increase the water solubility, and this helps to get rid of them.

So, for instance, cytochrome P450 can be used also preparatively, for instance, for oxidizing limonene to an alcohol highly selectively.

This one is called perilyl alcohol.

And as I said, you could use the isolated enzyme, or you just

use a microorganism strain, which you have isolated from microorganisms living on alkanes. For instance, such a strain, I think you can buy that, is called Thingomonas sphxn200, an aerobic bacterium.

So, and with this microorganism, it's possible to transform this benzoyl pyrrolidine, essentially with biocatalysis,

to enhance it selectively with 53% EE.

Well, that's not that good for enzymatic, for an enzymatic process, and 62% yield. Second example, similar but somewhat improved in EE, same microorganism, hydroxylation at the same position, 91% yield,

75% EE, but the opposite stereoselectivity, here it is the R derivative, whereas in that case, the S enantiomer is the preferred product.

All those enzymes are metalloenzymes based on iron catalysis.

Oh, what I forgot, you can do that on a rather large scale, two grams a litre. That's quite okay, I think. So, as I said, iron catalysis, therefore it should be a good idea to

test iron salts for oxidizing organic compounds, hydrocarbons, in the presence of the oxidizing agents.

Is that possible? Of course, yes. And the earliest example is Fenton's reagent, developed around 1894.

So, originally, iron 2 sulfate was applied as the iron salt in diluted sulfuric acid and hydrogen peroxide as the oxidizing agent.

So, what happens? Iron 2 plus plus hydrogen peroxide gives an iron 3 salt, so the iron is oxidized,

hydroxyl and iron as the counter anion, besides sulfate, and the hydroxyl radical, which then is the active species, which starts to react with the C-H bonds.

So, this Fenton's reagent is also nowadays still used for treating polluted waste water.

You can clean that up from organic waste that might be in there, but you can also use that preparatively.

For instance, tertiary butanol treated with iron 2 and hydrogen peroxide will deliver this diol.

So, the hydroxyl radicals grab a radical hydrogen at those, at the tertiary

butyl group, and then we just have a recombination of those primary radicals.

This 46% yield according to a procedure published in organic synthesis, and, you know, these are at least double-checked procedures, very, very reliable.

Also, aromatic C-H bond can be oxidized with Fenton's reagent to give phenol, let's call that A.

The problem is that you have then a higher electron density at the

aromatic ring, and it might be easier to be oxidized with additional oxidizing agents. So, and, well, what could happen then is, of course, further oxidation to our quinone.

In the case of the original Fenton's reagent, 21% of A are reported, plus quinone, and biphenyl, which is in accord with the radical process, 24%.

It has been improved, changing to copper-based system, then 57% yield of A have been reported.

And recently, back to Fenton's reagent, but in trifluoroacetic acid as the solvent, and a bit strange additional ligand, this one, an anoxide.

So, this is an additional ligand for the iron, then the best result was 78% of A.

So, let's have a look for the oxidation to the oxidation state of quinones, which is a lot easier to achieve. For instance, this methyl naphthalene can be oxidized with hydrogen peroxide to the naphtho quinone.

58% yield was reported, and as catalyst, metalloporphyrins, and it's also possible with methyl trioxorinium.

You can, of course, also start already from the phenol with copper chloride and the preferred oxidizing agent, oxygen under pressure,

in butanol, a solvent, then also the quinone, paraquinone, is obtained in good yield.

Another oxidizing agent, based on the transition, methyl alantenoid, is very interesting.

CAN oxidations. CAN is the abbreviation of ceramone nitrate, the cerium in the oxidation state plus four.

So, if you treat phenanthrene with CAN in sulfuric acid, room temperature, for six hours,

then you can produce a 60% yield of this ortho quinone.

It should also undergo these aldotype reactions with those two hetero atoms involved. And a 15% yield of a paraquinone.

This one. You might say that this reaction should not be in the range of this lecture since CAN is used stoichiometrically.

In this case, it's not catalytic. But there are reactions which apply CAN catalytically.

For instance, this allylic alcohol is oxidized to this aldehyde.

10% CAN, 10% TEMPO. So, what is the structure of TEMPO? This is a stabilized radical, sterically stabilized and oxide radical.

This one. And if you're interested in oxidizing agents or processes which oxidize alcohols to aldehydes and so on, selectively,

you should look up the TEMPO oxidation. A very modern, very nice oxidation process. And this you can call a CAN modified TEMPO oxidation.

You use, in this case, in normal TEMPO oxidation, you use hypochlorite. Here, in this case, with the CAN modified process, you can use molecular oxygen in aceto-nitrile,

heating that up, for this special case, 40 degrees, just three hours reaction time and a 99% yield of this aldehyde.

Widely used in various labs throughout industry, pharmaceutical industry nowadays.

Well, after the oxidation of an alcohol and these oxidations of arene back to the oxidation of alkanes, we've already seen there that Fenton's reagent is able to oxidize alkanes.

Here, the case that a CH activation took place at primary position with a primary radical as intermediate.

Normally, the Fenton's reagent, you have a selectivity that at the tertiary center, CH activation works better

compared to a secondary center and, of course, than at primary centers, the CH activation is comparable, slow.

This is a case for primary center because we don't have another center in the molecule. Therefore, you get that selectivity. I should mention so-called Jeev and Gouac systems developed by Sir Derek Barton.

They are related to Fenton's reagent.

Also, iron salts are involved based on which one, a Jeev system or Gouac, and there's Gouac-1 and Gouac-2.

These are the names of the Barton groups which have been given to them. Molecular oxygen can be used, H2O2, tertiary butyl, hydro peroxide, KO2 has been applied as the oxidizing agent.

Solvent system is usually a pyridine or picolin, acetic acid combination.

And sometimes, there are also some small amounts of reducing agents in there like that or simply iron powder. This gives some kind of magic mixture.

And then, also, alkanes can be oxidized. For instance, if adamantane has the model compound,

so the ratio between the secondary and tertiary oxidizing products with these Jeev systems are about 1.2 to 1.

Regular, somewhat in favor of the secondary CH groups in contrast to Fenton's reagent.

Therefore, it is an interesting mechanistic debate. Barton is convinced that this process with his systems is not based on hydroxyl radicals but on iron in the oxidation state plus five.

However, this is mechanistically interesting. Nevertheless, I would like to introduce an oxidizing agent also in this lecture,

although that doesn't have anything to do with organometallic or transition metal. Well, just those dioxiranes which you can easily produce from acetone and peroxodisulfates.

Oxone, this is such a salt that you can buy.

So, with oxone. And if you want to have that a bit more reactive, you can change to the one with one CF3 group.

So, and those dioxiranes, you have them as a solvent, can oxidize olefins to epoxide. They form an oxides from amines under, well, very moderate reaction conditions.

And these compounds are able for a direct oxygen insertion into a CH bond, sometimes rather selectively.

A very impressive example is this one. Since we are dealing with a functionalized steroid, this steroid has been treated with dioxiranes.

Well, it is a slow reaction, but 90% yield is reported of a product with the oxygen introduced right into this position stereoselectively.

I think it's worth to keep that in mind that these nice reagents are a preparative alternative to a lot of other combinations we have discussed.

You will never get this selectively with Fenton's reagent to that position, of course. So, let's change the subject to a transition metal catalyzed borylation developed by Hartwick's group at Yale.

So, the borylating agent has this abbreviation B2 pin 2, and pin derives from pinnacle.

We have a boron-boron bond.

So, this is the borylating agent. One example, octane, reacts with this boron compound under rhodium catalysis.

It's usually a CP star rhodium complex.

So, CP star is the abbreviation for pentamethylcyclopentadienyl. If you use that with about 2-5% catalyst loading, 150 degrees, 5 hours, octane as the solvent,

you will end up with an excellent yield of this N-octyl boron compound.

85% is reported based on boron. So, you can go further down to 0.5% rhodium catalyst as complex.

Same reaction conditions, 150 degrees, prolonged reaction time, 80 hours, or somewhat diminished yield, 72%.

Well, the mechanism you have as intermediates a hydro rhodium boron complex,

which is the one who is capable for an insertion reaction into the C-H bonds,

highly selective at the terminal position. The selectivity derives from steric hindrance. It's extremely sensitive against steric hindrance.

Well, then you will have, after the insertion into the C-H bond, such an intermediate.

And reductive elimination gives the final product and this dihydro rhodium complex,

which then reacts with the B2 pin2 and is also able to react with this HB pin,

since otherwise the stoichiometry of this reaction wouldn't work.

So, further examples.

I found this one, very interesting, a recent example.

Also C-H bonds at cyclopropyl groups can be borrelated.

Well, at hysterically least hindered position. And diastereo selectively.

96% yield and a diastereoisomeric ratio of 96 to 4 was reported, while this B2 pin2 has the borulating agent.

And in this case, the rhodium complexes work better. And for higher activity, also rhodium complexes work in this case, but not with that yield.

Very interesting is also the application of this borulation to aromatic compounds.

Metadichlorobenzene with this borulating agent.

One equivalent, bit excess 1.5, equivalent.

Again, 2% of an iridium catalyst. 100 degrees, 16 hours.

We give the borulated arene selectively borulated in the matter position.

As I said, it is highly sensitive to steric hindrance. The borulation avoids the author position. That's it. It's not electronically driven, steric hindrance. Very interesting, I think.

And of course, you can then use these products. For instance, for the Suzuki coupling, palladium catalyst getting to such a bioral product.

Other examples of products formed by this type of reaction. Reaction performed at a pyridine ring system, 69% with 4 hours reaction time.

Here an example with an astro functionality, 95% in 25 hours.

This orthodimethoxybenzene, I think the common name for that is Veratrol, but I'm not that sure about that.

But this is the structure of the product, 62% yield. Well, certainly there is some electronic influence, otherwise reaction wouldn't be that slow.

95 hours reaction time, but the rule that ortho-borulation is avoided is also true for that case.

Well, some more applications, still the same type of reaction.

Iridium catalyst, borulation always in the meta position. Well, then you could use, for instance, a nickel catalyst for a cross coupling reaction with an iodo compound giving this product in the 71% yield.

Well, this is the introduction of an alkyl group. Compare that with the Friedel-Crafts alkylation.

And here you are doing or synthesizing some kind of Friedel-Crafts products, not with the Friedel-Crafts reaction, but always in the meta position. Where you usually get ortho or para selectivity with the normal Friedel-Crafts process.

Or for instance this one, Friedel-Crafts type reaction, always here or symmetrically there of course.

So, with the borulation, you get the boron functionality in the meta position.

And the palladium catalyzed process with an allyl acetate, some suchetrost type reaction, will lead to this final product, 77% yield.

Meanwhile, an analogous cilulation has been developed by the Hartwig group. You can find that in a recent publication in the journal Science, 2014, volume 343, page 853.

Meta xylene as the substrate, with silyl hydride as the coupling component, 1% of rhodium catalyst, THF 16 hours at 45 degrees.

And an additional reagent we will talk about soon, will give the meta-silylated product with above 90% yield.

So, during that coupling process, if you have a look at the stoichiometry, one should anticipate that molecular hydrogen is developed. Well, to drive a reaction to completion, there is cyclohexene added for a transfer hydrogenation.

And last example for today, this one also from Hartwig group, published in Angewandte, Schimie, 2013, volume 52.

So, this is of course the international edition, 8984 as the page. This olefin, terminal olefin, with an epoxide functionality, so a rather sensitive substrate, nevertheless reaction worked very well.

The same silylating agent, 0.5% of an iridium catalyst, again THF 80 degrees.

All that means should be in a pressure tube, because THF volume point is below, or 64 degrees or so. So, we again need a hydrogen acceptor for the transfer hydrogenation, in that case it was norbornene.

83% yield of this vinyl silane is obtained preferentially in the E, in the Z configuration.

The Z to E ratio was 90 to 10.

So, highly interesting, very modern reaction, reactions which are still in development. Enough for today, subject of next week's Tuesday will be some Lewis acid catalyzed reactions, where the Lewis acid is based on transition metals.

Thank you for listening, see you next week.