Lecture Catalytic Organometallics 27 - 15.07.14
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00:00
GastrinStickstoffatomChemical reactionFunctional groupIronElektronenpaarEtomidateLanthanumAmineWursthülleSaltCytochrom P-450Human subject researchWine tasting descriptorsAqueous solutionRedoxStereoselectivityLactitolPyridineHydroxylMetallproteideEnzymeLanthanoideChiralität <Chemie>Metallorganische ChemieAzo couplingSulfideYield (engineering)AcidGesundheitsstörungConnective tissueEsterHydrogenActivity (UML)AcetateSetzen <Verfahrenstechnik>Base (chemistry)SulfoxideLecture/Conference
06:25
IronIronSystemic therapyYield (engineering)Chemical reactionMethylgruppeChemical structureWursthülleMultiprotein complexEpoxidationLigandSolventSaline (medicine)AcetylacetoneAmineSulfoxideChlorideDoppelbindungChiralität <Chemie>ElektronenpaarAqueous solutionSubstituentHydrogen peroxideFunctional groupLecture/Conference
12:46
AcetonitrileLigandChiralität <Chemie>Hydrogen peroxideChemical reactionMixtureAcetic acidSystemic therapyIronFunctional groupAminationMultiprotein complexBiomolecular structureStickstoffatomPyridineLecture/Conference
14:51
CycloalkaneSetzen <Verfahrenstechnik>Chiralität <Chemie>Chemical reactionAspirinIronHydroxylHydro TasmaniaRedoxChlorideCytochrom P-450ChemistryEsterYield (engineering)Benzyl alcoholIonenbindungLigandHeteroatomCarbon (fiber)ButylDiazoTransformation <Genetik>Addition reactionAcidChloroformChemical structureLecture/Conference
21:40
Chiralität <Chemie>Toll-like receptorProcess (computing)Azo couplingChlorideSystemic therapyHomocysteineHeterodimereIronSetzen <Verfahrenstechnik>Connective tissueYield (engineering)KupplungsreaktionLigandPlant breedingPhenyl groupChemical reactionAcidLecture/Conference
25:52
KaliumhydroxidSemioticsThermoformingIronOcean currentSaline (medicine)Multiprotein complexWine tasting descriptorsSystemic therapyCyclohexanTopicityMethylgruppeHydrogenWursthülleMethanolHuman body temperatureYield (engineering)Chemical reactionReducing agentProcess (computing)Base (chemistry)Azo couplingChemical structureLecture/Conference
30:46
IronGrignard-ReaktionAzo couplingNickelHaloalkaneChemical reactionProtein domainLecture/Conference
31:57
TetrahydrofuranProcess (computing)CopperSetzen <Verfahrenstechnik>Origin of replicationAzo couplingBromobenzeneKupplungsreaktionChlorideTrace elementChemical reactionWursthülleCopper(I) oxideIronLigandPotassiumPhosphatePalladiumYield (engineering)AcetateMerck KGaAMetalAlkylationLecture/Conference
40:03
TetrahydrofuranIronMetalIodideCopperCaesiumIonenbindungCarbamidsäureProcess (computing)StoichiometryChemical reactionDiphenyletherCarbonateCopper(I) oxidePhenolsAzo couplingFunctional groupLeadAddition reactionEisenpentacarbonylTransformation <Genetik>HydrocarboxylierungAryl halideEtomidateKupplungsreaktionEtherHuman subject researchSetzen <Verfahrenstechnik>WalkingLecture/Conference
48:09
StickstoffatomOxideChemical reactionIonenbindungGesundheitsstörungCarbonylkomplexeTolueneProcess (computing)HydrocarboxylierungMultiprotein complexDoppelbindungDiketoneCarbon (fiber)Systemic therapyAmmoniaManganeseChemical structureRedoxCarbon monoxideEisenpentacarbonylHydrogenYield (engineering)CarbonylverbindungenSideriteReaction mechanismSaltLecture/Conference
54:14
WalkingOxideSystemic therapyFunctional groupChemical reactionAzo couplingElectronWine tasting descriptorsButylDiolCarbon (fiber)MoleculeElectronic cigaretteBiosynthesisAlkeneProcess (computing)LigandBis (band)HydroxylSetzen <Verfahrenstechnik>NaturstoffChemical structureRedoxChiralität <Chemie>Lecture/Conference
01:00:19
Human body temperatureChemistryYield (engineering)WalkingChemical structurePotassium carbonateAryl halideAcetoneBiosynthesisBase (chemistry)Azo couplingLecture/Conference
01:01:58
Retrosynthetic analysisHuman subject researchBiosynthesisElectronic cigaretteLecture/Conference
Transcript: English(auto-generated)
00:05
Welcome to the lecture on catalytic organometallics. This is part 27. In the preceding lecture we discussed lanthanoids as catalysts.
00:21
I should add another rather important example in connection with the activation of esters for amide formation. So, pyridine 2 carboxylic acid ester plus a secondary amine with an acetal functionality included
01:05
reacts with just, catalyzed with just 1%, lanthanum triflate, 6 hours reaction time, room temperature, need without solvent.
01:32
And what is formed as expected is the corresponding amide.
01:51
So what is so special about that? Without the catalyst the reaction just doesn't work. You would have to heat it up to maybe 160°C or so and then you wouldn't get that selectivity.
02:07
So what is special about it? High yield. 99% yield is reported. Very mild reaction conditions. And, well, it is a Lewis acid catalyzed process.
02:28
And you have several positions where the Lewis acid can coordinate to. Here you have a 3 electron pair at that nitrogen. You have another basic center here.
02:45
And, as you know, acetals are extremely sensitive in the presence of acids. Nevertheless, this is selective enough to activate this carbonite group for the reaction with the nucleophilic nitrogen here.
03:07
So I think this is an important example for illustrating the immense chances that lanthanoid triflates and in this case lanthanum triflate is offering.
03:30
So, now to the subject of today. Iron catalysis.
03:43
Of course, iron catalysis is of special interest since iron is so abundant. It's cheap. And if you could use iron salts for various catalytic reactions instead of precious metals,
04:09
it's clear that this would be of tremendous importance. We already have discussed some iron catalyzed reactions.
04:24
Please remember Fenton's reagent for oxidizing agents setting free OH radicals, hydroxy radicals, then Derek Barton's GEEF systems, iron salts, pyridine and oxidizing agents,
04:50
then those naturally occurring enzymes with metalloenzymes based on iron catalysis.
05:06
We had a couple of examples, especially in the context of cytochrome P450. So, now to chiral iron catalysts for catalyzing oxidation reactions.
05:27
First example, sulphides can be oxidized with 1% iron catalyst.
05:47
I will draw the structure soon. Aqueous hydrogen peroxide, 1.5 equivalents in aqueous solution at room temperatures 3 hours.
06:11
This is reaction time and what you get then is a sulphoxide.
06:26
And as you know, sulphoxides can be chiral. They are configurationally stable with that three electron pair as one substituent.
06:43
So, for instance, with R para tolu and R' just a methyl group, one can achieve an 88% yield with 96% enantiomeric excess.
07:17
So, now to the structure of the catalyst.
07:22
So, I hope that you already notice the similarity to other catalysts you have already seen in this lecture.
08:37
This one is a bit more complicated as chiral centers here and chiral axis here and there.
09:24
So, in which context have you already seen a similar structure to that? This was the Jacobson-Katsuki epoxidation with manganese-saline complexes.
09:50
Now, this is work by Katsuki. Katsuki has the somewhat more complex structure and it's not a saline, but a saline complex since the double bond here, the amino group is missing.
10:12
It's than a tertiary amine in this case and it's not the manganese complex anymore, but an iron chloride.
10:25
So, just to add by the group of Karsten Pauln at Aachen University, another iron-based system or catalyst has been invented.
11:03
Much simpler in structure. Same reaction works in that case. 4% of that ligand plus 2% of iron III ACVAC.
11:31
Iron ACVAC. ACVAC is the abbreviation for acetylacetonate. So, what does this mean? It's this.
11:59
So, 30% hydrogen peroxide aqueous solution with some dichloromethane as solvent.
12:14
And the same reaction as outlined there succeeded then with up to 96% enantiomeric excess for the target chiral sulfoxide.
12:49
Other reactions which have been recently tested with chiral iron complexes are for instance this one.
13:09
5% catalyst in acetic acid H2O2 1.2 equivalents, acetonitrile as solvent, mixture of acetic acid and acetonitrile.
13:39
Room temperature, selectively the tertiary CH group is affected.
14:02
And lots of similar reactions are already known. As I said, those are reported with chiral ligand systems.
14:30
We have generally this structure. Two pyridine units, nitrogens here, amines that also coordinate and well, you have some chiral centers around.
14:57
Well, I think they initially tried to make oxidation reactions introduced in hydroxy groups in an unselective fashion.
15:09
While you have some diastereomeric selectivity, these products, this especially is not chiral as you might notice.
15:29
Well, another example that has been achieved, same reaction conditions, very complicated chiral structure but also obeying to that general scheme.
16:22
62% yield of this product, this by-product, a little bit of that, that has an additional hydroxy group here at this position. So, I think this type of chemistry in trying to get similar results as nature is
16:52
already doing with cytochrome P450 is still in the early stage but people are working on that.
17:03
Well, a simple catalyst, just iron chloride as an hydrate, 2.5%.
17:30
Then oxidizing agent, this tertiary butyl hydro peroxide, 3 equivalents, 80 degrees, 3 hours.
17:59
So, you use this one as reagent, as the substrate, 0.5 millimole scale, this has been done.
18:16
And the THF as a reagent and solvent, 1 milliliter.
18:30
And as a result, a CN bond has been formed, 90% of this NO-acetal on the CH transformation.
18:59
To illustrate the various reactions where iron catalysts have found to be active, another one for the formation of carbon hetero atom bonds,
19:21
a diazo ester reacts with benzylic alcohol at moderate reaction temperature, 40 degrees, chloroform as the solvent, 15 hours reaction time.
20:26
You need 5% of iron 2 chloride catalyst plus the chiral ligand to get a 94% yield of this phenoacetic acid.
21:00
Aster with chiral center in the 2 position here, the benzylic position, and 98%. The same reaction works as well if you just use water as reagent, then you have directly the OH group here, similar result.
21:30
So, what is the problem with that? Well, you have to synthesize that chiral ligand and therefore you have to put in quite a lot of effort, as you will see.
21:52
It's already somewhat tedious to draw that structure.
22:02
A spirocyclic system, this one.
22:35
So, with ours might be a phenyl group or an isopropyl group, this type of chiral ligand is called spiral box.
22:50
So, let's have a look, is that spiral box correct? No, it isn't, we have to change here, the connection should be to this position.
23:00
In our undergraduate lab, a couple of years ago we still had a nice reaction that was starting from better enough toll with excess iron chloride as Lewis acid and oxidizing agent.
23:52
Then, oxidatively, an oxidative dimerization getting to vinyl, this is the standard process for getting to this product.
24:06
Later on, one has to separate the enantiomers, remember that this is an atropic chiral system.
24:24
Well, somewhat new result, it's rather interesting, a cross coupling reaction has been reported.
24:47
Somewhat selectively, with 42% yield, about 30% yield were obtained of HOMO coupling products of these two regions.
25:13
But the cross coupling product with 42% yield and an already enantiomeric excess of 90% EE.
25:38
So, what has been used as the catalyst? Again, a katsuki type iron complex, some details are different.
25:59
Still hydrogens instead of methyl groups here, and here it's not the
26:04
cyclohexane moiety, but we have two phenyl groups, nevertheless chiral that system. So, iron catalyst, iron saline complex, catalytically just 4%, then you of course need an oxidizing agent, and in that case it was simply air.
26:48
Toluene, 40 degrees, 24 hours. I think this is really a remarkable result.
27:00
So that means we have couple of examples of more oxidative character. How about the opposite? Using iron catalysis for reductive processes. This is also known, meanwhile.
27:35
Just one example, there are of course many more, everything still in development.
27:51
Topic certainly, a hot topic in current research. Just the hydrogenation of these two bromoacetophenone.
28:08
So, just 0.5% iron catalyst, a chiral one, hydrogen 50 bar, KOH, basic system 20 mole percent, methanol and moderate temperatures.
28:55
98% yield and 99% EE in favor of the S enantiomer, that means this one.
29:21
So, structure of a chiral ligand, it's a macrocyclic system. This part is again, second time on the other side, this is a macrocycle.
30:28
And this forms a complex with iron, trisiron, dodecu, carbonite.
30:43
As I said, 0.5% of that complex are sufficient for that interesting hydrogenation reaction.
31:01
So, we have couple of lectures ago talked about the kumada coupling. Certainly remember that kumada coupling is a nice reaction for combining grignard reagents, arrow grignards with alkyl halides.
31:47
Initially with a domain of nickel catalysis, but meanwhile it's clear that iron is very active in this field.
32:02
Iron 3 chloride 5%, TMEDA as ligand 1.2, equivalence THF at 0 degrees, just 60 minutes reaction time.
32:25
And depending on the R, we have yield of 90 to 99%.
32:49
So, CC coupling for arrow centers and alkyl centers.
33:04
So, what about Ullmann coupling reactions? The original Ullmann coupling reaction is, for instance, bromobenzene reacts with copper branze to produce biphenyl.
33:44
Copper branze, in this case you have an excess.
34:02
You can achieve the same reaction in a palladium catalyzed process. For instance, with palladium acetate and DMF, then DMF is a reducing agent and 1 or 2% palladium is enough to achieve that type of process.
34:23
Meanwhile, there are non-classical Ullmann coupling processes where carbon-heterobonds are formed. We will discuss a few examples of that.
35:04
Very valuable chemistry for various purposes. So, this type of process was known to proceed rather well under copper catalysis.
35:26
This is also called an Ullmann coupling reaction. Now, catalyst with 20% DME DA.
35:53
Strangely enough, with this type of reaction you very often see this ligand.
36:04
With that one it works best. So, toluene, potassium phosphate as a base, 135 degrees, one day reaction time.
36:26
So, what about the catalyst? It was found that if you use 10% iron chloride, the one from Merck, with better 98% purity,
36:55
this is the one you would normally use, then you get an 87% yield of this Ullmann coupling product, iron catalyzed.
37:12
So, but if you change to 99.99% iron chloride was offered by Aldrich,
37:38
then just 9% of the product was formed.
37:48
So, the much cheaper iron chloride from Merck is the much better catalyst, obviously.
38:02
So, of course one should be suspicious if you take that Aldrich, expensive Aldrich pure iron chloride and add just 5 ppm of copper oxide.
38:27
Then you achieve a 78% yield again of your product. So, essentially it still is a copper catalyzed process.
38:48
And one should be suspicious about one or the other publication published between 2000 and 2010.
39:01
There might be another metal involved. This has been tested thoroughly by Steven Buchwald and Carsten Bollen.
39:20
They were also very active in the field of iron catalysis and found, well, okay, it's good to check sometimes, is it really iron catalysis. The same was found to be true for other Ullmann type couplings.
39:47
This one, 79% with the Merck and, well, only traces with Aldrich iron chloride
40:24
but adding some copper oxide then up to 98% was then found by this product. And another one which is again a typical example for the non-classical Ullmann coupling
40:45
is the formation of phenyl ethers. These are real ethers from phenols and aryl halides.
41:05
Well, up to 98% but again copper catalysis. Well, one further interesting example.
41:29
Copper, clearly it was tested, it's copper catalyzed and copper works best from Buchwald's group.
41:41
So that means copper catalysis is also a subject of today. This is the last copper example since we already discussed other copper catalyzed processes but that was in the preceding semester.
42:02
In the context of copper organyls conjugate addition reactions to alpha-beta unsaturated carbonyles and we then discussed already a copper catalyzed Wood's coupling process, as you might remember.
42:25
So, BOC, abbreviation for terzbutyl carbamoyl.
42:50
Here, that amide. Again, 20% DME DA.
43:04
Clearly, just as in the examples there, copper iodide 5%, cesium carbonate 3 equivalents, THF 80 degrees.
43:36
So, what will happen?
43:51
Clearly, an Ullmann coupling reaction will take place forming a CN bond here
44:06
and the second CN bond will be formed to this position and that is simply an SN2 process.
44:24
That's it. Since that SN2 process will proceed with inversion, we will end up with stereochemistry.
44:49
I think we must not discuss which step will be the first one in that process, the Ullmann coupling or the SN2 one.
45:01
So, 94%, very nice reaction. Back to iron catalysis. One example for iron catalyzed processes which are for sure catalyzed by iron
45:27
since there are no other metals known who catalyze this type of process. So, the transformation we will now discuss is this one.
47:03
No, I screwed something up here. Yes, now it's correct.
47:24
So, this transformation has been described a couple of years ago using stoichiometric amounts of iron carbonyles.
47:45
It has then been developed with this interesting example by Matthias Bellas group in Rostock. He is certainly one of the leading experts of catalysis which is of interest for industry.
48:08
So, and what are the reaction conditions? 20 bar carbon monoxide, ammonia, iron, carbonyl complexes added, THF 120 degrees, 65% of an intermediary product.
48:53
Secondly, that intermediate is then oxidized by DDQ or a manganese salt in toluene.
49:11
Room temperature one hour and the oxidization is rather clean process.
49:22
So, why does it have to be oxidized? Well, initially there is not a double bond here but two hydrogens and it has been oxidized to the maliumite system.
49:44
By the way, these structures are rather interesting as anti-tumor agents. So, we should discuss a bit the mechanism of this process.
50:01
In general, with an alkyne substituted on both sides, the iron carbonyl complex as catalyst.
50:43
So, what will happen? It will form this type of intermediate with a double insertion of carbon monoxide.
51:11
From these stoichiometric reactions it is known that under certain oxidative conditions you can transform that to cyclobutene diones
51:45
which are of course also highly interesting for applications in synthesis, indeed with high yield. If you have ammonia present, then that nucleophilic nitrogen will attack at the carbonyl group.
52:13
So, what will happen? As a result, the iron carbon bond is broken, actually representing a redox process.
52:47
There is one remaining hydrogen and this is then a hydride. So, you have then an intramolecular reducing agent for that double bond.
53:08
And this happens a second time that this nitrogen will attack that carbonyl group and then you have two hydride nucleophilic hydrogens.
53:25
And both are transferred. It was found that the product has this trans-stereochemistry.
54:03
You can isolate that. The catalyst is well restored by addition of carbon monoxide.
54:24
And well, here as I already outlined, you just need the oxidation process to form a final product.
54:45
So, as a final example for this type of chemistry, let's have a look at a natural product synthesis from the group of Matthias Beller.
55:07
Here we have the target molecule called Hemainimide B. I don't think that's important to keep that name in mind, however.
55:54
So, let's analyse the way to synthesise this molecule by a retro-synthetic analysis.
56:04
So, here we have that target structure for this type of reaction. But we should be suspicious that under the reaction conditions, well, this diol system won't survive.
56:30
So, it should be a good idea to introduce that chiral diol moiety at the end of our synthesis.
56:45
That means that in the retro-synthetic analysis, we should start with the introduction of that. So, that means how would we introduce the diol? Well, by a bis hydroxylation of an olefin, of course.
57:06
And therefore, retro-synthetic analysis will lead us to this more simple structure, simply the olefin.
57:30
And you should know how to introduce that diol. And unselectively, this is of course the Sharpless Asymmetric Dihydroxylation.
57:46
And we could use their AD mix, as we have already discussed a couple of weeks ago.
58:10
So, Bellas, catalytic, iron-catalyzed process, which we have discussed.
58:23
That means the iron, just say the iron, catalyst, ammonia, carbon monoxide, pressure, the first step.
58:43
And secondly, an oxidation will lead us to this intermediate, already quite simple, an alkyne group at an aromatic system.
59:31
This is a target for a Sonogashira coupling process that indeed worked with 99% palladium-catalyzed process.
59:54
The special ligand was used by the Bella group.
01:00:01
this one electron rich system with hysterically demanding bis tertiary butyl phosphineu group. So, well it's clear that we have the aryl bromide as the one coupling component
01:00:35
and we ventilate it as a Tulane as the second one.
01:00:46
So, and this is now rather, sorry, in retrosynthetic analysis, a rather simple structure.
01:01:09
Straightforward synthesis is of course achieved by nucleophilic substitution.
01:01:28
All this is undergraduate chemistry. Potassium carbonate as a base. This is deprotonated as the nucleophile preferentially done in acetone.
01:01:43
Reflux temperature for 16 hours and yield of that step is 98%. So, with this retrosynthetic analysis for the synthesis, innovative synthesis of such a natural product,
01:02:11
we are at the end of this semester's lecture. Subject of the lecture in winter semester will be retrosynthetic analysis designing organic synthesis.
01:02:31
Thank you for listening this semester. I hope to see you again in the winter semester. Bye bye.
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