And this is typically how you would see an isocyanide drawn, notizen isomer of a cyanide in a cyanide. We'd have the carbon attached to the other carbon with a triple bond to a nitrogen.

This is an isomer and if we look at the carbon form of an isocyanide we can see this carbon here is formally divalent and I've put a negative and a positive charge on that carbon. So formally it's a 6 electron carbon. However, we can use the lone pair on the nitrogen draw Canonical form where we have this dipole, a species which now has a positive charge on the nitrogen and a negative charge on the carbon, and it's this Canonical form where we can draw that positively charged nitrogen.

That acidifies that proton there.

So how do we go about making isocyanides? Well, there are two major methods, one of which is the Hoffman Car by amine reaction that's rather uncontrolled and by far the most common method is by the dehydration of the parent and formamide. So we start off with the primary aiming react that with methyl Formator. Again, we just have a simple addition elimination into the Esther that kicks out methoxide and then we get this N for my does the product from that reaction.

We then carry out a dehydration reaction. What we're doing in this process is we'll see is we are removing the elements of water. This hydrogen, this hydrogen oxygen to give the isocyanide. Typically you would use phosphorus oxychloride in the presence of a base such as triethanolamine, and again drawing mechanistically the carbonyl oxygen attacks at phosphorus displaces a chloride. This intermediate that undergoes deprotonation, and then the nitrogen lone pair kicks out the phosphorus.

And we generate the protonated isocyanide, which is deprotonated by triethanolamine to give the isocyanide. So we've lost the elements of water in that reaction.

As I said a minute ago, isocyanides are generally stable to base, but our acid label. So if we take an isocyanide, they are readily cleaved by dilute aqueous acid. I put the mechanism in here again. If we draw the isocyanide in its carbon form, it's easy to see. We protonate the isocyanide carbon water adds into that carbon there.

We generated into me like that. We then lose a proton and then effectively tautomer eyes and that gives our former mind back. So this is quite a nice, easy way to take an isocyanide and convert it back through to an AI derivative.

Now typically a strong base such as butyl lithium is needed to deprotonate simple isocyanides. Weaker bases can be used when one of the substituents, for example the R group. Here is an electron withdrawing groups, such as an Ester.

So let's see how this works out in practice.

If we simply take methyl isocyanide, react that with N Butyl Lithium.

THF at low temperature. We get deprotonation generation of the organolithium intermediate. In this particular case is being trapped out with trauma farsala chloride. To give this trimethyl solo substituted isocyanide.

This example here we've now got an Ester attached to the same carbon used in Butte. I left him, but you could probably use a much weaker base such as potassium to Butoxide. Nevertheless, this simply deprotonates in this particular case, the electrophile that's trapping out the Alpha lithium species. Is this broma Esther and that gives this intermediate here hydrolysis of the isocyanide gives us back our formamide and again, I'm not going to go through the mechanism which was discussed on the previous page, but we protonate the isocyanide carbon.

Add water in and then taught on rise.

Now one of the group that we can consider is the Nitro Group and of course the Protons Alpha to a Nitro group are relatively acidic, a simple.

Nitro component nitromethane. The PK of that Proton is around about 10. If we take that and react that with LDA, that's a strong enough base easily to remove that proton and.

We generate the nitrate anion. This species here.

My pretend to alkyl ate this if we desire to get alkylation on the carbon. This is often difficult to achieve and this is Becausw. This is a relatively unreactive nucleophile.

And what very often happens is in fact we get alkylation on oxygen, which is not the desired process. So it bends our bromide. That gives an intermediate like that, and I've drawn the arrows in. You can see that undergoes fragmentation to give benzaldehyde.

And the N Nitroso on the nitroso compound, and that simply taught Tom rises you to give the oxy.

So what you can do to circumvent this problem is carry out a deep, direct deprotonation.

And then carry out a second deprotonation. So if we look at this night Ranade an eye, and

carry out a deeper second deprotonation with LDA, we remove the second proton that's on that carbon.

And we generate a diagonal and that Diane I'm.

Will see in the next page.

This species here.

He is now very much more reactive than the mono airline.

So we're at now it bends or bromide. We do not get alkylation. What we get is reaction of the carbon lithium bond with the benzal bromide and that gives this species. Here. We then do an acid work up, protonate the nitrogen oxygen and then we just simply lose a proton and that goes back to the Nitro compound.

And so that illustrates the powerful electron withdrawing effect of that positively charged nitrogen from the Nitro Group.

Alile means can be deprotonated with strong basis and result in anions trapped out with a wide range of electrophile.

Certainly the there are two factors here. If we deprotonate analele aiming with a strong base, such as second, reboot all lithium.

Then the resulting carbonite.

Is stabilized first of all by delocalization into the double bond, and also by the fact that we have an SP2 hybridized carbon here, which is inductively electron withdrawing. So these two factors.

Reinforce the possibility of Deprotonating Alpha to the nitrogen.

That anion can then be trapped out with a suitable electrophile or ketone. In this play, in this particular instance, and we can get either Alpha selectivity where the anion we draw it in the Canonical form where it's on this Alpha carbon reacts with the electrophile, or in the alternate Canonical form where the negative charges on the terminal carbon. We get an isomeric product.

Now, which of these two products you get the Alpha or the gamma alkylation product or isolation product very much depends on the reaction conditions on the solvent on the base and on the temperature.

And in many cases you can change the selectivity simply by changing one of those fundamental parameters, solvent temperature, or indeed the base.

We can also deprotonate Alpha to oxygen.

This tends to be a little bit more difficult than Lithiation. Alta Nitrogen is the deep stabilizing interaction is more powerful. However, we can use a very similar strategy to the one we used with nitrogen. We can take an alcohol and convert it into a carbonate, and this is done by taking our alcohol with a base and a family of compounds called carbamoyl chlorides. These are commercially available and again we observe nucleophilic addition into the carbonyl group with loss of chloride.

To generate or copper urethane derivative.

So again, we treat this species with strong base, such as secondary butyl lithium in the presence of TM media is an additive and we get initial complexation of the lithium cation to the carbonyl oxygen, followed by the base deprotonating at this position here, and the corresponding, we're going to. Lithium is stabilized by intramolecular coordination, and again we can track that species out with a suitable electrophile, and followed by an aqueous workup.

So again.

An example of that.

Benzyl alcohol this diisopropyl covermore chloride addition elimination.

The Little Cat and coordinates the secondary beuttel removes that proton and the resulting intermediate is stabilized by coordination of the lithium cation onto the carbonyl oxygen.

Dropping that out with propanone gives the alkoxide and then aqueous workup gives our tertiary alcohol derivative.

Now again, this, this particular carbanion is stabilized by the fact that we have the possibility of resonance of the negative charge into that benzylic group as well, so that does help make sure that we get deprotonation here. And again, we can use al ethers.

Which are effectively truncated aromatic compounds. We only have 1 double bond, so again, this substrate here.

Coordination of the lithium cation to the carbonyl oxygen. The second review tile based removes the proton and we get this lithiated intermediate.

And again, this is a delocalized species that we can that negative charge. We can either draw being on the gamma carbon or on the Alpha carbon.

And So what you get depends very much on, again, the reaction conditions under these particular conditions. In fact, this species here is favored because of intramolecular coordination onto the carbonyl oxygen. So we so we see very very high gamma selectivity in this particular case.

And in fact, we can actually do this with other derivatives. We don't actually need to use a carbonate derivative.

So when we have this affinal al ether.

Again, strong base beuttel lithium removes the Proton Alpha to the oxygen and again we're getting deprotonation here because the electronegative SP2 carbon is acidifying this proton an anion that we generate is a delocalized species, so the negative charge we can delocalize into that double bond.

And again, we can actually get alkylation at both positions. So in this particular case with methyl iodide we get a roughly 3 two or mixture of the Alpha alkylation over the gamma alkylation. But this next reaction illustrates just how fickle, sometimes these type of reactions can be.

If we simply change the O phenol ether to an O trimethyl silyl ether, so relatively small structural structural change, we use the same base, the same electrophile. Then we completely reverse the selectivity. Sorry, we've completely enhanced the selectivity, so we now get 92% of this gamma and only 3%. So you can see that we can change the selectivity by very very small structural changes.

Another useful method for deprotonation Alpha to oxygen is the use of vinyl ethers.

So if you recall, a vinyl ether is a ether in which one of the substituents on the oxygen is a double bond.

We can remove the proton here using a strong base. In fact you have to use tertiary butyl lithium to do this. This is relatively acidic because we have this is attached to an SP2 carbon and of course we have the inductive effect of the oxygen Atom withdrawing electron density away from that position.

Reaction again with T Butyl Lithium Lithium cation coordinates to the oxygen that ur beuttel anion is delivered into proximity and removes that proton and then we can calculate that this is a compound called Prenyl bromide that works very very nicely to give this compound here.

Now, one of the nice things about vinyl ethers is that they are very very easily hydrolized to the corresponding carbonyl compound. So if we take this intermediate treated with dilute aqueous acid.

The reaction proceeds by protonation of the double bond, not the oxygen.

This oxonium ion intermediate is trapped out by water. We get proton transfer, loss of methanol, and that that gets converted into the parent key term. So, in fact, if you look at the structure of this compound here, what we've done is we've deprotonated vinyl ether, and the product essentially has carried out an alkylation reaction on an eisai landline. So the vinyl ether has affectively behaved.

As an asile anion equivalent, and that's something we'll be coming back to. Look at for those of you doing chem 433, but vinyl ethers are very useful and I've given you another example of that on the next page, just to show you this is not a one off. This is a sugar derivative. You can see buried in the structure. We have a vinyl ether again reaction with tertiary butyl lithium. TH F - 78.

We get deprotonation in this case. We're trapping out with carbon dioxide. That gives the carboxylates salt, and then that's simply protonated with dilute aqueous acid to give the carboxylic acid.

Now, oxygen is not sufficiently activated to generate carbon ions on an adjacent SP3 carbon by direct deprotonation.

However, we can prepare such compounds by using a process called Tin Lithium Exchange and below I've given you a typical sequence.

And we'll go through that step by step.

So we start off with tribute art in hydride and that's reacted with lda in TH F - 78.

So the diisopropyl amide anion removes the proton and we generate the corresponding tin lithium species.

This is nucleophilic ontine, so we can consider this to be SN minus Li plus. So the tribute art in anion ads into formaldehyde. In this case that generates this alkoxide and then a dilute aqueous workup. We protonate that oxy anion and we generate this tribute art in hydroxy methyl alcohol.

We then do essentially what is an acetal exchange reaction.

So we react that with dimethoxy propane in the presence of acid catalyst and anhydrous acid catalyst and the acid catalyst is there to generate the reactive intermediate. This oxonium ion. So the acid catalysts protonates the Dimethoxy.

Anything we then lose methanol and generate the oxonium ion. The oxonium ion is the reactive intermediate, so it's here and the alcohol then adds into that Oxonia. Mine and we generate a species like this.

Note how what we've done is we've generated a carbon tin bond.

Adjacent to this carbon oxygen bond and what we're going to do in the next step is actually replace that tin carbon bond with that in lithium bond. And this is a tin lithium exchange reaction.

This reaction proceeds by reacting this compound. Here with N butyl lithium in TH F we will look at the mechanism in more detail later on, but it essentially involves the Butte. I'll an I'm adding onto that in and that cleaves this relatively weak tin carbon bond and generates this Alpha lithiated oxy anion species.

This in fact is stabilized by intra intramolecular coordination, so I've drawn it in the open chain form there, but in fact it probably exists largely in this intramolecular coordinated confirmation here.

The other by product from this reaction is of course Tetrabutyl Tin, which is inert.

This we're going to lithium can then add into electrophile, cyclohexanone. In this case that generates an alkoxide and again dilute aqueous acid protonates that to give this tertiary alcohol here and then if we expose this to more acid stronger acid we can then hydrolyze the acetal. Here again I put the mechanism in its protonation of the methoxy group loss of methanol addition of water into the oxonium ion and then loss of formaldehyde to give.

This tertiary alcohol.

So this is an example here of where the Lithio Anaheim.

It's behaving as a hydroxy methyl anion equivalent and this is pretty much the only way you can generate an organic lithium next to an oxygen that's activated. But these species are extremely reactive and useful and will finish off with one example of using this in a cyclization reaction.

So if we take this substrate here, you can see we have this tin carbon bond here adjacent to the oxygen we react with immune to lithium debut Tyler and attacks that in.

We generate the hypervalent in species, which then loses tetrabutyl tin to give the Alpha Lithio annelid. This react rapidly reacts with this alkene and gives us this species. Here the equilibrium for this lies on the side of this cyclized product because we don't have the destabilizing effect of the oxygen lone pair on that lithium. So in fact this is a much more stable species than the pre cyclization compound here.

That can then be protonated on aqueous work up to give you this two for sis Tetra hydro furan derivative. Cyclization happens to proceed through and even though it's a 5 membered ring through a pseudo chair like transition state.

And if we include an extra substituent on the double bond, we can do the same sequence butyllithium attacking at the Tim.

We lose tetrabutyl tin and we generate the Alpha Lithio oxy species. Now we can kick out methoxide and that generates the compound here which we now have a double bond which we can functionalize further on.