Lecture Stoechiometric Organometallics 1 - 15.10.13
Dyker, Gerald
Comments on Pearsons HSAB principle (hard soft acid base) in the contexts of stoechiometric organometallic chemistry
 So, ladies and gentlemen, welcome to the lecture Organic Synthesis 1, Stichometric Organometallics. And of course, a special welcome to Sandra Lee and the Rupkast team, who will video cast the lecture throughout the whole semester. So, this lecture is the first part, and the second part with the title Catalytic Organometallics is scheduled for the summer semester. So, now to Stichometric Organometallics. When we have a look at the periodic system of elements, and unfortunately in this lecture hole there is no one, well, then we notice an awful lot of metals. And you might get the impression that it could be some kind of nightmare if you have to choose a metal for your purposes, for your synthesis. On the other hand, the awful lot of metals offers us the opportunity to find a suitable one. And indeed, therefore, well, almost any given synthetic problems involving organometallics, you will find some organometallics reagents with the correct properties you need. And moreover, you have the opportunity to trigger the reactivity by adding further ligands. But this is, of course, more used in terms of catalytic organometallics. So, but the possibilities which are imminent in organometallic synthesis makes that so successful. First example, so we have an allulic organometallic species, two substituents here, and we let that react with carbon dioxide. And after hydrolysis, we will obtain either this carboxylic acid or the one with the quaternary center. If the metal is potassium, an allulic potassium species, we will get a product ratio of 90 to 10. So let's change the metal to a Grignet reagent. In that case, it was found that it will result in a 1 to 99 ratio. Well, somehow this is a rather strange result. Why? Clearly, the organoprotassium compound is much more reactive than a Grignet reagent. Nevertheless, the more reactive reagent leads to the thermodynamically more stable product. Clearly, with the Grignet reagent, 99% of the thermodynamically less stable product means this reaction to that product is clearly kinetically controlled. We can explain that if we have a closer look to the structures that are involved. In case of the potassium species, we have a potassium that is coordinated to the allulic anion. Well, it is an extremely polar bond. It is a pi complex. Actually, it is a trihaptopi complex because the potassium is bound to the three centers, coordinated to the three centers. We can also call it an etter three complex. This is a usual abbreviation for that case. So highly reactive system, and now it is clear that at that terminal carbon, we have a minor steric hindrance compared to this center. And therefore, it is clear that we see a two-can more easily attack at that center, resulting finally in this also thermodynamically more stable compound. On the other hand, the Grignet reagent, in this case, the magnesium is more covalently bound to the terminal position. In this case, it is an etter one complex or a sigma complex in contrast to the pi complex in that case. We have with the magnesium the electrophilic center. Magnesium is, as you know, a Lewis acid. While in Grignet reagent, usually ether molecules are coordinated to the magnesium, but in equilibrium, an ether molecule pops off, giving three-vat coordination site. And then the CO2 coordinates to the magnesium. And through a six-membered transition state, the CC bond is formed. Well, and this is, of course, the magnesium carboxylate. And after acidic hydrolysis, we have the final product. So this example makes clear that it is indeed useful to choose between different metals, because we have clearly different selectivities. The corresponding allulithium species is, in this case, similar. Now, it's in between potassium and Grignet. Whereas the allulzinc behaves, in this case, at least similar to the Grignet reagent. So a basic concept which is regarded to be rather useful in choosing the right reagents for synthesis, you know already is the HSAB concept. Or HSAB principle. And the name, the abbreviation, derives from hard, soft, acid, base principle. It was introduced in the early 1960s by Pearson as an extension of the Lewis acid base concept. So Lewis, as you know, defines acids as electron pair acceptors, while you can use the expression electrophile as a synonym. Then, of course, an electron pair donator. Or you can use also the word nucleophile. Now, to Pearson's extension, he differentiates between hard acids, soft acids, and well, there is, of course, something in between, medium or borderline acids. And he introduced the same differentiation to the Lewis basis. Again, hard, medium, and soft. So how did he characterize the expression hard? So a hard Lewis acid is generally small, has a high charge density, and is weakly polarizable, or I would say hardly polarizable. So on soft, or simply is the opposite. So OK, let's draw that to the blackboard. Soft, big, low charge density, and strongly polarizable. Or I think this becomes more clear if we put on some examples. For instance, a hard acid. So what is really small, has a high charge density, and is weakly polarizable. The record holder, of course, is a proton. That's it. So H plus. In this category, we have also lithium plus, could see also magnesium 2 plus, and iron 3 plus. Soft, while metals in the oxidation state 0, can be never less Lewis acids, or rather soft Lewis acids. Nickel plus, but also palladium 2, or the silver, cut iron. And medium, well, there we have then iron 2 plus zinc 2 plus, and copper 2 plus is also regarded as medium. Now to the bases. Fluoride, and iron is the prototype of a hard base. Hydroxylu and iron is also a hard base, although relatively a bit more soft than fluoride. Then ammonium, ammonia, NH3, well, a hard base. We have a free electron pair, and we have an element there with a high electronegativity. Nevertheless, it is basic. It is more basic than that. That means this is more nucleophilic than that. So all those are regarded to be relatively hard, although, of course, NH3 is more soft than fluoride. And also here, in this category, alcoholates. Medium bromide, somewhere here, also chloride, I had forgotten. And soft, clearly, the iodide, a big anion. Or conjugated anions. Enolate, conjugated systems, a big systems, strongly polarizable, should be regarded as soft, Lewis acids, or soft nucleophiles. Thiolates, phosphines, hydrides are in this category. And what is rather important for us in this lecture, organometallic reagents, alkyl or aryl anions. That means alkyl metal species. So now to the core statement of the Hart-Soft acid base principle, I will write down that core statement. So the core statement, soft acids, react faster and form moreange. Whereas, hard acids all react faster and form stronger bonds with hard bases. OK. So what is the explanation? A hard, hard interaction, what could it be? Well, for instance, a lithium plus and an F minus. Reaction of a lithium plus and an F minus would be driven by the electrostatic charge. OK. So hard, hard interaction is charge controlled. And two centers with opposite charge from high density will react rather fast with each other if we put aside salvation effects, of course. On the other hand, soft, soft interaction, according to this principle, is also favored. This is regarded to be controlled by frontier orbital interaction. Well, the first one is easy to understand. The second one you have to think a bit about that. So for instance, a soft anion. The soft anion, we have to look at the energy level of the highest occupied molecular orbital. The soft anion has the homo on a relatively high energy level. This, I think, is easy to understand. Just take into account the opposite, a fluoride, electronegative. It holds to its electron pairs. The electron pairs of the fluoride are on a low energy level. That means with a soft anion, it has to be the opposite. A soft Lewis acid or cation, homo energy level are low. Relatively high energy level, relatively high. With a cation, we have to take a look at the lowest unoccupied molecular orbital. This is, of course, the frontier orbital. And in this case, the energy level of the lumo is relatively low. For instance, as an example, the allylic cation. A allylic cation are rather medium or relatively big electron system compared to an H plus or a lithium plus. It is conjugated. It is polarizable. So the allylic cation is a prototype of a soft cation. And because of the conjugation, you have the lumo in a relatively low energy level. You could easily put on an electron forming an allylic radical. And the homo on a relatively high level, the lumo of the Lewis acid on a rather low level, that means they have almost the same energy level. And then it's easy to transform electron density. It just fits. Forming, then, of course, are rather stable covalent bonds. And it's a rather fast reaction. So this model here is called or known as the Klopman-Salen concept. OK, at this point, let us go back to this core statement. Once again, soft acids react faster and form stronger bonds with soft bases. The expression reacts faster, of course, addresses the kinetics of a reaction. And form stronger bonds. This expression addresses the thermodynamics. So I think this sounds great. If the hard soft acid base concept, we have the impression that we address both kinetics and thermodynamics. This is, of course, not true. Kinetics and thermodynamics are clearly neglected within the hard soft acid base concept. We just don't differentiate between kinetics and thermodynamics. And while this is clearly an over simplification. And that's the reason why a lot of chemists are not in favor of the hard soft acid base concept. And I think the best review article criticizing this concept was published about two years ago by Herbert Meyer from the LMU in Munich. And it was published in Angewandte Chemie International Edition 2011 on page 6470. And it's about 35 pages long. And the article has the interesting title, Farewell to the HSAB Treatment of Ambident Reactivity. Wow. Very interesting article. And he is right in a lot of points. However, if you use the HSAB concept as some kind of qualitative guideline, as some kind of rule of thumb, it will help a lot and still makes sense. So, it's time for some examples. An asshole cat iron. Of course, highly electrophilic hard electrophile. So, a hypothetic reaction with a hard base. Let's have a look for a hard base. A hard base we have, for instance, an alcohol aid. Should result in an aster. And we all know an aster is a rather stable compound. Of course, not alone based on the hard soft interaction, but it has something to do with a conjugated system there. So, but let's check, does the hard soft as a base principle, the Pearson principle work out in similar cases? If we add a soft base, for instance, an iodide or a thionate. Well, what do we get then? A carboxylic acid, iodide or such a thioaster. Well, you can handle those iodides. No problem. But both compounds are far more reactive against hydrolysis with water, for instance. Now, an interesting argument is what about the fluoride? Fluoride is clearly a hard base, harder than the alcohol aid. And in that case, we should discuss the stability of the carboxylic acid fluoride. It makes a bit suspicious to all of us. And it was also a surprise for me to find that carboxylic acid fluorides are more stable against hydrolysis as carboxylic acid chlorides. So, acidic acid fluoride is more stable against the interaction with water hydrolysis as acidic acid chloride. Then carboxylic acid chlorides. Well, next type of reaction. A nitrile. A nitrile is regarded to be a hard electrophile. So, hard Lewis acid at the carbon center and a hard Lewis base of a free electron pair at the nitrogen. Plus hydrogen fluoride with the hard base fluoride here will react in an addition process. And gives this iminium, this imine of a carboxylic acid fluoride, which of course will react with additional HF to form the iminium salt. So, again, the concept works. Hard acid, hard base, also the other way round, hard acid the proton and hard base here the nitrogen. The addition reaction works. Try that with hydrogen iodide and it won't work. So, not to a bit more interesting. Examples. Carbonyl compounds. The oxygen, hard base, the carbon is regarded to be a hard acid. Here we have a substrate which has alderhyde functionality and a tosylate within the same molecule. This carbon, a hard electrophile. This carbon with the tosylate leaving group is also an electrophile, also regarded to be rather hard electrophile, although somehow softer than that. So, softer, not softer, softer than this position. Here we have a thiophenolate. Thiolates are soft nucleophiles, especially if conjugated to an aromatic system. So, this is soft and on the other hand, a cyanide has a relatively hard, well, both are soft. Both are soft systems, but this is of course harder than that, or this softer than that. So, both soft, but this is relatively hard compared to the thiolate. And indeed, that thiolate selectively reacts with the softer position. Simply a nucleophilic substitution as an asin-2 trusses. With the thiolate, a completely different pathway, reaction pathway is observed. It detects the harder electrophilic center. So, that means we get this intermediate and now an intramolecular asin-2 process is observed with the alkylate as the nucleophilic center. And that carbon as the electrophilic center resulting in this product. So, enolates as ambident nucleophiles. Enolates with the two mesomeric structures. Of course, the oxygen is the hard nucleophilic center and the carbon is the soft nucleophilic centers. That means the hard soft acid base concept suggests that hard electrophiles should form a bond to the oxygen and soft electrophiles should form a bond to the carbon. So, is that true? As it turned out, it is somewhat an overinterpretation of the hard soft acid base concept. Because the enolate of cyclohexanone plus bromomethane in the gas phase. Has been tested to give exclusively the O-alculation product. Although the methyl, the bromomethane is regarded to be rather soft. This is somewhat contradictory to what we expect from the hard soft acid base concept. Another example is lithium enolates have been shown by the famous Dieter Sebach from Zurich University. He invented the activity of reactivity. And found that under the right reaction conditions, lithium enolates with acyclerides in THF at low temperature minus 100 degrees to minus 80 degrees react under CC bond. Formation also contradictory to what we expect from the Pearson concept. And indeed there are numerous examples known where normally the acylation takes place at the oxygen. It can easily form that. It depends on the reaction conditions. So, this is contradictory or it gives the impression that it is contradictory to the hard soft acid base principle. But as I said, predicting this is soft and therefore it has to react here is an over interpretation of it. You can use it as a rule of thumb if you make for instance a test reaction and you find with a bromide you have a certain product ratio. With the hard soft acid base principle you can then predict how the product ratio will change if you change from the bromide to the chloride to the iodide or to the tosylate. So, you need one experimental result to make a prediction based on the HSAB concept. And this can be very useful. We will see that in a couple of more examples. A sodium enolate with a butyl compound and X is a leaving group. We would anticipate two products while here this and trans maybe. The O-alculation product and the C-alculation product. So, let's form a table with percentage of O-alculation. And it depends very much on the solvent which is used. HMPT as a solvent. Hexamethylphosphoric acid triamide. First with the iodide just 15% O-alculation. With the bromide we have more 40% alculation. Butyl chloride is more hard electrophile than the bromide. So, we should get even more O-alculation. And indeed it turns out to be right 67%. The tosylate 85%. And then let's go to the fluoride 96% O-alculation. Fluorobutane is the hardest electrophile. So, it gives indeed the best yield of the O-alculation product. Something wrong? Okay, it's okay. Well, let's change to DMSO. 10%, 23%, 46%. Well, here we have 44% and the fluoride has not been tested. Generally, lower percentage of O-alculation. But HMPT and DMSO both are rather polar solvents. Similar, but this is much more polar. Let's go to a far less polar solvent, diaphyl ether. So, just 1% of O-alculation in the case of iodide. Then 5% with the bromide, 18% with the chloride, and the tosylate 20%. And well, this means 80% of the C-alculation. Generally, we can say that if we have dissociated enolates, naked enolates separated from the counter-cut iron by the solvent, which is indeed the case in HMPT and similarly in DMSO, and maybe a bit also in DMF, then we have a high oxygen-carbon ratio. If we have iron pairs, well, then we will get an intermediate result. And if we have higher aggregates as frequently observed in ethos solvents, then we have a low oxygen-carbon ratio. So that means or that shows that the solvent has indeed a tremendous influence on the outcome of the reaction. However, again, if we have tested here, the bromide gives the 23% yield of O-alculation, and we want to increase the amount of O-alculation, well, we know that we will get a better result if we go to the chloride or to the tosylate. But nevertheless, if we could even more influence the outcome with changing the solvent. That's what we should learn from this example. Another interesting case is the alkylation of the enolate of acetic acid, acetoacetic acid ester. In this case, the potassium enolate has been tested in the reaction with ethyl halides. Again, in HMPT, in order to examine the influence of the leaving group on the ratio between O-alculation and C-alculation. So, X and B-O-C ratio. Iodide, the softest ethyl alkyl, which has been tested, 0.15. That means we have far more C-C bond formation than C-O bond formation in this case. Bromide, 0.65, we get more reaction, a bit more reaction at the oxygen. With the chloride, we already have the turnaround, more O-alculation than C-alculation. Consequently, with the tosylate, we get a rather high amount of O-alculation. Now to organometallic species. The carbon-metal bond. Methyl group sitting at a metal, then an ethyl group, ethyl group, an isopropyl group, and a tertiary butyl group. Those are all regarded as soft bases at the carbon center. But from the methyl species to the tertiary butyl species, they get softer. So this one is harder and this is softer simply because it is bigger. And the anionic charge is stabilized through that molecule. For example, although with this example one should be a bit careful, however, if we choose to let this react with methylgrinier, we will get predominantly the 1,2 addition product. Changing to the isopropylgrinier will give us predominantly the 1,4 addition product or it is called conjugate. Addition product. All. We have in that alphabet unsaturated ketone two electrophilic centers. One of the carbonyl group, this is the hard electrophile and this center, the conjugated one, is regarded to be the soft one. And while you can interpret that in terms of the hard soft SS base concept, this is harder, reacts here, this is softer, reacts there. But maybe one has to, in the explanation, this is not certainly not a good mechanistic explanation. You should take in a mechanistic explanation also into account steric hindrance, steric interaction, of course. Nevertheless, let's have a look at a similar reaction, cyclohexanone plus tertiary-routile lithium. This clearly gives this product. This tells us that the structure of the carbon nucleophile is less influential than the nature of the metal. Lithium is harder than magnesium. So, hardness, lithium harder than a grignet reagent and this is harder than any cuprate. Again, cyclohexanone. First, methyl lithium, secondly, hydrolysis will result in the allylic alcohol and while cuprate, for instance, this one, hydrolyzed after C-C bond formation will give the conjugate addition product. Until now, we have only interpreted this in terms of the arts of acid base principle in focusing on the carbon center. We could also interpret it in focusing on the metal. Lithium, the lithium cation, harder than a copper cation and therefore the lithium cation as a Lewis acid coordinates preferentially at the free electron pairs of the oxygen. On the other hand, the cuprate might coordinate with the electron density of that double bond. Indeed, Norbert Krause from our neighboring university Dortmund a couple of years ago found some interesting examples that proved that with NMR spectroscopy that the cuprates are indeed coordinating to that double bond. Two further examples for today. More complicated ones. An isolated pyridine and isolated with a counter anion, presumably simply a chloride. So where do we have electrophilic centers here? So of course, this carbon is very electrophilic and this is certainly the hardest electrophilic center. Here in this aromatic system, a conjugated system, we could write down some mesomeric structures with positive charge there and there and there. This visualizes that we have electrophilic centers here in the ortho position of a nitrogen and also in the para position. These in the conjugated systems are of course regarded to be much softer than that. And well, okay, here and there, we have a soft position and there, this is even softer. So a reaction and what you live them at minus 78 degrees was found out to react exclusively almost exclusively at this carbon. Well, this is in accord with what we have already seen here with alkylithium species. And it simply set free the pyridine and formed that astro. Next test was done with agrinia reagent and motile magnesium bromide also at minus 78 degrees. And here, we observed predominantly the reaction at the soft and softer positions. What is the result in that case? This and the para isomer was found in the ratio 67 to 33. Of course, this means there is no real discrimination between the ortho and the para position because we have the ortho position twice and the para position only once. It's just the ratio of one to one to one and this is the result then. So the organomagnetium discriminates between the heart center and the soft centers but not between soft and softer. Going to softer organometallic reagent and organosync which is less reactive and they have done the reaction at higher temperature at zero degrees and the copper, the compound organocopper would react similarly. In this case, they achieved a ratio of 19 to 81. That means with the less reactive organosync you indeed can discriminate between the soft and the softer position and get predominantly the reaction in the para position. Last example for today. Once again, the enolate of the 1,3-dicarbonide compound and focus is the reaction with an allyl compound, an allyl electrophile, with the c-alculated product as the target. The first attempt simply with allyl bromide gave a 30% yield of the target compound. Interesting is the result with an allyl acetate which is not reactive to this nucleophile, not that reactive to this nucleophile in the moderate reaction conditions, but adding a catalyst, a palladium zero catalyst. Again, this product was isolated in a 94% yield while actually this is the so-called Suji-Trost reaction and the palladium zero catalyst as a very soft nucleophile reacts with the allyl acetate forming such an allyl palladium complex and this is indeed a very, very soft electrophile and this gives then a high yield. We will see more of these catalytic systems of course in summer semester. So, okay, I think we should finish for today. See you tomorrow with remarks on basic reaction types in organometallic, stoichiometric organometallics chemistry. Thanks for listening. See you tomorrow.
 So, ladies and gentlemen, welcome to the lecture Organic Synthesis 1,  Stichometric Organometallics.  And of course, a special welcome to Sandra Lee and the Rupkast team,  who will video cast the lecture throughout the whole semester.  So, this lecture is the first part, and the second part with the title  Catalytic Organometallics is scheduled for the summer semester.  So, now to Stichometric Organometallics.  When we have a look at the periodic system of elements,  and unfortunately in this lecture hole there is no one,  well, then we notice an awful lot of metals.  And you might get the impression that it could be some kind of nightmare  if you have to choose a metal for your purposes, for your synthesis.  On the other hand, the awful lot of metals offers us the opportunity  to find a suitable one.  And indeed, therefore, well, almost any given synthetic problems  involving organometallics, you will find some organometallics reagents  with the correct properties you need.  And moreover, you have the opportunity to trigger the reactivity  by adding further ligands.  But this is, of course, more used in terms of catalytic organometallics.  So, but the possibilities which are imminent in organometallic synthesis  makes that so successful.  First example, so we have an allulic organometallic species,  two substituents here, and we let that react with carbon dioxide.  And after hydrolysis, we will obtain either this carboxylic acid  or the one with the quaternary center.  If the metal is potassium, an allulic potassium species,  we will get a product ratio of 90 to 10.  So let's change the metal to a Grignet reagent.  In that case, it was found that it will result in a 1 to 99 ratio.  Well, somehow this is a rather strange result.  Why?  Clearly, the organoprotassium compound is much more reactive  than a Grignet reagent.  Nevertheless, the more reactive reagent leads to the thermodynamically  more stable product.  Clearly, with the Grignet reagent, 99% of the thermodynamically  less stable product means this reaction to that product  is clearly kinetically controlled.  We can explain that if we have a closer look to the structures  that are involved.  In case of the potassium species,  we have a potassium that is coordinated to the allulic anion.  Well, it is an extremely polar bond.  It is a pi complex.  Actually, it is a trihaptopi complex  because the potassium is bound to the three centers,  coordinated to the three centers.  We can also call it an etter three complex.  This is a usual abbreviation for that case.  So highly reactive system, and now it  is clear that at that terminal carbon,  we have a minor steric hindrance compared to this center.  And therefore, it is clear that we see a two-can more easily  attack at that center, resulting finally in this also  thermodynamically more stable compound.  On the other hand, the Grignet reagent,  in this case, the magnesium is more covalently bound  to the terminal position.  In this case, it is an etter one complex or a sigma complex  in contrast to the pi complex in that case.  We have with the magnesium the electrophilic center.  Magnesium is, as you know, a Lewis acid.  While in Grignet reagent, usually ether molecules  are coordinated to the magnesium,  but in equilibrium, an ether molecule  pops off, giving three-vat coordination site.  And then the CO2 coordinates to the magnesium.  And through a six-membered transition state,  the CC bond is formed.  Well, and this is, of course, the magnesium carboxylate.  And after acidic hydrolysis, we have the final product.  So this example makes clear that it is indeed  useful to choose between different metals,  because we have clearly different selectivities.  The corresponding allulithium species is, in this case,  similar.  Now, it's in between potassium and Grignet.  Whereas the allulzinc behaves, in this case, at least  similar to the Grignet reagent.  So a basic concept which is regarded to be rather useful  in choosing the right reagents for synthesis,  you know already is the HSAB concept.  Or HSAB principle.  And the name, the abbreviation, derives from hard, soft, acid,  base principle.  It was introduced in the early 1960s by Pearson  as an extension of the Lewis acid base concept.  So Lewis, as you know, defines acids as electron pair  acceptors, while you can use the expression  electrophile as a synonym.  Then, of course, an electron pair donator.  Or you can use also the word nucleophile.  Now, to Pearson's extension, he differentiates  between hard acids, soft acids, and well, there is, of course,  something in between, medium or borderline acids.  And he introduced the same differentiation  to the Lewis basis.  Again, hard, medium, and soft.  So how did he characterize the expression hard?  So a hard Lewis acid is generally small, has a high  charge density, and is weakly polarizable, or I would say  hardly polarizable.  So on soft, or simply is the opposite.  So OK, let's draw that to the blackboard.  Soft, big, low charge density, and strongly polarizable.  Or I think this becomes more clear if we put on some examples.  For instance, a hard acid.  So what is really small, has a high charge density,  and is weakly polarizable.  The record holder, of course, is a proton.  That's it.  So H plus.  In this category, we have also lithium plus, could see also  magnesium 2 plus, and iron 3 plus.  Soft, while metals in the oxidation state 0, can be  never less Lewis acids, or rather soft Lewis acids.  Nickel plus, but also palladium 2, or the silver,  cut iron.  And medium, well, there we have then iron 2 plus zinc  2 plus, and copper 2 plus is also regarded as medium.  Now to the bases.  Fluoride, and iron is the prototype of a hard base.  Hydroxylu and iron is also a hard base, although relatively  a bit more soft than fluoride.  Then ammonium, ammonia, NH3, well, a hard base.  We have a free electron pair, and we have an element there  with a high electronegativity.  Nevertheless, it is basic.  It is more basic than that.  That means this is more nucleophilic than that.  So all those are regarded to be relatively hard, although,  of course, NH3 is more soft than fluoride.  And also here, in this category, alcoholates.  Medium bromide, somewhere here, also chloride, I had forgotten.  And soft, clearly, the iodide, a big anion.  Or conjugated anions.  Enolate, conjugated systems, a big systems, strongly  polarizable, should be regarded as soft,  Lewis acids, or soft nucleophiles.  Thiolates, phosphines, hydrides are in this category.  And what is rather important for us in this lecture,  organometallic reagents, alkyl or aryl anions.  That means alkyl metal species.  So now to the core statement of the Hart-Soft acid base  principle, I will write down that core statement.  So the core statement, soft acids, react faster and form  moreange.  Whereas, hard acids all react faster and form stronger bonds  with hard bases.  OK.  So what is the explanation?  A hard, hard interaction, what could it be?  Well, for instance, a lithium plus and an F minus.  Reaction of a lithium plus and an F minus would be driven by  the electrostatic charge.  OK.  So hard, hard interaction is charge controlled.  And two centers with opposite charge from high density  will react rather fast with each other if we put aside  salvation effects, of course.  On the other hand, soft, soft interaction, according to  this principle, is also favored.  This is regarded to be controlled by frontier orbital  interaction.  Well, the first one is easy to understand.  The second one you have to think a bit about that.  So for instance, a soft anion.  The soft anion, we have to look at the energy level of the  highest occupied molecular orbital.  The soft anion has the homo on a relatively  high energy level.  This, I think, is easy to understand.  Just take into account the opposite, a fluoride,  electronegative.  It holds to its electron pairs.  The electron pairs of the fluoride are on a low energy  level.  That means with a soft anion, it has to be the opposite.  A soft Lewis acid or cation, homo energy level are low.  Relatively high energy level, relatively high.  With a cation, we have to take a look at the lowest  unoccupied molecular orbital.  This is, of course, the frontier orbital.  And in this case, the energy level of the  lumo is relatively low.  For instance, as an example, the allylic cation.  A allylic cation are rather medium or relatively big  electron system compared to an H plus or a lithium plus.  It is conjugated.  It is polarizable.  So the allylic cation is a prototype of a soft cation.  And because of the conjugation, you have the lumo in a  relatively low energy level.  You could easily put on an electron  forming an allylic radical.  And the homo on a relatively high level, the lumo of the  Lewis acid on a rather low level, that means they have  almost the same energy level.  And then it's easy to transform electron density.  It just fits.  Forming, then, of course, are rather stable covalent  bonds.  And it's a rather fast reaction.  So this model here is called or known as the Klopman-Salen  concept.  OK, at this point, let us go back to this core statement.  Once again, soft acids react faster and form stronger  bonds with soft bases.  The expression reacts faster, of course, addresses the  kinetics of a reaction.  And form stronger bonds.  This expression addresses the thermodynamics.  So I think this sounds great.  If the hard soft acid base concept, we have the impression  that we address both kinetics and thermodynamics.  This is, of course, not true.  Kinetics and thermodynamics are clearly neglected within the  hard soft acid base concept.  We just don't differentiate between kinetics and thermodynamics.  And while this is clearly an over simplification.  And that's the reason why a lot of chemists are not in favor of  the hard soft acid base concept.  And I think the best review article criticizing this  concept was published about two years ago by Herbert Meyer  from the LMU in Munich.  And it was published in Angewandte Chemie International  Edition 2011 on page 6470.  And it's about 35 pages long.  And the article has the interesting title,  Farewell to the HSAB Treatment of Ambident Reactivity.  Wow.  Very interesting article.  And he is right in a lot of points.  However, if you use the HSAB concept as some kind of qualitative  guideline, as some kind of rule of thumb, it will help a lot  and still makes sense.  So, it's time for some examples.  An asshole cat iron.  Of course, highly electrophilic hard electrophile.  So, a hypothetic reaction with a hard base.  Let's have a look for a hard base.  A hard base we have, for instance, an alcohol aid.  Should result in an aster.  And we all know an aster is a rather stable compound.  Of course, not alone based on the hard soft interaction,  but it has something to do with a conjugated system there.  So, but let's check, does the hard soft as a base  principle, the Pearson principle work out in similar cases?  If we add a soft base, for instance, an iodide or a thionate.  Well, what do we get then? A carboxylic acid, iodide or such a thioaster.  Well, you can handle those iodides.  No problem.  But both compounds are far more reactive against hydrolysis with water, for instance.  Now, an interesting argument is what about the fluoride?  Fluoride is clearly a hard base, harder than the alcohol aid.  And in that case, we should discuss the stability of the carboxylic acid fluoride.  It makes a bit suspicious to all of us.  And it was also a surprise for me to find that carboxylic acid fluorides are more stable against hydrolysis as carboxylic acid chlorides.  So, acidic acid fluoride is more stable against the interaction with water hydrolysis as acidic acid chloride.  Then carboxylic acid chlorides.  Well, next type of reaction. A nitrile.  A nitrile is regarded to be a hard electrophile.  So, hard Lewis acid at the carbon center and a hard Lewis base of a free electron pair at the nitrogen.  Plus hydrogen fluoride with the hard base fluoride here will react in an addition process.  And gives this iminium, this imine of a carboxylic acid fluoride,  which of course will react with additional HF to form the iminium salt.  So, again, the concept works. Hard acid, hard base, also the other way round, hard acid the proton and hard base here the nitrogen.  The addition reaction works. Try that with hydrogen iodide and it won't work.  So, not to a bit more interesting. Examples.  Carbonyl compounds. The oxygen, hard base, the carbon is regarded to be a hard acid.  Here we have a substrate which has alderhyde functionality and a tosylate within the same molecule.  This carbon, a hard electrophile.  This carbon with the tosylate leaving group is also an electrophile, also regarded to be rather hard electrophile, although somehow softer than that.  So, softer, not softer, softer than this position.  Here we have a thiophenolate. Thiolates are soft nucleophiles, especially if conjugated to an aromatic system.  So, this is soft and on the other hand, a cyanide has a relatively hard, well, both are soft.  Both are soft systems, but this is of course harder than that, or this softer than that.  So, both soft, but this is relatively hard compared to the thiolate.  And indeed, that thiolate selectively reacts with the softer position.  Simply a nucleophilic substitution as an asin-2 trusses.  With the thiolate, a completely different pathway, reaction pathway is observed. It detects the harder electrophilic center.  So, that means we get this intermediate and now an intramolecular asin-2 process is observed with the alkylate as the nucleophilic center.  And that carbon as the electrophilic center resulting in this product.  So, enolates as ambident nucleophiles.  Enolates with the two mesomeric structures.  Of course, the oxygen is the hard nucleophilic center and the carbon is the soft nucleophilic centers.  That means the hard soft acid base concept suggests that hard electrophiles should form a bond to the oxygen and soft electrophiles should form a bond to the carbon.  So, is that true? As it turned out, it is somewhat an overinterpretation of the hard soft acid base concept.  Because the enolate of cyclohexanone plus bromomethane in the gas phase.  Has been tested to give exclusively the O-alculation product.  Although the methyl, the bromomethane is regarded to be rather soft.  This is somewhat contradictory to what we expect from the hard soft acid base concept.  Another example is lithium enolates have been shown by the famous Dieter Sebach from Zurich University.  He invented the activity of reactivity.  And found that under the right reaction conditions, lithium enolates with acyclerides in THF at low temperature minus 100 degrees to minus 80 degrees react under CC bond.  Formation also contradictory to what we expect from the Pearson concept.  And indeed there are numerous examples known where normally the acylation takes place at the oxygen.  It can easily form that. It depends on the reaction conditions.  So, this is contradictory or it gives the impression that it is contradictory to the hard soft acid base principle.  But as I said, predicting this is soft and therefore it has to react here is an over interpretation of it.  You can use it as a rule of thumb if you make for instance a test reaction and you find with a bromide you have a certain product ratio.  With the hard soft acid base principle you can then predict how the product ratio will change if you change from the bromide to the chloride to the iodide or to the tosylate.  So, you need one experimental result to make a prediction based on the HSAB concept.  And this can be very useful.  We will see that in a couple of more examples.  A sodium enolate with a butyl compound and X is a leaving group.  We would anticipate two products while here this and trans maybe.  The O-alculation product and the C-alculation product.  So, let's form a table with percentage of O-alculation.  And it depends very much on the solvent which is used.  HMPT as a solvent.  Hexamethylphosphoric acid triamide.  First with the iodide just 15% O-alculation.  With the bromide we have more 40% alculation.  Butyl chloride is more hard electrophile than the bromide.  So, we should get even more O-alculation.  And indeed it turns out to be right 67%.  The tosylate 85%.  And then let's go to the fluoride 96% O-alculation.  Fluorobutane is the hardest electrophile.  So, it gives indeed the best yield of the O-alculation product.  Something wrong?  Okay, it's okay.  Well, let's change to DMSO.  10%, 23%, 46%.  Well, here we have 44% and the fluoride has not been tested.  Generally, lower percentage of O-alculation.  But HMPT and DMSO both are rather polar solvents.  Similar, but this is much more polar.  Let's go to a far less polar solvent, diaphyl ether.  So, just 1% of O-alculation in the case of iodide.  Then 5% with the bromide, 18% with the chloride,  and the tosylate 20%.  And well, this means 80% of the C-alculation.  Generally, we can say that if we have dissociated enolates,  naked enolates separated from the counter-cut iron by the solvent,  which is indeed the case in HMPT and similarly in DMSO,  and maybe a bit also in DMF,  then we have a high oxygen-carbon ratio.  If we have iron pairs, well, then we will get an intermediate result.  And if we have higher aggregates as frequently observed in ethos solvents,  then we have a low oxygen-carbon ratio.  So that means or that shows that the solvent has indeed a tremendous influence on the outcome of the reaction.  However, again, if we have tested here,  the bromide gives the 23% yield of O-alculation,  and we want to increase the amount of O-alculation,  well, we know that we will get a better result if we go to the chloride or to the tosylate.  But nevertheless, if we could even more influence the outcome with changing the solvent.  That's what we should learn from this example.  Another interesting case is the alkylation of the enolate of acetic acid, acetoacetic acid ester.  In this case, the potassium enolate has been tested in the reaction with ethyl halides.  Again, in HMPT, in order to examine the influence of the leaving group on the ratio between O-alculation and C-alculation.  So, X and B-O-C ratio.  Iodide, the softest ethyl alkyl, which has been tested, 0.15.  That means we have far more C-C bond formation than C-O bond formation in this case.  Bromide, 0.65, we get more reaction, a bit more reaction at the oxygen.  With the chloride, we already have the turnaround, more O-alculation than C-alculation.  Consequently, with the tosylate, we get a rather high amount of O-alculation.  Now to organometallic species.  The carbon-metal bond. Methyl group sitting at a metal, then an ethyl group, ethyl group, an isopropyl group, and a tertiary butyl group.  Those are all regarded as soft bases at the carbon center.  But from the methyl species to the tertiary butyl species, they get softer.  So this one is harder and this is softer simply because it is bigger.  And the anionic charge is stabilized through that molecule.  For example, although with this example one should be a bit careful, however, if we choose to let this react with methylgrinier,  we will get predominantly the 1,2 addition product.  Changing to the isopropylgrinier will give us predominantly the 1,4 addition product or it is called conjugate.  Addition product.  All.  We have in that alphabet unsaturated ketone two electrophilic centers.  One of the carbonyl group, this is the hard electrophile and this center, the conjugated one, is regarded to be the soft one.  And while you can interpret that in terms of the hard soft SS base concept, this is harder, reacts here, this is softer, reacts there.  But maybe one has to, in the explanation, this is not certainly not a good mechanistic explanation.  You should take in a mechanistic explanation also into account steric hindrance, steric interaction, of course.  Nevertheless, let's have a look at a similar reaction, cyclohexanone plus tertiary-routile lithium.  This clearly gives this product.  This tells us that the structure of the carbon nucleophile is less influential than the nature of the metal.  Lithium is harder than magnesium.  So, hardness, lithium harder than a grignet reagent and this is harder than any cuprate.  Again, cyclohexanone.  First, methyl lithium, secondly, hydrolysis will result in the allylic alcohol and while cuprate, for instance, this one,  hydrolyzed after C-C bond formation will give the conjugate addition product.  Until now, we have only interpreted this in terms of the arts of acid base principle in focusing on the carbon center.  We could also interpret it in focusing on the metal.  Lithium, the lithium cation, harder than a copper cation and therefore the lithium cation as a Lewis acid coordinates preferentially at the free electron pairs of the oxygen.  On the other hand, the cuprate might coordinate with the electron density of that double bond.  Indeed, Norbert Krause from our neighboring university Dortmund a couple of years ago found some interesting examples that proved that with NMR spectroscopy that the cuprates are indeed coordinating to that double bond.  Two further examples for today.  More complicated ones. An isolated pyridine and isolated with a counter anion, presumably simply a chloride.  So where do we have electrophilic centers here?  So of course, this carbon is very electrophilic and this is certainly the hardest electrophilic center.  Here in this aromatic system, a conjugated system, we could write down some mesomeric structures with positive charge there and there and there.  This visualizes that we have electrophilic centers here in the ortho position of a nitrogen and also in the para position.  These in the conjugated systems are of course regarded to be much softer than that.  And well, okay, here and there, we have a soft position and there, this is even softer.  So a reaction and what you live them at minus 78 degrees was found out to react exclusively almost exclusively at this carbon.  Well, this is in accord with what we have already seen here with alkylithium species.  And it simply set free the pyridine and formed that astro.  Next test was done with agrinia reagent and motile magnesium bromide also at minus 78 degrees.  And here, we observed predominantly the reaction at the soft and softer positions.  What is the result in that case?  This and the para isomer was found in the ratio 67 to 33.  Of course, this means there is no real discrimination between the ortho and the para position because we have the ortho position twice and the para position only once.  It's just the ratio of one to one to one and this is the result then.  So the organomagnetium discriminates between the heart center and the soft centers but not between soft and softer.  Going to softer organometallic reagent and organosync which is less reactive and they have done the reaction at higher temperature at zero degrees and the copper,  the compound organocopper would react similarly. In this case, they achieved a ratio of 19 to 81.  That means with the less reactive organosync you indeed can discriminate between the soft and the softer position and get predominantly the reaction in the para position.  Last example for today.  Once again, the enolate of the 1,3-dicarbonide compound  and focus is the reaction with an allyl compound, an allyl electrophile,  with the c-alculated product as the target.  The first attempt simply with allyl bromide gave a 30% yield of the target compound.  Interesting is the result with an allyl acetate which is not reactive to this nucleophile, not that reactive to this nucleophile in the moderate reaction conditions,  but adding a catalyst, a palladium zero catalyst.  Again, this product was isolated in a 94% yield while actually this is the so-called Suji-Trost reaction  and the palladium zero catalyst as a very soft nucleophile reacts with the allyl acetate  forming such an allyl palladium complex and this is indeed a very, very soft electrophile and this gives then a high yield.  We will see more of these catalytic systems of course in summer semester.  So, okay, I think we should finish for today. See you tomorrow with remarks on basic reaction types in organometallic, stoichiometric organometallics chemistry.  Thanks for listening. See you tomorrow.
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So, ladies and gentlemen, welcome to the lecture Organic Synthesis 1, Stichometric Organometallics. And of course, a special welcome to Sandra Lee and the Rupkast team, who will video cast the lecture throughout the whole semester. So, this lecture is the first part, and the second part with the title Catalytic Organometallics is scheduled for the summer semester. So, now to Stichometric Organometallics. When we have a look at the periodic system of elements, and unfortunately in this lecture hole there is no one, well, then we notice an awful lot of metals. And you might get the impression that it could be some kind of nightmare if you have to choose a metal for your purposes, for your synthesis. On the other hand, the awful lot of metals offers us the opportunity to find a suitable one. And indeed, therefore, well, almost any given synthetic problems involving organometallics, you will find some organometallics reagents with the correct properties you need. And moreover, you have the opportunity to trigger the reactivity by adding further ligands. But this is, of course, more used in terms of catalytic organometallics. So, but the possibilities which are imminent in organometallic synthesis makes that so successful. First example, so we have an allulic organometallic species, two substituents here, and we let that react with carbon dioxide. And after hydrolysis, we will obtain either this carboxylic acid or the one with the quaternary center. If the metal is potassium, an allulic potassium species, we will get a product ratio of 90 to 10. So let's change the metal to a Grignet reagent. In that case, it was found that it will result in a 1 to 99 ratio. Well, somehow this is a rather strange result. Why? Clearly, the organoprotassium compound is much more reactive than a Grignet reagent. Nevertheless, the more reactive reagent leads to the thermodynamically more stable product. Clearly, with the Grignet reagent, 99% of the thermodynamically less stable product means this reaction to that product is clearly kinetically controlled. We can explain that if we have a closer look to the structures that are involved. In case of the potassium species, we have a potassium that is coordinated to the allulic anion. Well, it is an extremely polar bond. It is a pi complex. Actually, it is a trihaptopi complex because the potassium is bound to the three centers, coordinated to the three centers. We can also call it an etter three complex. This is a usual abbreviation for that case. So highly reactive system, and now it is clear that at that terminal carbon, we have a minor steric hindrance compared to this center. And therefore, it is clear that we see a two-can more easily attack at that center, resulting finally in this also thermodynamically more stable compound. On the other hand, the Grignet reagent, in this case, the magnesium is more covalently bound to the terminal position. In this case, it is an etter one complex or a sigma complex in contrast to the pi complex in that case. We have with the magnesium the electrophilic center. Magnesium is, as you know, a Lewis acid. While in Grignet reagent, usually ether molecules are coordinated to the magnesium, but in equilibrium, an ether molecule pops off, giving three-vat coordination site. And then the CO2 coordinates to the magnesium. And through a six-membered transition state, the CC bond is formed. Well, and this is, of course, the magnesium carboxylate. And after acidic hydrolysis, we have the final product. So this example makes clear that it is indeed useful to choose between different metals, because we have clearly different selectivities. The corresponding allulithium species is, in this case, similar. Now, it's in between potassium and Grignet. Whereas the allulzinc behaves, in this case, at least similar to the Grignet reagent. So a basic concept which is regarded to be rather useful in choosing the right reagents for synthesis, you know already is the HSAB concept. Or HSAB principle. And the name, the abbreviation, derives from hard, soft, acid, base principle. It was introduced in the early 1960s by Pearson as an extension of the Lewis acid base concept. So Lewis, as you know, defines acids as electron pair acceptors, while you can use the expression electrophile as a synonym. Then, of course, an electron pair donator. Or you can use also the word nucleophile. Now, to Pearson's extension, he differentiates between hard acids, soft acids, and well, there is, of course, something in between, medium or borderline acids. And he introduced the same differentiation to the Lewis basis. Again, hard, medium, and soft. So how did he characterize the expression hard? So a hard Lewis acid is generally small, has a high charge density, and is weakly polarizable, or I would say hardly polarizable. So on soft, or simply is the opposite. So OK, let's draw that to the blackboard. Soft, big, low charge density, and strongly polarizable. Or I think this becomes more clear if we put on some examples. For instance, a hard acid. So what is really small, has a high charge density, and is weakly polarizable. The record holder, of course, is a proton. That's it. So H plus. In this category, we have also lithium plus, could see also magnesium 2 plus, and iron 3 plus. Soft, while metals in the oxidation state 0, can be never less Lewis acids, or rather soft Lewis acids. Nickel plus, but also palladium 2, or the silver, cut iron. And medium, well, there we have then iron 2 plus zinc 2 plus, and copper 2 plus is also regarded as medium. Now to the bases. Fluoride, and iron is the prototype of a hard base. Hydroxylu and iron is also a hard base, although relatively a bit more soft than fluoride. Then ammonium, ammonia, NH3, well, a hard base. We have a free electron pair, and we have an element there with a high electronegativity. Nevertheless, it is basic. It is more basic than that. That means this is more nucleophilic than that. So all those are regarded to be relatively hard, although, of course, NH3 is more soft than fluoride. And also here, in this category, alcoholates. Medium bromide, somewhere here, also chloride, I had forgotten. And soft, clearly, the iodide, a big anion. Or conjugated anions. Enolate, conjugated systems, a big systems, strongly polarizable, should be regarded as soft, Lewis acids, or soft nucleophiles. Thiolates, phosphines, hydrides are in this category. And what is rather important for us in this lecture, organometallic reagents, alkyl or aryl anions. That means alkyl metal species. So now to the core statement of the Hart-Soft acid base principle, I will write down that core statement. So the core statement, soft acids, react faster and form moreange. Whereas, hard acids all react faster and form stronger bonds with hard bases. OK. So what is the explanation? A hard, hard interaction, what could it be? Well, for instance, a lithium plus and an F minus. Reaction of a lithium plus and an F minus would be driven by the electrostatic charge. OK. So hard, hard interaction is charge controlled. And two centers with opposite charge from high density will react rather fast with each other if we put aside salvation effects, of course. On the other hand, soft, soft interaction, according to this principle, is also favored. This is regarded to be controlled by frontier orbital interaction. Well, the first one is easy to understand. The second one you have to think a bit about that. So for instance, a soft anion. The soft anion, we have to look at the energy level of the highest occupied molecular orbital. The soft anion has the homo on a relatively high energy level. This, I think, is easy to understand. Just take into account the opposite, a fluoride, electronegative. It holds to its electron pairs. The electron pairs of the fluoride are on a low energy level. That means with a soft anion, it has to be the opposite. A soft Lewis acid or cation, homo energy level are low. Relatively high energy level, relatively high. With a cation, we have to take a look at the lowest unoccupied molecular orbital. This is, of course, the frontier orbital. And in this case, the energy level of the lumo is relatively low. For instance, as an example, the allylic cation. A allylic cation are rather medium or relatively big electron system compared to an H plus or a lithium plus. It is conjugated. It is polarizable. So the allylic cation is a prototype of a soft cation. And because of the conjugation, you have the lumo in a relatively low energy level. You could easily put on an electron forming an allylic radical. And the homo on a relatively high level, the lumo of the Lewis acid on a rather low level, that means they have almost the same energy level. And then it's easy to transform electron density. It just fits. Forming, then, of course, are rather stable covalent bonds. And it's a rather fast reaction. So this model here is called or known as the Klopman-Salen concept. OK, at this point, let us go back to this core statement. Once again, soft acids react faster and form stronger bonds with soft bases. The expression reacts faster, of course, addresses the kinetics of a reaction. And form stronger bonds. This expression addresses the thermodynamics. So I think this sounds great. If the hard soft acid base concept, we have the impression that we address both kinetics and thermodynamics. This is, of course, not true. Kinetics and thermodynamics are clearly neglected within the hard soft acid base concept. We just don't differentiate between kinetics and thermodynamics. And while this is clearly an over simplification. And that's the reason why a lot of chemists are not in favor of the hard soft acid base concept. And I think the best review article criticizing this concept was published about two years ago by Herbert Meyer from the LMU in Munich. And it was published in Angewandte Chemie International Edition 2011 on page 6470. And it's about 35 pages long. And the article has the interesting title, Farewell to the HSAB Treatment of Ambident Reactivity. Wow. Very interesting article. And he is right in a lot of points. However, if you use the HSAB concept as some kind of qualitative guideline, as some kind of rule of thumb, it will help a lot and still makes sense. So, it's time for some examples. An asshole cat iron. Of course, highly electrophilic hard electrophile. So, a hypothetic reaction with a hard base. Let's have a look for a hard base. A hard base we have, for instance, an alcohol aid. Should result in an aster. And we all know an aster is a rather stable compound. Of course, not alone based on the hard soft interaction, but it has something to do with a conjugated system there. So, but let's check, does the hard soft as a base principle, the Pearson principle work out in similar cases? If we add a soft base, for instance, an iodide or a thionate. Well, what do we get then? A carboxylic acid, iodide or such a thioaster. Well, you can handle those iodides. No problem. But both compounds are far more reactive against hydrolysis with water, for instance. Now, an interesting argument is what about the fluoride? Fluoride is clearly a hard base, harder than the alcohol aid. And in that case, we should discuss the stability of the carboxylic acid fluoride. It makes a bit suspicious to all of us. And it was also a surprise for me to find that carboxylic acid fluorides are more stable against hydrolysis as carboxylic acid chlorides. So, acidic acid fluoride is more stable against the interaction with water hydrolysis as acidic acid chloride. Then carboxylic acid chlorides. Well, next type of reaction. A nitrile. A nitrile is regarded to be a hard electrophile. So, hard Lewis acid at the carbon center and a hard Lewis base of a free electron pair at the nitrogen. Plus hydrogen fluoride with the hard base fluoride here will react in an addition process. And gives this iminium, this imine of a carboxylic acid fluoride, which of course will react with additional HF to form the iminium salt. So, again, the concept works. Hard acid, hard base, also the other way round, hard acid the proton and hard base here the nitrogen. The addition reaction works. Try that with hydrogen iodide and it won't work. So, not to a bit more interesting. Examples. Carbonyl compounds. The oxygen, hard base, the carbon is regarded to be a hard acid. Here we have a substrate which has alderhyde functionality and a tosylate within the same molecule. This carbon, a hard electrophile. This carbon with the tosylate leaving group is also an electrophile, also regarded to be rather hard electrophile, although somehow softer than that. So, softer, not softer, softer than this position. Here we have a thiophenolate. Thiolates are soft nucleophiles, especially if conjugated to an aromatic system. So, this is soft and on the other hand, a cyanide has a relatively hard, well, both are soft. Both are soft systems, but this is of course harder than that, or this softer than that. So, both soft, but this is relatively hard compared to the thiolate. And indeed, that thiolate selectively reacts with the softer position. Simply a nucleophilic substitution as an asin-2 trusses. With the thiolate, a completely different pathway, reaction pathway is observed. It detects the harder electrophilic center. So, that means we get this intermediate and now an intramolecular asin-2 process is observed with the alkylate as the nucleophilic center. And that carbon as the electrophilic center resulting in this product. So, enolates as ambident nucleophiles. Enolates with the two mesomeric structures. Of course, the oxygen is the hard nucleophilic center and the carbon is the soft nucleophilic centers. That means the hard soft acid base concept suggests that hard electrophiles should form a bond to the oxygen and soft electrophiles should form a bond to the carbon. So, is that true? As it turned out, it is somewhat an overinterpretation of the hard soft acid base concept. Because the enolate of cyclohexanone plus bromomethane in the gas phase. Has been tested to give exclusively the O-alculation product. Although the methyl, the bromomethane is regarded to be rather soft. This is somewhat contradictory to what we expect from the hard soft acid base concept. Another example is lithium enolates have been shown by the famous Dieter Sebach from Zurich University. He invented the activity of reactivity. And found that under the right reaction conditions, lithium enolates with acyclerides in THF at low temperature minus 100 degrees to minus 80 degrees react under CC bond. Formation also contradictory to what we expect from the Pearson concept. And indeed there are numerous examples known where normally the acylation takes place at the oxygen. It can easily form that. It depends on the reaction conditions. So, this is contradictory or it gives the impression that it is contradictory to the hard soft acid base principle. But as I said, predicting this is soft and therefore it has to react here is an over interpretation of it. You can use it as a rule of thumb if you make for instance a test reaction and you find with a bromide you have a certain product ratio. With the hard soft acid base principle you can then predict how the product ratio will change if you change from the bromide to the chloride to the iodide or to the tosylate. So, you need one experimental result to make a prediction based on the HSAB concept. And this can be very useful. We will see that in a couple of more examples. A sodium enolate with a butyl compound and X is a leaving group. We would anticipate two products while here this and trans maybe. The O-alculation product and the C-alculation product. So, let's form a table with percentage of O-alculation. And it depends very much on the solvent which is used. HMPT as a solvent. Hexamethylphosphoric acid triamide. First with the iodide just 15% O-alculation. With the bromide we have more 40% alculation. Butyl chloride is more hard electrophile than the bromide. So, we should get even more O-alculation. And indeed it turns out to be right 67%. The tosylate 85%. And then let's go to the fluoride 96% O-alculation. Fluorobutane is the hardest electrophile. So, it gives indeed the best yield of the O-alculation product. Something wrong? Okay, it's okay. Well, let's change to DMSO. 10%, 23%, 46%. Well, here we have 44% and the fluoride has not been tested. Generally, lower percentage of O-alculation. But HMPT and DMSO both are rather polar solvents. Similar, but this is much more polar. Let's go to a far less polar solvent, diaphyl ether. So, just 1% of O-alculation in the case of iodide. Then 5% with the bromide, 18% with the chloride, and the tosylate 20%. And well, this means 80% of the C-alculation. Generally, we can say that if we have dissociated enolates, naked enolates separated from the counter-cut iron by the solvent, which is indeed the case in HMPT and similarly in DMSO, and maybe a bit also in DMF, then we have a high oxygen-carbon ratio. If we have iron pairs, well, then we will get an intermediate result. And if we have higher aggregates as frequently observed in ethos solvents, then we have a low oxygen-carbon ratio. So that means or that shows that the solvent has indeed a tremendous influence on the outcome of the reaction. However, again, if we have tested here, the bromide gives the 23% yield of O-alculation, and we want to increase the amount of O-alculation, well, we know that we will get a better result if we go to the chloride or to the tosylate. But nevertheless, if we could even more influence the outcome with changing the solvent. That's what we should learn from this example. Another interesting case is the alkylation of the enolate of acetic acid, acetoacetic acid ester. In this case, the potassium enolate has been tested in the reaction with ethyl halides. Again, in HMPT, in order to examine the influence of the leaving group on the ratio between O-alculation and C-alculation. So, X and B-O-C ratio. Iodide, the softest ethyl alkyl, which has been tested, 0.15. That means we have far more C-C bond formation than C-O bond formation in this case. Bromide, 0.65, we get more reaction, a bit more reaction at the oxygen. With the chloride, we already have the turnaround, more O-alculation than C-alculation. Consequently, with the tosylate, we get a rather high amount of O-alculation. Now to organometallic species. The carbon-metal bond. Methyl group sitting at a metal, then an ethyl group, ethyl group, an isopropyl group, and a tertiary butyl group. Those are all regarded as soft bases at the carbon center. But from the methyl species to the tertiary butyl species, they get softer. So this one is harder and this is softer simply because it is bigger. And the anionic charge is stabilized through that molecule. For example, although with this example one should be a bit careful, however, if we choose to let this react with methylgrinier, we will get predominantly the 1,2 addition product. Changing to the isopropylgrinier will give us predominantly the 1,4 addition product or it is called conjugate. Addition product. All. We have in that alphabet unsaturated ketone two electrophilic centers. One of the carbonyl group, this is the hard electrophile and this center, the conjugated one, is regarded to be the soft one. And while you can interpret that in terms of the hard soft SS base concept, this is harder, reacts here, this is softer, reacts there. But maybe one has to, in the explanation, this is not certainly not a good mechanistic explanation. You should take in a mechanistic explanation also into account steric hindrance, steric interaction, of course. Nevertheless, let's have a look at a similar reaction, cyclohexanone plus tertiary-routile lithium. This clearly gives this product. This tells us that the structure of the carbon nucleophile is less influential than the nature of the metal. Lithium is harder than magnesium. So, hardness, lithium harder than a grignet reagent and this is harder than any cuprate. Again, cyclohexanone. First, methyl lithium, secondly, hydrolysis will result in the allylic alcohol and while cuprate, for instance, this one, hydrolyzed after C-C bond formation will give the conjugate addition product. Until now, we have only interpreted this in terms of the arts of acid base principle in focusing on the carbon center. We could also interpret it in focusing on the metal. Lithium, the lithium cation, harder than a copper cation and therefore the lithium cation as a Lewis acid coordinates preferentially at the free electron pairs of the oxygen. On the other hand, the cuprate might coordinate with the electron density of that double bond. Indeed, Norbert Krause from our neighboring university Dortmund a couple of years ago found some interesting examples that proved that with NMR spectroscopy that the cuprates are indeed coordinating to that double bond. Two further examples for today. More complicated ones. An isolated pyridine and isolated with a counter anion, presumably simply a chloride. So where do we have electrophilic centers here? So of course, this carbon is very electrophilic and this is certainly the hardest electrophilic center. Here in this aromatic system, a conjugated system, we could write down some mesomeric structures with positive charge there and there and there. This visualizes that we have electrophilic centers here in the ortho position of a nitrogen and also in the para position. These in the conjugated systems are of course regarded to be much softer than that. And well, okay, here and there, we have a soft position and there, this is even softer. So a reaction and what you live them at minus 78 degrees was found out to react exclusively almost exclusively at this carbon. Well, this is in accord with what we have already seen here with alkylithium species. And it simply set free the pyridine and formed that astro. Next test was done with agrinia reagent and motile magnesium bromide also at minus 78 degrees. And here, we observed predominantly the reaction at the soft and softer positions. What is the result in that case? This and the para isomer was found in the ratio 67 to 33. Of course, this means there is no real discrimination between the ortho and the para position because we have the ortho position twice and the para position only once. It's just the ratio of one to one to one and this is the result then. So the organomagnetium discriminates between the heart center and the soft centers but not between soft and softer. Going to softer organometallic reagent and organosync which is less reactive and they have done the reaction at higher temperature at zero degrees and the copper, the compound organocopper would react similarly. In this case, they achieved a ratio of 19 to 81. That means with the less reactive organosync you indeed can discriminate between the soft and the softer position and get predominantly the reaction in the para position. Last example for today. Once again, the enolate of the 1,3-dicarbonide compound and focus is the reaction with an allyl compound, an allyl electrophile, with the c-alculated product as the target. The first attempt simply with allyl bromide gave a 30% yield of the target compound. Interesting is the result with an allyl acetate which is not reactive to this nucleophile, not that reactive to this nucleophile in the moderate reaction conditions, but adding a catalyst, a palladium zero catalyst. Again, this product was isolated in a 94% yield while actually this is the so-called Suji-Trost reaction and the palladium zero catalyst as a very soft nucleophile reacts with the allyl acetate forming such an allyl palladium complex and this is indeed a very, very soft electrophile and this gives then a high yield. We will see more of these catalytic systems of course in summer semester. So, okay, I think we should finish for today. See you tomorrow with remarks on basic reaction types in organometallic, stoichiometric organometallics chemistry. Thanks for listening. See you tomorrow.
Or HSAB principle. And the name, the abbreviation, derives from hard, soft, acid, base arts of acid base principle in focusing on the