Miss America facts or resonance effects. Again, play a very important role in the stabilization of many carbons and these I'm sure you've all seen before, but just to remind you, if we look at a carboxylate anion, that negative charge is delocalized between the two oxygens and that gives the PK of a carboxylic acid is just below 5.

If we look at a ketone in late, we can delocalize the negative charge between the carbon and the oxygen. But because carbon is less electronegative than oxygen it is not as good as stabilizing a negative charge and therefore the PK of a ketone is significantly higher than that of a carboxylic acid.

And again, we can draw delocalized structures for Esther in late anions for nitrile anions and nitrate anions. And in fact, the Nitro group is extremely good at stabilizing adjacent negative charge. The Pico of the Proton A2 Nitro group is about 10, but in fact the Nitro group stabilizes by both inductive effects because we have a positively charged nitrogen and buy me some Eric effect because we can do delocalized. The negative charge into the Nitro group itself.

Combining some of these things together, we can actually look at some PK's of carboxylic acids.

If we take.

Ethanoic acid itself, the Picos 4.8 if we take the trichloro methyl derivative PK drops to nought .6 and this is an example of the carboxylate anion being stabilized by the inductive electron withdrawing trichloro methyl group.

If we take propionic acid, the PK that is 4.9. If we replace that ethos sidechain with an alkyne, remembering and our kind the electronegative, this carbon is significantly enhanced compared to an SP3 carbon. And that is an example of the inductive effect of the SP hybridized carbon, increasing the acidity. The PK drops to 1.9.

And then obviously we just looked at the example of. If we replace the OH with a methyl group, we see significant increase in the PK, because the enolate anion is less stable than the corresponding carboxylated line.

Finally, in this section is worth noting that kinetic acidity is also important.

And removal of a Ch proton is usually relatively slow compared to the removal of an NHOH proton, and this is because carbon acids are generally stabilized by resonance effects and significant structural reorganization upon deprotonation.

This is nicely illustrated by the example down here. We have fenal and nitromethane.

The PK of both of these species is around the same around about 10. When we remove the phenomic proton with the base.

We generate the phenoxide anion.

In that process of proton removal, we start off with the electron density between the oxygen in the hydronic hydrogen. It's closer to the oxygen because Metro because it is more electronegative.

And that gives a relative rate of about 10 to the six, and the electron density ends up on that oxygen.

If we remove a Proton A2, the Nitro Group where cleaving this carbon hydrogen bond on this SP3 hybridized carbon.

And moving the electron density onto this oxygen and this SP3 carbon has to undergo re hybridization to an SP2 carbon.

So this process is more complicated. The charge moves and with the carbon has to undergo re hybridization and this leads to a much slower rate of deprotonation, and the relative rate is 1 compared to the removal of a proton from the phenol.

And in general, the greater structural reorganization during the Proton Azatian, the lower the kinetic acidity.

And.

I've kind of summarized.

Some of these points by looking at a range of functional groups. The PK of Protons, Alpha to them, and in fact the typical basis that you may need to deprotonate Alpha to them so very strongly. Activating groups are Nitro groups and diazo groups. The PK Alpha to these functional groups is usually between about 10 and 20, and you can use relatively weak bases to remove a proton from those.

For us, this is probably the most important section here. Strong and intermediate. So strong activating groups include ketones, esters and then positively charged species such as sulfonium and phosphonium ylides. Antri Flake groups, typically the PK protons Alpha to these groups, is 20 to 30, but we now need to use stronger bases to move a proton after these functional groups.

Intermediate groups include nitriles cell phone, sulfoxides, phosphine, oxides, amides, carboxylated name I'd anions. Now the PK is dropped between 30 and 40 and we have to use really quite strong basis through the proteins after these, and then there are a number of groups which are weak or very weak and the PK is correspondingly much lower and we have to resort to using very very strong bases and bases in the presence of additives such as T. MDA.

Before we move on to look at lithium amide bases, I want to briefly mention super bases.

These are species that are formed by the reaction of simple organolithium such as butyl lithium with potassium alkoxide salt and the most commonly used one is potassium Tert Butoxide. These are commonly referred to as schlosses basis. After the scientist, the chemist who developed these.

The exact structure of these compounds is not known, but they are thought to involve organic potassium intermediate or get attaching type intermediates which you cannot generate by direct deprotonation. Whatever the structure, they are very very very powerful bases. Coordination effects are usually very small, and deprotonation is primary on the acidity of the proton that's being removed. Their soluble in hydrocarbons.

And she also has actually come up with what he calls a zoo of reactivity in a cartoon form. I will only pick out two of these compounds, so in his terminology, N butyl lithium, which of course is a very strong basis represented by the snail and the combination of N Butyl Lithium and potassium Tert Butoxide is called like or and that's the workhorse of these bases.

Just to give you an example of some of the deprotonation's that you can carry out, we can carry out vinylic deprotonation's allylic deprotonation's. We can directly deprotonate aromatic bending type rings and even.

Double deprotonation, so we can do benzylic deprotonation's trap out the corresponding intermediate with trimethyl so low chloride and even generates the 18 dipotassium species from naphthalene, which again can be trapped out with a suitable electrophile. We will come back later on to look at Schloss spaces in more detail and he did a very elegant synthesis of ibuprofen using these compounds.

So my way really, but a little bit of revision will look at the simple reactivity of organolithium's. They are highly reactive, highly basic and nucleophilic, and the reaction I'm going to go through now illustrates both of those facets. So if we take a carboxylic acid such as benzoic acid, react that with two equivalence of N butyl lithium in the first step, the Butte are. Lithium removes the most acidic proton, which is obviously the carboxyl proton to give the car. But lithium copulates salt butyllithium is acting as a base in this step.

The second equivalent will then react with dicarboxylate. Salted is so reactive it can add into that negatively charged species an it will generate this double alkoxide here that is where the reaction stops until we add a proton source, usually a dilute aqueous acid. We protonate both of those oxygens and that gives a ketone hydrate and that loses water to give the parent ketone. Normally that equilibrium does along the side of the ketone, not hydrate form.

This illustrates the point that these are extremely reactive species and butyllithium methyllithium, and it's quite often very difficult to control their reactivity, and this is resulted in the development of a range of derivatives.

Probably the most important of these are lifting a my basis and one of the most important uses of butyl lithium is in the preparation of a compound called LDA or lithium diisopropyl amide. In this process we take this diisopropyl aiming react that with butyl lithium, the PK of the proton here is around about 3637 and so butyllithium is a strong enough base to remove that and we generate an amide anion.

Now we can either draw this in its ionic form with a negative charge on the nitrogen or in a covalent. It doesn't really matter. The by product from this reaction is of course butane, which bubbles from the reaction, making this essentially an irreversible process.

Now, this is still a highly basic species, but what it does possess are two bulky isopropal groups and this allows this to behave as a selective base and carry out so called kinetic deprotonation's and this is illustrated.

In the next reaction.

So if we take a simple compound such as two methylcyclohexane note, react that with our bulky hindered LDA in TH F - 78.

We have a choice of the base to remove either this proton here adjacent to the methyl group or one of the two protons on the other side of the key to.

This proton here because of the presence of the methyl group is more sterically here.

So the bulky base will preferentially remove one of the less into Protons to generate the so called kinetic enolate, and it's called the kinetic in late, because it's the Elate That's formed fastest and the least hindered proton is removed.

The isomer which would result from removal of this proton is the so called thermodynamic in late because the double bond is more substituted and that is usually the most thermodynamically stable species. But this is a very useful base for actually generating kinetic species and there are a number of variants of this which have been developed over the years. All of them are based on the same principle. We have a nitrogen which is flanked by two bulky substituents and obviously a lithium cation associated with that.

So 2266 Lithium Tetramethyl Paradise is also widely used and will come across that later on as is lithium hexamethyl di Sila Side Lithium Hexamethyl di Sila side.

Is quite a useful compound the PK of the proton here is about 10 log units less or more acidic than it is in Diisopropylamine. Again, we can generate the anion by reaction with butyl lithium. And again we can draw this species either with a covalent bond between the nitrogen lithium or as an ionic species here. But these silicones, first of all, hates help stabilize the negative charge, and they're also very bulky, and this allows lithium hexamethyl.

Di Sila side to be used in quite selective reactions. So for example, if we add this Alpha Beta Unsaturated Quito, we observed no conjugate addition of this base into this system, simply deprotonation on the methyl group Alpha to the Carbonell.

So moving on, I want to summarize now and this again is largely revision. Some of the common functional groups and.

The ease with turn to go deprotonation.

We start off with aldehydes. This is acetaldehyde, the simplest aldehyde, the peak of the proton. Often aldehyde is about 17 or 18 and aldehyde in late anions are extremely reactive approach to self condensation reactions and are very rarely used. In fact, will look at the use of Matallo ina means as a substitute for these in a minute.

LDA can be used to deprotonate Alpha to a ketone. This is a well behaved reaction. The enolates are reasonably stable, and the only problem that can be usually encountered is Poly alkylation.

We can deprotonate Alberto and Esther. These Ester enolates are highly reactive and at higher temperatures, usually about minus 40. They undergo elimination to give a ketting.

Carboxylic acids can undergo double deprotonation.

So with two equivalents of a strong base, such as LDA, we first of all remove the acidic proton on the carboxylic acid, and then can deprotonate Alpha to the Carbonell to generate a Diane, and these are very reactive, as you may imagine, but solubility of these can also be problematic.

A mites are capable of being deprotonated, but the alkylated products are stable, and if you wish to hydrolyze the aim, I'd off. That can usually be quite difficult, and of course if we have a primary or secondary amide, in other words, we have a proton that nitrogen we would get deprotonation of that NH first.

Finally, Knight Trials nitrile anions are easily formed again using a base such as LDA in TH F - 78 and they are really rather well behaved. In fact, nitrile anions are well behaved and quite reactive, so they are good species to generate. I mentioned the problem with aldehydes forming Elates from them. They are highly reactive.

And one solution to this problem is to generate matallo enemies. So in this process we take an aldehyde. We react it with. In this case a simple primary aiming to generate the corresponding imming. This is an acid catalyzed reaction and requires the removal of water, but once this has been purified, we can deprotonate at this position here generating matallo ina mean and this can undergo alkylation.

With an electrophile this brumer acetal, in this case to generate this species here.

Now the imine, we can selectively hydrolyze back to the carbonyl compound with very weak aqueous acid, and this can be done selectively. In this case with stronger acid, we can also. We can also hydrolyze that acetal back to the corresponding carbonyl compound.

Now we talked about.

In lights and then alkylation reactions is worth mentioning that the nature of the electrophile is also extremely important in these reactions.

Not all electrophiles are as reactive. Good alkylating reagents are usually primary allylic or benzylic species, so here is a list of very reactive alkylating agents. Mythology I'd al bromide, benzyl bromide, propala job bromide, and this methyl chlorate. Promo esters and in fact, an iodo nitrile compound. Here, all of these react readily with in late anions.

Usually with no little, no problems whatsoever.

Borderline alkylating reagents include compounds where we now have secondary halides as opposed to primary halides, and this is because we're essentially doing SN two reaction and SN two reactions are faster on primary halides than they are in secondary halides.

So I sub profile iodide two butyl bromide, epoxides and more sterically hindered benzal bromides will undergo reaction within lights. But the reactions are much slower and elimination reactions become a problem.

Critically.

Alkylating agents that do not work or vinyl halides and that includes vinyl bromide, vinyl iodide, Aaron bromides.

Tertiary butyl bromide Zoraida hides and so-called near Pentile bromides.

And the neopentyl doesn't look first look surprising, but this tertiary butyl group here is close enough to that carbon to prevent the approach of enolate anion.

And so none of these will react at any appreciable rate with a reactive England Anile.

Just to finish off on the inlet section E, let's derive from acid clouds. In a hydrides you can generate them, but even at low temperature there unstable and undergo elimination to form kettins, which polymerize under basic conditions.

So I want to finish this lecture by looking at the major methods for the synthesis of functionalized organolithium's.

We will be looking at two of them and the first of those is deprotonation, where we take a substrate which I've defined here as our one H. React that with a gun, lithium species, and in most cases will be looking at using species such as Beuttel. Set beuttel are tertiary butyl lithium. We get direct removal of a proton to generate a second organolithium and if we're using butyl lithium, this would become butane and would bubble off from reaction mixture.

The second method is so-called transmetalation and halogen metal exchange.

This is something you probably not come across before, but in this process we take a substrate where we now have a carbon bound to a bromine, iodine, or what I've defined as M and metal and the row variety of species that we can use. But the one we will build it later is that in.

And it's important that we use bromide or iodide. This reaction does not work terribly well with either chloro or fluoro substituents.

Again, in this process, we take the substrate we treat it with a simple alkyl lithium such as butyl lithium at low temperature and effectively we get an exchange reaction where.

The X.

Substituent halogen or tin substituent.

Is exchange with the beuttel group, so we generate the organolithium and the R2 Halide. So we effectively do an exchange. The lithium replaces the X and the X becomes attached to hydrogen becomes attached to the R2 Group. Now I've drawn this as a one directional process. In fact, it is an equilibrium process, but there are fairly well defined rules on the direction of this process and this reaction occurs to give the more stable.

All kind of lithium, so if this is a more stable organolithium than this one then the reaction will proceed.

Two of the methods which I won't be covering, our reductive lithiation in, which again we take a carbon bearing. A halogen, usually again bromine or idine, and react that with a source of Electrons.

And we get a series of single electron transfers to generate the organolithium and now we generate the lithium halides as the byproduct and this can be done using a number of electron sources. Typically species like lithium nathaly door. You can even do it Electro chemically.

And then finally, Carbo. Lithiation is a process where we taken organolithium and add that into an unsaturated unit. I've just simply used.

And alkene here ethylene but in fact there's a wide range of different unsaturated units that you can use alkynes and alkenes and we get effect.

Only an insertion into that unsaturated unit to give a homologated organolithium.