Lecture Stoechiometric Organometallics 14 - 27.11.13
Dyker, Gerald
Metal-specific features: Cerium in Organic Synthesis, Copper: Organocuprates
 Welcome to part 14 of the lecture on Stochium Metric Organometallics. Again today, metal specific features this time, cerium in organic synthesis. Cerium in organic synthesis is connected with a name reaction, the so-called Lusche reduction. So if you have, for instance, an alphabet or unsaturated ketone, cyclopentenone as an example, and you treat that with sodium borohydride, usually in methanol as solvent, well, part of the methanol will react with a sodium borohydride forming better soluble methoxyborates, hydro-methoxyborates, and these will then reduce the starting material. Usually, under these reaction conditions, you can anticipate to get a product mixture, simple, simple in brackets, reduction of a carbonyl functionality, giving rise to an interesting allylic alcohol. Well, as a competing reaction, you might get the one-four addition product of the borohydride. After hydrolysis, it might give then the ketone. On the other hand, if you have reaction conditions, the enolate can already react with a proton source, like in this case with a methanol, then in equilibrium, the ketone will be already formed in presence of a sodium borohydride, and then, of course, the ketone will be reduced since the normal ketone is more reactive against nucleophiles and alpha-beta unsaturated ketones. So, what you should get in this case is cyclopentenone. Just try this reaction, and what will be the result? These reaction conditions without additional Lewis acid, then you will get, well, just about 1% of this product, the allylic alcohol, which is, of course, the most interesting product, since you have functionality which you can work in organic synthesis, you will get nothing of a ketone and 99% of the relatively cheap cyclopentenone. So, since this one is the most interesting product, organic chemists are most interested in getting selectively this one. And there are reaction conditions, especially adding special Lewis acids. The best one turned out to be cerium chloride. Add cerium chloride, stoichiometrically, and then you can achieve an up to 97 to 3 selectivity in favor to the target allylic alcohol. So, this has been tested with a lot of Lewis acids. Another example, oeuropeium chloride, 93 to 7, as I said, cerium chloride turned out to be definitively the best one. And another transition metal chloride, nickel chloride, well, in this case you don't get anything of that target molecule, 76% of the ketone, 6% of the alcohol plus 18% starting material. Well, this seems to be a catalytic reduction with nickel hydride. Well, there are better reaction conditions where you get this more selectively than with a simple nickel chloride. So, next example, not an unsaturated carbonyl, but a substrate where you have both a ketone and an alderhyde in the same substrate. So, generally, alderhydes have the higher carbonyl activity, that means they are more reactive against nucleophiles. On the other hand, ketones are more Lewis basic at the oxygen. Well, if you bound, for instance, proton, here, it's more easily protonated because the corresponding cation is more stabilized due to the additional methyl group. And that means that Lewis acids preferentially bind to a ketone rather than to an alderhyde. And you can make use of that. So, if you add cerium chloride and then, again, sodium borohydride in methanol, you can selectively reduce the ketone in the presence of the alderhyde. Some solvent effects might also have some effect in this reaction, but essentially it should be the preferred coordination of cerium at the ketone. Well, now to organo cerium chemistry, that means reagents with a carbon cerium bond. So, this is the Iyodo aceto phenone, NTHF at minus 65 degrees, 3 hours reaction time. And we need this with butylythium. What could happen? Wall. So, I tried that, had in mind to synthesize the tertiary alcohol, because one could guess that the N-butylythium just as a granite reagent would attack the carbonyl group. Actually, they had in mind that this reaction won't work very well. And indeed, they proved that they get 0% for the tertiary alcohol. A bit surprising, but if you remember the beginning of this lecture series, well, what could be the competing reaction in this case? It's the halogen metal exchange. Please remember, this is a very fast reaction, even faster than a protonation, a deprotonation. So, halide metal exchange at the Iyodo functionality, well, lithiation at this position. And this, of course, gives then, following reactions, this attacks as a nucleophile, a carbonyl group of the next molecule, and so on. Forming polymeric systems, or the base deprotonates here. Well, the solution to the problem is, at one equivalent of, of course, dry cerium chloride, then the metal exchange, you will get the organo cerium compound, and then after hydrolysis, you are able to isolate up to 93% of that tertiary alcohol. Well, why not using a simple Grignet? Yes, indeed, the Grignet reagent is slower in the halogen metal exchange through eight complexes, but as we have learned from Knuchels result with isopropyl Grignet, it also works. This is then a competing reaction, and also Grignet reagents are somewhat basic, can deprotonate to enolates, whereas organo cerium is essentially non-basic. This is, I think, an important message. Well, we will see that in the next example. Cyclopentanone, THF, 0°1 hour is first treated with isopropyl magnesium chloride. The first guess based on organic chemistry, what we have learned in organic chemistry one, would be, well, okay, presumably after hydrolysis, we will have these tertiary alcohol, here with the isopropyl group. This has been tried, and it was found that just a 3% yield was obtained in this process. The main product, isolated with 88% yield, is also a tertiary alcohol, but the substituent is the cyclopentanone. Well, what kind of reaction is this? This is a simple and aldol addition process. So, the somewhat sterically hindered isopropyl magnesium chloride prefers to deprotonate the cyclopentanone, forming the magnesium enolate, which then reacts with the second equivalent of a ketone under aldol addition. Isopropyl magnesium chloride first treated with one equivalent of cerium chloride, forming the organo cerium compound. Then, we have just trace amounts of that aldol addition product, but we can isolate an 80% yield of that target molecule. The aldol addition product of acetone can be isolated, and if we treat that with an alkynyl cerium chloride, THF, at minus 70 degrees, minus 78 degrees, and after hydrolysis, we will get this product, a rather nice yield. I think indeed this is remarkable, since if we try such a reaction with organolythium or organomagnetium, it is clear that very fast an alcoholosis will occur with that alcohol functionality. But since cerium reagent is non-basic, this does not happen in organo cerium chemistry. Also, sterically very hindered systems are accessible when we switch to organo cerium chemistry. This ketone, sterically hindered due to this quaternary crowded center in alpha position, with methyl magnesium bromide, V-Gat, none of the tertiary alcohol, switch to the cerium, organo cerium compound, then 95% yield was isolated. The cerium enolates are also known as interesting organometallic reagents. Here is one example. There is a ketone in somewhat sterically hindered position, then an aster enolate, a cerium aster enolate, also sterically somewhat hindered due to that tertiary butyl oxy. Nevertheless, the reaction works very well, forming that aster aldol product, this one, with a 95% yield. With cerium chemistry, you often get yields above 90%. The price for cerium salts, unfortunately, increased in recent years, but nevertheless, the price of cerium chloride, approximately 4-5€. It is okay for special chemistry, at least when you have methods to recover the cerium. Here is one more example. Alpha-better unsaturated systems. This one has the model compound, the stoichiometric addition of the organometallic reagent, either one-two-addition product or the one-four conjugate addition product. With methyl cerium chloride, you get this one, the one-two-addition product with 98%, and from this one, only trace amounts. Compare that to a result with methyl lithium, 65% of this one, isolated yields, 17% of the other one. And with methyl magnesium bromide, 38%, and around 60% of the conjugate addition product. We can explain that with the hard-soft acid base concept, at least in this line, the magnesium compound is the softest one. Here, directly at the carbonyl carbon, we have the hard electrophile, and this one here, the better carbon is regarded to be the soft electrophile. Compare that to an aryl metal reagent phenyl cerium chloride, 90% to 4 phenyl lithium, 85% to 10. And phenyl magnesium bromide, 14% to 78%. So essentially, it's the same with those aryl metal species. So that means, generally, if you have an alpha-better unsaturated carbonyl, treat that with an alkyl or aryl cerium dichloride. We will achieve a very high yield of the 1, 2 addition product, this one. What about a method to get to the conjugate addition product selectively? Very often, organocopper chemistry is the method of choice. I abbreviate that with copper in brackets. It also details how those organocopper reagents are built up, will be the subject of the second part of this lesson today. So, now again, metal-specific features, copper chemistry. The founder of the organic copper chemistry is known to be Gilman. He invented that double titration because it was especially important for the organocopper chemistry to definitely know the concentration of organolithium reagents. So, Gilman, in 1952, he performed a trans-metalation with organolithium reagents, adding copper bromide or copper Iodide. Then, an organocopper compound is formed, plus of course the corresponding lithium salt. Usually, if you do that in ether solution, the organocopper compound precipitates. Since it has low solubility in organic solvents generally, the structure is some kind of polymeric chain structure. So, these simple organocopper complexes have low solubility and therefore, they are sensitive and therefore, they are less suitable for organic synthesis. But also, Gilman found out that if one adds a second equivalent of the organolithium reagent, then the precipitate goes into solution again. And what is formed then is something like an R2 copper lithium complex. There might be one equivalent of lithium bromide incorporated in the aggregates. So, these complexes are called lower order organo-couprates. And nowadays, they are also called Gilman reagents. So, how do those Gilman reagents look like? What is the structure? So, they consist of cuprate units. So, they are eight complexes and simply the LE plus as the counter cation. Normally, in solution, most stable component in solution, which in some cases can be crystallized, is dimer. Dimer consists of two almost linear copper eight complexes. Then, we have a lithium plus electrostatically coordinated and the solvent, for instance, diethyl ether coordinated to a lithium plus. Well, those Gilman reagents have an obvious disadvantage. You have the group, the R group, that's substituent, nucleophilic carbon substituent twice in the molecule, but generally only one is transferred in that reaction. This is, of course, an disadvantage. Imagine you have spent a couple of weeks to synthesize a rather complex structure, metalate that, and then making the organo-copper Gilman reagent, and half of what you have produced simply doesn't go into the target product. So, that is everything else, but atom economic, of course. What could be the solution of that problem, you have to synthesize mixed Gilman reagents. That means R and R-prime copper lithium complexes. If the R-prime is a substituent that is cheaply introduced and, moreover, a substituent that tends to stay at the copper, well, this is then the solution to the problem. So, R-prime is then called the dummy ligand. With examples, for instance, the satellite substituents tend to stay at the copper. If the psi of the new groups, with those it's the same, then we have alkoxy, tertiary-butyl oxy, and some more which, in addition, trigger the reactivity of the organo-copper complex, but one which is used very often, also with an SP1-hybridized carbon center, cyanides. In case of the cyanide, we can produce those, also starting with organo-lythium, plus copper cyanide, giving essentially a mixed Gilman reagent with cyanide as the dummy ligand. This method was introduced to my knowledge by the group of Bruce Lipschitz, which is then called lower-order cyano-couprates, widely applied in organo-copper chemistry, because it's easy to synthesize those, and then they have generally a higher nucleophilicity with that R group compared to a normal Gilman reagent, and this is very important, they are more stable at temperatures up to minus 30 degrees in THF and ether solution. You can further increase the reactivity if you add another equivalent of organo-lythium. What you get then is R2-copper-cyano-lythium-2. These are called higher-order organo-couprates. All this reaction is regarded to proceed with some of the change in structure. In this case with a lower order organo-couprates, you have this situation, R-group, the R-coup group, and the cyanide sitting at the copper is an 8-complex, and here lithium-plus. The most stable species in solution with higher order organo-couprates is this one. Having the culprit with two alkyl or aryl substituents, and both lithium-ketions bound to the cyanide. From calculations and measurements, it is clear that this is the most stable species in solution. However, that does not mean that this is the reactive species, which then does the job, the transfer of the organic nucleophile. Higher-order organo-couprates are somewhat more reactive than the lower-order cyanocouprates, but again we have a problem in this case. Again, we have two nucleophilic R-groups, and again it would be a good idea to change one into a dummy ligand. This has been tested and rather well established than this one, the thiophilic R-group, 8-complex with this counter-ket ion. Higher-order hetero-couprates. Well, okay, this should be the overview on those copper reagents. Later on, within the next weeks, we will talk about the fact that you can further trigger reactivity if you change the metal-ket ion, for instance, against zinc. This has then a much better functional group compatibility, and these copper-zinc mixtures have also been invented by a knochel-group, and while they became rather important, we will study in detail in a couple of weeks. So, let's go on with this copper chemistry. As I said, it's very often a method of choice for conjugate addition reactions. So, alphabet-unsaturated ketones, here cyclo-exanone, plus organo-copper reagent, no matter which type, will give a conjugate addition product first an enolate, then after hydrolysis, you return to the ketone functionality, but you can, of course, trap that enolate. For instance, let's say TMS chloride, then you have that TMS enolate you could use for chemistry, or you can directly add an electrophile EX, getting the substituent in the two position. Norbert Krauser from our neighboring university, Dortmund, studied mechanistic details for conjugate addition processes. Here we have the 1,4 conjugate addition, and Krauser studied mechanistic details with examples of 1,6 conjugate addition up to 1,12 conjugate addition. And a preferred model compound is this one, an alkene functionality in addition, in conjugation, to an alphabet-unsaturated astro. Let's call that compound A. So this compound A was treated with a higher order cyanocuprate, which should transfer tertiary butyl groups. At minus 80 degrees, to my knowledge, it was in diaphyl ether, but it should be in deuterated diaphyl ether, because this test has been done in an MR tube. So it was a rather high concentration or long measuring time, since Krauser group was interested in carbon-carbon coupling constants. So JCC, coupling constants of carbon-carbon coupling, between these two carbons here, alkenue carbons, were found in the starting material, 175 Hertz. So indeed, they found 74 Hertz. Adding one equivalent of that higher order cyanocuprates, we indeed noticed a change in coupling constants, while the change was very small between those alkenue carbons. But it was significant at the olefinic part, from 74 Hertz to 51 Hertz. And therefore, they interpreted this straightforwardly, that the olefinic part is coordinated to the copper. Lithium plus should be coordinated here at the carbonyl group, at the carbonyl oxygen. And mechanistically, the nucleophilic adrub is transferred from the copper to this position. So I think a rather nice explanation. And in the NMRs, they could observe that increasing the temperature to minus 20 degrees, then produces the alanulic system, so an allene, with that ester enolate. And after hydrolysis, well, hydrolysis means simply protonation here at this position. They isolated this ester with that alanulic group. Now to an interesting experiment also made by the Krause group with this starting material A. I think I should draw it once again. The starting material was treated with simple Gilman reagent dimethyl copper, dimethyl culprit with a lithium counter cation. The first step should be that ester enolate formed. This was then trapped with benz aldehyde. And finally, hydrolysis under moderate conditions gave an interesting product. With a 91% yield and in the publication, there was claimed that they found a diastereoselectivity of 8 to 8 to 4 to 1. As an exercise, please try to figure out the structure of that product. And please try to explain why do we have, obviously, four diastereoisomers. So the Gilman reagent with nucleophilic methyl groups, well, in this case the methyl groups are sterically smaller. And they can more easily react at the terminal position. Remember in the preceding example we had to transfer tertiary butyl groups at a sterically hindered position. That means we need rather high nucleophilicity, high reactivity, and we higher order. Cyanocruprates are more reactive than the Gilman reagents. But in this case, the Gilman reagent is just fine, the nucleophile attacks here. And we get this conjugated system with the ester enolate. And the ester enolate is then trapped with the aldehyde. This is a simple aldehyde addition process. So how should that look like? This is a methyl group that has been transferred. An allene system is formed. We have the ester group here and at that carbon the aldole addition process takes place giving this product. So let's count the, well, stereogenic factors. We have a chiral center at this position. A second chiral center here. Two chiral centers means we have two diastereoisomers. We also have the enantiomers, but this is a racemic, of course. So two chiral centers, two diastereoisomers. But the scientists found that we have four diastereoisomers. So we need an additional chiral element. And indeed we have that because allenes can be chiral. So remember that these four substituents are not in one plane. These substituents here are perpendicular to each other. So, and therefore we have the factor of two for the diastereoisomers and overall four of them. Of course we do not know which one is preferred. Okay, enough for today with organocopa chemistry. Of course we have to go on with that next week. And so subject next Tuesday will be organocopa applications in organic synthesis. Thank you for listening. See you next week.
 Welcome to part 14 of the lecture on Stochium Metric Organometallics.  Again today, metal specific features this time, cerium in organic synthesis.  Cerium in organic synthesis is connected with a name reaction, the so-called Lusche reduction.  So if you have, for instance, an alphabet or unsaturated ketone, cyclopentenone as an example,  and you treat that with sodium borohydride, usually in methanol as solvent,  well, part of the methanol will react with a sodium borohydride forming better soluble methoxyborates, hydro-methoxyborates,  and these will then reduce the starting material.  Usually, under these reaction conditions, you can anticipate to get a product mixture,  simple, simple in brackets, reduction of a carbonyl functionality, giving rise to an interesting allylic alcohol.  Well, as a competing reaction, you might get the one-four addition product of the borohydride.  After hydrolysis, it might give then the ketone.  On the other hand, if you have reaction conditions, the enolate can already react with a proton source,  like in this case with a methanol, then in equilibrium, the ketone will be already formed in presence of a sodium borohydride,  and then, of course, the ketone will be reduced since the normal ketone is more reactive against nucleophiles and alpha-beta unsaturated ketones.  So, what you should get in this case is cyclopentenone.  Just try this reaction, and what will be the result?  These reaction conditions without additional Lewis acid,  then you will get, well, just about 1% of this product, the allylic alcohol,  which is, of course, the most interesting product, since you have functionality which you can work in organic synthesis,  you will get nothing of a ketone and 99% of the relatively cheap cyclopentenone.  So, since this one is the most interesting product, organic chemists are most interested in getting selectively this one.  And there are reaction conditions, especially adding special Lewis acids.  The best one turned out to be cerium chloride.  Add cerium chloride, stoichiometrically,  and then you can achieve an up to 97 to 3 selectivity in favor to the target allylic alcohol.  So, this has been tested with a lot of Lewis acids.  Another example, oeuropeium chloride, 93 to 7, as I said, cerium chloride turned out to be definitively the best one.  And another transition metal chloride, nickel chloride, well,  in this case you don't get anything of that target molecule, 76% of the ketone,  6% of the alcohol plus 18% starting material.  Well, this seems to be a catalytic reduction with nickel hydride.  Well, there are better reaction conditions where you get this more selectively than with a simple nickel chloride.  So, next example, not an unsaturated carbonyl,  but a substrate where you have both a ketone and an alderhyde in the same substrate.  So, generally, alderhydes have the higher carbonyl activity, that means they are more reactive against nucleophiles.  On the other hand, ketones are more Lewis basic at the oxygen.  Well, if you bound, for instance, proton, here, it's more easily protonated because the corresponding cation is more stabilized due to the additional methyl group.  And that means that Lewis acids preferentially bind to a ketone rather than to an alderhyde.  And you can make use of that.  So, if you add cerium chloride and then, again, sodium borohydride in methanol,  you can selectively reduce the ketone in the presence of the alderhyde.  Some solvent effects might also have some effect in this reaction, but essentially it should be the preferred coordination of cerium at the ketone.  Well, now to organo cerium chemistry, that means reagents with a carbon cerium bond.  So, this is the Iyodo aceto phenone, NTHF at minus 65 degrees, 3 hours reaction time.  And we need this with butylythium. What could happen? Wall.  So, I tried that, had in mind to synthesize the tertiary alcohol, because one could guess that the N-butylythium just as a granite reagent would attack the carbonyl group.  Actually, they had in mind that this reaction won't work very well.  And indeed, they proved that they get 0% for the tertiary alcohol.  A bit surprising, but if you remember the beginning of this lecture series, well, what could be the competing reaction in this case?  It's the halogen metal exchange. Please remember, this is a very fast reaction, even faster than a protonation, a deprotonation.  So, halide metal exchange at the Iyodo functionality, well, lithiation at this position. And this, of course, gives then, following reactions, this attacks as a nucleophile, a carbonyl group of the next molecule, and so on.  Forming polymeric systems, or the base deprotonates here. Well, the solution to the problem is, at one equivalent of, of course, dry cerium chloride,  then the metal exchange, you will get the organo cerium compound, and then after hydrolysis, you are able to isolate up to 93% of that tertiary alcohol.  Well, why not using a simple Grignet?  Yes, indeed, the Grignet reagent is slower in the halogen metal exchange through eight complexes, but as we have learned from Knuchels result with isopropyl Grignet, it also works.  This is then a competing reaction, and also Grignet reagents are somewhat basic, can deprotonate to enolates, whereas organo cerium is essentially non-basic.  This is, I think, an important message. Well, we will see that in the next example.  Cyclopentanone, THF, 0°1 hour is first treated with isopropyl magnesium chloride.  The first guess based on organic chemistry, what we have learned in organic chemistry one, would be, well, okay, presumably after hydrolysis, we will have these tertiary alcohol, here with the isopropyl group.  This has been tried, and it was found that just a 3% yield was obtained in this process.  The main product, isolated with 88% yield, is also a tertiary alcohol, but the substituent is the cyclopentanone.  Well, what kind of reaction is this? This is a simple and aldol addition process.  So, the somewhat sterically hindered isopropyl magnesium chloride prefers to deprotonate the cyclopentanone, forming the magnesium enolate, which then reacts with the second equivalent of a ketone under aldol addition.  Isopropyl magnesium chloride first treated with one equivalent of cerium chloride, forming the organo cerium compound.  Then, we have just trace amounts of that aldol addition product, but we can isolate an 80% yield of that target molecule.  The aldol addition product of acetone can be isolated, and if we treat that with an alkynyl cerium chloride, THF, at minus 70 degrees, minus 78 degrees,  and after hydrolysis, we will get this product, a rather nice yield.  I think indeed this is remarkable, since if we try such a reaction with organolythium or organomagnetium, it is clear that very fast an alcoholosis will occur with that alcohol functionality.  But since cerium reagent is non-basic, this does not happen in organo cerium chemistry.  Also, sterically very hindered systems are accessible when we switch to organo cerium chemistry.  This ketone, sterically hindered due to this quaternary crowded center in alpha position,  with methyl magnesium bromide, V-Gat, none of the tertiary alcohol,  switch to the cerium, organo cerium compound, then 95% yield was isolated.  The cerium enolates are also known as interesting organometallic reagents.  Here is one example.  There is a ketone in somewhat sterically hindered position, then an aster enolate, a cerium aster enolate, also sterically somewhat hindered due to that tertiary butyl oxy.  Nevertheless, the reaction works very well,  forming that aster aldol product, this one, with a 95% yield.  With cerium chemistry, you often get yields above 90%.  The price for cerium salts, unfortunately, increased in recent years, but nevertheless,  the price of cerium chloride, approximately 4-5€.  It is okay for special chemistry, at least when you have methods to recover the cerium.  Here is one more example.  Alpha-better unsaturated systems.  This one has the model compound,  the stoichiometric addition of the organometallic reagent, either one-two-addition product  or the one-four conjugate addition product.  With methyl cerium chloride, you get this one, the one-two-addition product with 98%, and from this one, only trace amounts.  Compare that to a result with methyl lithium, 65% of this one, isolated yields, 17% of the other one.  And with methyl magnesium bromide, 38%, and around 60% of the conjugate addition product.  We can explain that with the hard-soft acid base concept, at least in this line, the magnesium compound is the softest one.  Here, directly at the carbonyl carbon, we have the hard electrophile, and this one here, the better carbon is regarded to be the soft electrophile.  Compare that to an aryl metal reagent phenyl cerium chloride, 90% to 4 phenyl lithium, 85% to 10.  And phenyl magnesium bromide, 14% to 78%.  So essentially, it's the same with those aryl metal species.  So that means, generally, if you have an alpha-better unsaturated carbonyl, treat that with an alkyl or aryl cerium dichloride.  We will achieve a very high yield of the 1, 2 addition product, this one.  What about a method to get to the conjugate addition product selectively?  Very often, organocopper chemistry is the method of choice.  I abbreviate that with copper in brackets.  It also details how those organocopper reagents are built up, will be the subject of the second part of this lesson today.  So, now again, metal-specific features, copper chemistry.  The founder of the organic copper chemistry is known to be Gilman.  He invented that double titration because it was especially important for the organocopper chemistry to definitely know the concentration of organolithium reagents.  So, Gilman, in 1952, he performed a trans-metalation with organolithium reagents,  adding copper bromide or copper Iodide.  Then, an organocopper compound is formed, plus of course the corresponding lithium salt.  Usually, if you do that in ether solution, the organocopper compound precipitates.  Since it has low solubility in organic solvents generally, the structure is some kind of polymeric chain structure.  So, these simple organocopper complexes have low solubility and therefore,  they are sensitive and therefore, they are less suitable for organic synthesis.  But also, Gilman found out that if one adds a second equivalent of the organolithium reagent,  then the precipitate goes into solution again. And what is formed then is something like an R2 copper lithium complex.  There might be one equivalent of lithium bromide incorporated in the aggregates.  So, these complexes are called lower order organo-couprates.  And nowadays, they are also called Gilman reagents.  So, how do those Gilman reagents look like? What is the structure?  So, they consist of cuprate units.  So, they are eight complexes and simply the LE plus as the counter cation.  Normally, in solution, most stable component in solution, which in some cases can be crystallized, is dimer.  Dimer consists of two almost linear copper eight complexes.  Then, we have a lithium plus electrostatically coordinated and the solvent,  for instance, diethyl ether coordinated to a lithium plus.  Well, those Gilman reagents have an obvious disadvantage.  You have the group, the R group, that's substituent, nucleophilic carbon substituent twice in the molecule,  but generally only one is transferred in that reaction.  This is, of course, an disadvantage.  Imagine you have spent a couple of weeks to synthesize a rather complex structure, metalate that,  and then making the organo-copper Gilman reagent,  and half of what you have produced simply doesn't go into the target product.  So, that is everything else, but atom economic, of course.  What could be the solution of that problem, you have to synthesize mixed Gilman reagents.  That means R and R-prime copper lithium complexes.  If the R-prime is a substituent that is cheaply introduced and, moreover, a substituent that tends to stay at the copper,  well, this is then the solution to the problem.  So, R-prime is then called the dummy ligand.  With examples, for instance, the satellite substituents tend to stay at the copper.  If the psi of the new groups, with those it's the same, then we have alkoxy, tertiary-butyl oxy,  and some more which, in addition, trigger the reactivity of the organo-copper complex,  but one which is used very often, also with an SP1-hybridized carbon center, cyanides.  In case of the cyanide, we can produce those, also starting with organo-lythium,  plus copper cyanide, giving essentially a mixed Gilman reagent with cyanide as the dummy ligand.  This method was introduced to my knowledge by the group of Bruce Lipschitz,  which is then called lower-order cyano-couprates,  widely applied in organo-copper chemistry, because it's easy to synthesize those,  and then they have generally a higher nucleophilicity with that R group compared to a normal Gilman reagent,  and this is very important, they are more stable at temperatures up to minus 30 degrees in THF and ether solution.  You can further increase the reactivity if you add another equivalent of organo-lythium.  What you get then is R2-copper-cyano-lythium-2.  These are called higher-order organo-couprates.  All this reaction is regarded to proceed with some of the change in structure.  In this case with a lower order organo-couprates, you have this situation, R-group, the R-coup group,  and the cyanide sitting at the copper is an 8-complex, and here lithium-plus.  The most stable species in solution with higher order organo-couprates is this one.  Having the culprit with two alkyl or aryl substituents,  and both lithium-ketions bound to the cyanide.  From calculations and measurements, it is clear that this is the most stable species in solution.  However, that does not mean that this is the reactive species, which then does the job,  the transfer of the organic nucleophile.  Higher-order organo-couprates are somewhat more reactive than the lower-order cyanocouprates,  but again we have a problem in this case.  Again, we have two nucleophilic R-groups, and again it would be a good idea to change one into a dummy ligand.  This has been tested and rather well established than this one, the thiophilic R-group,  8-complex with this counter-ket ion.  Higher-order hetero-couprates.  Well, okay, this should be the overview on those copper reagents.  Later on, within the next weeks, we will talk about the fact that you can further trigger reactivity  if you change the metal-ket ion, for instance, against zinc.  This has then a much better functional group compatibility, and these copper-zinc mixtures  have also been invented by a knochel-group, and while they became rather important,  we will study in detail in a couple of weeks.  So, let's go on with this copper chemistry. As I said, it's very often a method of choice for conjugate addition reactions.  So, alphabet-unsaturated ketones, here cyclo-exanone, plus organo-copper reagent, no matter which type,  will give a conjugate addition product first an enolate, then after hydrolysis,  you return to the ketone functionality, but you can, of course, trap that enolate.  For instance, let's say TMS chloride,  then you have that TMS enolate you could use for chemistry,  or you can directly add an electrophile EX, getting the substituent in the two position.  Norbert Krauser from our neighboring university, Dortmund,  studied mechanistic details for conjugate addition processes.  Here we have the 1,4 conjugate addition,  and Krauser studied mechanistic details with examples of 1,6 conjugate addition up to 1,12 conjugate addition.  And a preferred model compound is this one, an alkene functionality in addition, in conjugation,  to an alphabet-unsaturated astro.  Let's call that compound A.  So this compound A was treated with a higher order cyanocuprate,  which should transfer tertiary butyl groups.  At minus 80 degrees, to my knowledge, it was in diaphyl ether, but it should be in deuterated diaphyl ether,  because this test has been done in an MR tube.  So it was a rather high concentration or long measuring time, since Krauser group was interested in carbon-carbon coupling constants.  So JCC, coupling constants of carbon-carbon coupling, between these two carbons here, alkenue carbons,  were found in the starting material, 175 Hertz.  So indeed, they found 74 Hertz.  Adding one equivalent of that higher order cyanocuprates,  we indeed noticed a change in coupling constants, while the change was very small between those alkenue carbons.  But it was significant at the olefinic part, from 74 Hertz to 51 Hertz.  And therefore, they interpreted this straightforwardly, that the olefinic part is coordinated to the copper.  Lithium plus should be coordinated here at the carbonyl group, at the carbonyl oxygen.  And mechanistically, the nucleophilic adrub is transferred from the copper to this position.  So I think a rather nice explanation. And in the NMRs, they could observe that increasing the temperature to minus 20 degrees,  then produces the alanulic system, so an allene,  with that ester enolate.  And after hydrolysis, well, hydrolysis means simply protonation here at this position.  They isolated this ester with that alanulic group.  Now to an interesting experiment also made by the Krause group with this starting material A.  I think I should draw it once again.  The starting material was treated with simple Gilman reagent dimethyl copper, dimethyl culprit with a lithium counter cation.  The first step should be that ester enolate formed. This was then trapped with benz aldehyde.  And finally, hydrolysis under moderate conditions gave an interesting product.  With a 91% yield and in the publication, there was claimed that they found a diastereoselectivity of 8 to 8 to 4 to 1.  As an exercise, please try to figure out the structure of that product.  And please try to explain why do we have, obviously, four diastereoisomers.  So the Gilman reagent with nucleophilic methyl groups, well, in this case the methyl groups are sterically smaller.  And they can more easily react at the terminal position.  Remember in the preceding example we had to transfer tertiary butyl groups at a sterically hindered position.  That means we need rather high nucleophilicity, high reactivity, and we higher order.  Cyanocruprates are more reactive than the Gilman reagents.  But in this case, the Gilman reagent is just fine, the nucleophile attacks here.  And we get this conjugated system with the ester enolate.  And the ester enolate is then trapped with the aldehyde.  This is a simple aldehyde addition process.  So how should that look like?  This is a methyl group that has been transferred.  An allene system is formed.  We have the ester group here and at that carbon the aldole addition process takes place giving this product.  So let's count the, well, stereogenic factors.  We have a chiral center at this position.  A second chiral center here.  Two chiral centers means we have two diastereoisomers.  We also have the enantiomers, but this is a racemic, of course.  So two chiral centers, two diastereoisomers.  But the scientists found that we have four diastereoisomers.  So we need an additional chiral element.  And indeed we have that because allenes can be chiral.  So remember that these four substituents are not in one plane.  These substituents here are perpendicular to each other.  So, and therefore we have the factor of two for the diastereoisomers and overall four of them.  Of course we do not know which one is preferred.  Okay, enough for today with organocopa chemistry.  Of course we have to go on with that next week.  And so subject next Tuesday will be organocopa applications in organic synthesis.  Thank you for listening. See you next week.
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Welcome to part 14 of the lecture on Stochium Metric Organometallics. Again today, metal specific features this time, cerium in organic synthesis. Cerium in organic synthesis is connected with a name reaction, the so-called Lusche reduction. So if you have, for instance, an alphabet or unsaturated ketone, cyclopentenone as an example, and you treat that with sodium borohydride, usually in methanol as solvent, well, part of the methanol will react with a sodium borohydride forming better soluble methoxyborates, hydro-methoxyborates, and these will then reduce the starting material. Usually, under these reaction conditions, you can anticipate to get a product mixture, simple, simple in brackets, reduction of a carbonyl functionality, giving rise to an interesting allylic alcohol. Well, as a competing reaction, you might get the one-four addition product of the borohydride. After hydrolysis, it might give then the ketone. On the other hand, if you have reaction conditions, the enolate can already react with a proton source, like in this case with a methanol, then in equilibrium, the ketone will be already formed in presence of a sodium borohydride, and then, of course, the ketone will be reduced since the normal ketone is more reactive against nucleophiles and alpha-beta unsaturated ketones. So, what you should get in this case is cyclopentenone. Just try this reaction, and what will be the result? These reaction conditions without additional Lewis acid, then you will get, well, just about 1% of this product, the allylic alcohol, which is, of course, the most interesting product, since you have functionality which you can work in organic synthesis, you will get nothing of a ketone and 99% of the relatively cheap cyclopentenone. So, since this one is the most interesting product, organic chemists are most interested in getting selectively this one. And there are reaction conditions, especially adding special Lewis acids. The best one turned out to be cerium chloride. Add cerium chloride, stoichiometrically, and then you can achieve an up to 97 to 3 selectivity in favor to the target allylic alcohol. So, this has been tested with a lot of Lewis acids. Another example, oeuropeium chloride, 93 to 7, as I said, cerium chloride turned out to be definitively the best one. And another transition metal chloride, nickel chloride, well, in this case you don't get anything of that target molecule, 76% of the ketone, 6% of the alcohol plus 18% starting material. Well, this seems to be a catalytic reduction with nickel hydride. Well, there are better reaction conditions where you get this more selectively than with a simple nickel chloride. So, next example, not an unsaturated carbonyl, but a substrate where you have both a ketone and an alderhyde in the same substrate. So, generally, alderhydes have the higher carbonyl activity, that means they are more reactive against nucleophiles. On the other hand, ketones are more Lewis basic at the oxygen. Well, if you bound, for instance, proton, here, it's more easily protonated because the corresponding cation is more stabilized due to the additional methyl group. And that means that Lewis acids preferentially bind to a ketone rather than to an alderhyde. And you can make use of that. So, if you add cerium chloride and then, again, sodium borohydride in methanol, you can selectively reduce the ketone in the presence of the alderhyde. Some solvent effects might also have some effect in this reaction, but essentially it should be the preferred coordination of cerium at the ketone. Well, now to organo cerium chemistry, that means reagents with a carbon cerium bond. So, this is the Iyodo aceto phenone, NTHF at minus 65 degrees, 3 hours reaction time. And we need this with butylythium. What could happen? Wall. So, I tried that, had in mind to synthesize the tertiary alcohol, because one could guess that the N-butylythium just as a granite reagent would attack the carbonyl group. Actually, they had in mind that this reaction won't work very well. And indeed, they proved that they get 0% for the tertiary alcohol. A bit surprising, but if you remember the beginning of this lecture series, well, what could be the competing reaction in this case? It's the halogen metal exchange. Please remember, this is a very fast reaction, even faster than a protonation, a deprotonation. So, halide metal exchange at the Iyodo functionality, well, lithiation at this position. And this, of course, gives then, following reactions, this attacks as a nucleophile, a carbonyl group of the next molecule, and so on. Forming polymeric systems, or the base deprotonates here. Well, the solution to the problem is, at one equivalent of, of course, dry cerium chloride, then the metal exchange, you will get the organo cerium compound, and then after hydrolysis, you are able to isolate up to 93% of that tertiary alcohol. Well, why not using a simple Grignet? Yes, indeed, the Grignet reagent is slower in the halogen metal exchange through eight complexes, but as we have learned from Knuchels result with isopropyl Grignet, it also works. This is then a competing reaction, and also Grignet reagents are somewhat basic, can deprotonate to enolates, whereas organo cerium is essentially non-basic. This is, I think, an important message. Well, we will see that in the next example. Cyclopentanone, THF, 0°1 hour is first treated with isopropyl magnesium chloride. The first guess based on organic chemistry, what we have learned in organic chemistry one, would be, well, okay, presumably after hydrolysis, we will have these tertiary alcohol, here with the isopropyl group. This has been tried, and it was found that just a 3% yield was obtained in this process. The main product, isolated with 88% yield, is also a tertiary alcohol, but the substituent is the cyclopentanone. Well, what kind of reaction is this? This is a simple and aldol addition process. So, the somewhat sterically hindered isopropyl magnesium chloride prefers to deprotonate the cyclopentanone, forming the magnesium enolate, which then reacts with the second equivalent of a ketone under aldol addition. Isopropyl magnesium chloride first treated with one equivalent of cerium chloride, forming the organo cerium compound. Then, we have just trace amounts of that aldol addition product, but we can isolate an 80% yield of that target molecule. The aldol addition product of acetone can be isolated, and if we treat that with an alkynyl cerium chloride, THF, at minus 70 degrees, minus 78 degrees, and after hydrolysis, we will get this product, a rather nice yield. I think indeed this is remarkable, since if we try such a reaction with organolythium or organomagnetium, it is clear that very fast an alcoholosis will occur with that alcohol functionality. But since cerium reagent is non-basic, this does not happen in organo cerium chemistry. Also, sterically very hindered systems are accessible when we switch to organo cerium chemistry. This ketone, sterically hindered due to this quaternary crowded center in alpha position, with methyl magnesium bromide, V-Gat, none of the tertiary alcohol, switch to the cerium, organo cerium compound, then 95% yield was isolated. The cerium enolates are also known as interesting organometallic reagents. Here is one example. There is a ketone in somewhat sterically hindered position, then an aster enolate, a cerium aster enolate, also sterically somewhat hindered due to that tertiary butyl oxy. Nevertheless, the reaction works very well, forming that aster aldol product, this one, with a 95% yield. With cerium chemistry, you often get yields above 90%. The price for cerium salts, unfortunately, increased in recent years, but nevertheless, the price of cerium chloride, approximately 4-5€. It is okay for special chemistry, at least when you have methods to recover the cerium. Here is one more example. Alpha-better unsaturated systems. This one has the model compound, the stoichiometric addition of the organometallic reagent, either one-two-addition product or the one-four conjugate addition product. With methyl cerium chloride, you get this one, the one-two-addition product with 98%, and from this one, only trace amounts. Compare that to a result with methyl lithium, 65% of this one, isolated yields, 17% of the other one. And with methyl magnesium bromide, 38%, and around 60% of the conjugate addition product. We can explain that with the hard-soft acid base concept, at least in this line, the magnesium compound is the softest one. Here, directly at the carbonyl carbon, we have the hard electrophile, and this one here, the better carbon is regarded to be the soft electrophile. Compare that to an aryl metal reagent phenyl cerium chloride, 90% to 4 phenyl lithium, 85% to 10. And phenyl magnesium bromide, 14% to 78%. So essentially, it's the same with those aryl metal species. So that means, generally, if you have an alpha-better unsaturated carbonyl, treat that with an alkyl or aryl cerium dichloride. We will achieve a very high yield of the 1, 2 addition product, this one. What about a method to get to the conjugate addition product selectively? Very often, organocopper chemistry is the method of choice. I abbreviate that with copper in brackets. It also details how those organocopper reagents are built up, will be the subject of the second part of this lesson today. So, now again, metal-specific features, copper chemistry. The founder of the organic copper chemistry is known to be Gilman. He invented that double titration because it was especially important for the organocopper chemistry to definitely know the concentration of organolithium reagents. So, Gilman, in 1952, he performed a trans-metalation with organolithium reagents, adding copper bromide or copper Iodide. Then, an organocopper compound is formed, plus of course the corresponding lithium salt. Usually, if you do that in ether solution, the organocopper compound precipitates. Since it has low solubility in organic solvents generally, the structure is some kind of polymeric chain structure. So, these simple organocopper complexes have low solubility and therefore, they are sensitive and therefore, they are less suitable for organic synthesis. But also, Gilman found out that if one adds a second equivalent of the organolithium reagent, then the precipitate goes into solution again. And what is formed then is something like an R2 copper lithium complex. There might be one equivalent of lithium bromide incorporated in the aggregates. So, these complexes are called lower order organo-couprates. And nowadays, they are also called Gilman reagents. So, how do those Gilman reagents look like? What is the structure? So, they consist of cuprate units. So, they are eight complexes and simply the LE plus as the counter cation. Normally, in solution, most stable component in solution, which in some cases can be crystallized, is dimer. Dimer consists of two almost linear copper eight complexes. Then, we have a lithium plus electrostatically coordinated and the solvent, for instance, diethyl ether coordinated to a lithium plus. Well, those Gilman reagents have an obvious disadvantage. You have the group, the R group, that's substituent, nucleophilic carbon substituent twice in the molecule, but generally only one is transferred in that reaction. This is, of course, an disadvantage. Imagine you have spent a couple of weeks to synthesize a rather complex structure, metalate that, and then making the organo-copper Gilman reagent, and half of what you have produced simply doesn't go into the target product. So, that is everything else, but atom economic, of course. What could be the solution of that problem, you have to synthesize mixed Gilman reagents. That means R and R-prime copper lithium complexes. If the R-prime is a substituent that is cheaply introduced and, moreover, a substituent that tends to stay at the copper, well, this is then the solution to the problem. So, R-prime is then called the dummy ligand. With examples, for instance, the satellite substituents tend to stay at the copper. If the psi of the new groups, with those it's the same, then we have alkoxy, tertiary-butyl oxy, and some more which, in addition, trigger the reactivity of the organo-copper complex, but one which is used very often, also with an SP1-hybridized carbon center, cyanides. In case of the cyanide, we can produce those, also starting with organo-lythium, plus copper cyanide, giving essentially a mixed Gilman reagent with cyanide as the dummy ligand. This method was introduced to my knowledge by the group of Bruce Lipschitz, which is then called lower-order cyano-couprates, widely applied in organo-copper chemistry, because it's easy to synthesize those, and then they have generally a higher nucleophilicity with that R group compared to a normal Gilman reagent, and this is very important, they are more stable at temperatures up to minus 30 degrees in THF and ether solution. You can further increase the reactivity if you add another equivalent of organo-lythium. What you get then is R2-copper-cyano-lythium-2. These are called higher-order organo-couprates. All this reaction is regarded to proceed with some of the change in structure. In this case with a lower order organo-couprates, you have this situation, R-group, the R-coup group, and the cyanide sitting at the copper is an 8-complex, and here lithium-plus. The most stable species in solution with higher order organo-couprates is this one. Having the culprit with two alkyl or aryl substituents, and both lithium-ketions bound to the cyanide. From calculations and measurements, it is clear that this is the most stable species in solution. However, that does not mean that this is the reactive species, which then does the job, the transfer of the organic nucleophile. Higher-order organo-couprates are somewhat more reactive than the lower-order cyanocouprates, but again we have a problem in this case. Again, we have two nucleophilic R-groups, and again it would be a good idea to change one into a dummy ligand. This has been tested and rather well established than this one, the thiophilic R-group, 8-complex with this counter-ket ion. Higher-order hetero-couprates. Well, okay, this should be the overview on those copper reagents. Later on, within the next weeks, we will talk about the fact that you can further trigger reactivity if you change the metal-ket ion, for instance, against zinc. This has then a much better functional group compatibility, and these copper-zinc mixtures have also been invented by a knochel-group, and while they became rather important, we will study in detail in a couple of weeks. So, let's go on with this copper chemistry. As I said, it's very often a method of choice for conjugate addition reactions. So, alphabet-unsaturated ketones, here cyclo-exanone, plus organo-copper reagent, no matter which type, will give a conjugate addition product first an enolate, then after hydrolysis, you return to the ketone functionality, but you can, of course, trap that enolate. For instance, let's say TMS chloride, then you have that TMS enolate you could use for chemistry, or you can directly add an electrophile EX, getting the substituent in the two position. Norbert Krauser from our neighboring university, Dortmund, studied mechanistic details for conjugate addition processes. Here we have the 1,4 conjugate addition, and Krauser studied mechanistic details with examples of 1,6 conjugate addition up to 1,12 conjugate addition. And a preferred model compound is this one, an alkene functionality in addition, in conjugation, to an alphabet-unsaturated astro. Let's call that compound A. So this compound A was treated with a higher order cyanocuprate, which should transfer tertiary butyl groups. At minus 80 degrees, to my knowledge, it was in diaphyl ether, but it should be in deuterated diaphyl ether, because this test has been done in an MR tube. So it was a rather high concentration or long measuring time, since Krauser group was interested in carbon-carbon coupling constants. So JCC, coupling constants of carbon-carbon coupling, between these two carbons here, alkenue carbons, were found in the starting material, 175 Hertz. So indeed, they found 74 Hertz. Adding one equivalent of that higher order cyanocuprates, we indeed noticed a change in coupling constants, while the change was very small between those alkenue carbons. But it was significant at the olefinic part, from 74 Hertz to 51 Hertz. And therefore, they interpreted this straightforwardly, that the olefinic part is coordinated to the copper. Lithium plus should be coordinated here at the carbonyl group, at the carbonyl oxygen. And mechanistically, the nucleophilic adrub is transferred from the copper to this position. So I think a rather nice explanation. And in the NMRs, they could observe that increasing the temperature to minus 20 degrees, then produces the alanulic system, so an allene, with that ester enolate. And after hydrolysis, well, hydrolysis means simply protonation here at this position. They isolated this ester with that alanulic group. Now to an interesting experiment also made by the Krause group with this starting material A. I think I should draw it once again. The starting material was treated with simple Gilman reagent dimethyl copper, dimethyl culprit with a lithium counter cation. The first step should be that ester enolate formed. This was then trapped with benz aldehyde. And finally, hydrolysis under moderate conditions gave an interesting product. With a 91% yield and in the publication, there was claimed that they found a diastereoselectivity of 8 to 8 to 4 to 1. As an exercise, please try to figure out the structure of that product. And please try to explain why do we have, obviously, four diastereoisomers. So the Gilman reagent with nucleophilic methyl groups, well, in this case the methyl groups are sterically smaller. And they can more easily react at the terminal position. Remember in the preceding example we had to transfer tertiary butyl groups at a sterically hindered position. That means we need rather high nucleophilicity, high reactivity, and we higher order. Cyanocruprates are more reactive than the Gilman reagents. But in this case, the Gilman reagent is just fine, the nucleophile attacks here. And we get this conjugated system with the ester enolate. And the ester enolate is then trapped with the aldehyde. This is a simple aldehyde addition process. So how should that look like? This is a methyl group that has been transferred. An allene system is formed. We have the ester group here and at that carbon the aldole addition process takes place giving this product. So let's count the, well, stereogenic factors. We have a chiral center at this position. A second chiral center here. Two chiral centers means we have two diastereoisomers. We also have the enantiomers, but this is a racemic, of course. So two chiral centers, two diastereoisomers. But the scientists found that we have four diastereoisomers. So we need an additional chiral element. And indeed we have that because allenes can be chiral. So remember that these four substituents are not in one plane. These substituents here are perpendicular to each other. So, and therefore we have the factor of two for the diastereoisomers and overall four of them. Of course we do not know which one is preferred. Okay, enough for today with organocopa chemistry. Of course we have to go on with that next week. And so subject next Tuesday will be organocopa applications in organic synthesis. Thank you for listening. See you next week.
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