Lecture Designing Organic Syntheses 20 - 17.12.14
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GastrinLD-VerfahrenHuman subject researchHydrocarbonCyclohexanConformational isomerismNorbornaneDiolRing strainAlkeneProcess (computing)Functional groupBiosynthesisSystemic therapyEthaneReactivity (chemistry)Thin filmCycloalkaneHexaneDyeingAlkoholfreies GetränkTeaLecture/Conference
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TuffAdamantaneHydrocarbonTheoretische ChemieIonenbindungHydrogenRock (geology)SodiumChemical reactionPalladiumHydro TasmaniaMuffinCycloalkaneSystemic therapyAgeingUranhexafluoridMoleculeHexaneFatty acid methyl esterFunctional groupCaveYield (engineering)OctaneDoppelbindungSodium amalgamVinylverbindungenChemical formulaProcess (computing)MolecularityCyclohexanCycloadditionIsomerLecture/Conference
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Rearrangement reactionHydrideSetzen <Verfahrenstechnik>ZellmigrationTeaHydro TasmaniaHydrogenPalladiumLeadPenning trapChemical compoundReaction mechanismWalkingChlorideDyeingAluminium oxideTiermodellAluminium chlorideAgeingKatalaseGesundheitsstörungIonenbindungAdamantaneColourantMolekulardynamikChemical structureChemical formulaRock (geology)AssetChemical reactionHeterodimereWine tasting descriptorsCyclopentadieneHydrocarbonFunctional groupAluminiumNorborneneAcidLecture/Conference
12:45
AdamantaneWalkingAzo couplingRearrangement reactionConformational isomerismFunctional groupLibrary (computing)Lecture/Conference
13:35
Chemical formulaCarbonylverbindungenReactivity (chemistry)Aluminium chlorideHydrocarbonChemical reactionOrgan donationBiosynthesisElektronenakzeptorYield (engineering)Functional groupIonenbindungActivity (UML)Chemical clockWursthülleWaterSense DistrictBrown adipose tissueMoleculeGesundheitsstörungLecture/Conference
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AcidHydrolysatLithiumSense DistrictAluminiumReducing agentChronic (medicine)Schweflige SäureAluminium hydrideOxideCyanideChemical reactionGrowth mediumSulfurFunctional groupChlorideWine tasting descriptorsMoleculeAgeingWalkingChromsäureAdamantaneSchwefelblüteAlcoholSetzen <Verfahrenstechnik>MethansulfonylchloridBiosynthesisNucleophilic substitutionSulfurylchloridEthylene glycolYield (engineering)Chiralität <Chemie>HydroxymethylgruppeCarbon (fiber)IodidePyridineLecture/Conference
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WalkingChain (unit)Yield (engineering)Sodium hydrideProteinChemical structureNitrogen fixationIonenbindungReducing agentThermoformingHydrazineFunctional groupSurface scienceBiosynthesisKetoneHydrocarboxylierungLecture/Conference
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Ion transporterPan (magazine)DyeingReducing agentMixtureChemistryDyeFolsäureStereoselectivityGesundheitsstörungDioxaneSodiumFunctional groupPotenz <Homöopathie>NaphthalinChemical reactionHuman body temperatureBiosynthesisMetabolic pathwayOxideChromerzYield (engineering)HydrocarbonEthanolHydrogenIslandKetoneStereochemistryBy-productDiketoneDetection limitAcidWalkingSodium hydrideSynthetic oilNucleophilic substitutionAcetateHydrolysatLecture/Conference
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Highway Addressable Remote Transducer ProtocolPentose phosphate pathwayPhotochemistrySodium hydroxideBirch reductionSynthetic oilMeatCycloalkaneHydrogenDyeingAcidFoodChemical reactionMoleculeBleitetraethylHydrocarbonFunctional groupGesundheitsstörungTeaAreaWaterReducing agentChemical compoundBiosynthesisWalkingButadienAcid anhydrideCarbon (fiber)SilverCyclohexanHydrolysatSaltHalideEsterFatty acid methyl esterCarboxylateConformational isomerismDicarboxylic acidDecompositionAcetyleneBromineCarbonateLecture/Conference
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Thermisches KrackenProteinCondensationSeparation processMoleculeMolecularityBleitetraethylPenning trapIonenbindungHydrocarbonTrisDecompositionActivity (UML)Chemical reactionWalkingChemical structureButcherEthanolAcetateRing strainAssetSynthetic oilBiosynthesisAldolProcess (computing)SodiumEnolAldol reactionAcidElektronenakzeptorReactivity (chemistry)Functional groupYield (engineering)Lecture/Conference
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Computer animation
Transcript: English(auto-generated)
00:05
Welcome to part 20 of the lecture on designing organic synthesis. Subject of today are special hydrocarbons,
00:22
those who represent fixed conformers of cyclohexane.
00:47
So, you of course all know the conformers of cyclohexane, the most stable one is the so-called chair conformation.
01:10
And you have to go 5.5 kcal up to a higher energy level.
01:25
And there you then find the so-called twist boat conformer. And finally another 1.6 kcal more than you end up with the boat conformation.
02:00
So, stabilizing or fixing this conformation.
02:10
Well, this is rather easy with that boat conformation.
02:20
Just put on an ethane diol bridge. Of course, you also know norbornane.
02:44
Here you have a methylene bridge. And it is in principle also a fixed boat conformation. However, the norbornane is far more strained. With that three six-membered rings all in the boat conformation,
03:13
there is much less strain than here with the norbornane. And if we add an olefin moiety there to the norbornene,
03:22
then this olefin is of exceptional reactivity for addition processes. That is also due to the elevated strain of this system. Well, the twist boat conformer you can fix this moiety by adding two ethane diol bridges.
04:03
And here for that chair, well, then this is a nice possibility to fix that.
04:21
So, here the name of this hydrocarbon that is edamantine. This is the so-called twistane.
04:41
And this is just a bicyclic hydrocarbon, the bicyclo-222 octane.
05:00
Now, let's have a look how to synthesize these three hydrocarbons. Well, the most easy, easiest one is certainly the bicyclo-222 octane.
05:21
So, having three cyclohexane units, you all know, well, we could then think of adding a double bond in there, having a cyclohexane moiety and therefore then a redrawn of the Diels-Alder reaction.
05:42
So, cycloaddition process should be typical to approach this molecule. And this has been done in several ways. One simply is that cyclohexadiene plus a vinyl sulphone, 89% for the Diels-Alder product.
06:13
Then we already have the bicyclic system.
06:22
Hydrogenation, molecular hydrogen, palladium on car coal, that gave an 87% yield of that molecule, missing that double bond.
06:41
And then you can get rid of that sulphonyl group simply with sodium amalgam.
07:02
The presence of methanol, reducing that off, that gave 78% of the final product.
07:28
For adamantine, once again its structure, easily drawn.
07:47
So this actually represents the smallest diamond, I would say, saturated with hydrogen.
08:02
And, well, it is important to notice that its molecular formula is C10H16. So the famous theoretical chemist, Paul von Ragschleier,
08:35
calculated all possible isomers and, well, I think he didn't need to calculate it.
08:44
It was already clear that this one, the adamantine structure, is the thermodynamically most stable C10H16 hydrocarbon.
09:02
That's clear. So, and then Paul von Ragschleier had the simple idea, well, we could take any C10H16 compound, have to find the right isomerisation protocol, isomerisation conditions,
09:26
and it will finally isomerise to this one if there is some kind of equilibrium. And indeed, we found a very nice way. Well, C10, that's twice C5.
09:47
And we know a C5 compound which easily dimerises. Actually, to get cyclopentadiene in your hand, you have to crack the Diels-Alder dimer.
10:01
So, and the Diels-Alder dimer, again a norbornene moiety dimer looks like that. Hydrogenation of that leads to this hydrocarbon,
10:27
and this is again C10H16 as molecular formula. Now, we certainly tried a lot, and rearrangements should be cationic rearrangements,
10:50
Wagner-Mehrwein type rearrangements. And we could induce that by adding strong Lewis acids. We first tried aluminum chloride, but we optimised it.
11:05
So heating it up with a catalytic amount of palladium dichloride on aluminum oxide gave adamantane in an up to 60% yield.
11:32
What a marvellous reaction. So, and the mechanism, a lot of steps, a cation has to be formed.
11:46
So, maybe the electrophilic palladium gives a CH insertion, or net result and hydride is eliminated.
12:11
We have a cation there. And then, first migration, Wagner-Mehrwein rearrangement can take place,
12:40
having the next cation there.
12:43
And then a lot of 1, 2 hydrogen shifts can occur, and other Wagner-Mehrwein rearrangements. There is, well, indeed, a couple of steps. One more intermediate I will draw.
13:04
This is another intermediate, and a couple of more steps you will finally end up with, that adamantane. So, what about putting on more cyclohexane moieties with, well, in the chair, conformation.
13:41
This is possible, for instance, this one.
14:07
The same reaction principle as for the simple adamantane. You need the appropriate hydrocarbon with the same molecular formula.
14:33
And in that case, was tried with aluminum chloride and heating it up.
14:42
And under optimized conditions, approximately 10% yield of the final product was obtained. So, next we should have a look at the synthesis of twistane.
15:23
Let's try to analyze this one. Well, we have to find retrosynthetic analysis, strategic bonds,
15:44
and that means, well, let us, for instance, disconnect here.
16:06
Therefore, one suggestion is, let's assume having donator reactivity here,
16:28
and acceptor reactivity there. So, then, should be regarded as straightforward, leaving group here next,
17:00
and introducing a carbonyl group there, that we can easily get donator reactivity there.
17:22
So, at least this is disconnection R1.
17:49
Another disconnection could be this one, let's call that R2.
18:05
So, what do we have here? One, two, three, four, five, six. Two annihilated six-membered rings.
18:22
Sys-fused, donator, acceptor reactivity. Okay, this is the alternative.
18:54
So, let us now have a look at real synthesis of that molecule.
19:03
How was the synthesis of twistane achieved? So, the first one was reported by Whitlock in 1962.
19:24
Well, he chose an approach like that, following R1 in principle. First, the Diels-Alder reaction.
20:01
Well, at that time, an unselective catalysis of Diels-Alder reaction with chiral Lewis acids was not known. So, therefore, this is just a racemic synthesis.
20:23
Well, if I see it correctly, then adamantane is a chiral molecule. So, Whitlock did it as a racemic synthesis. And, well, Diels-Alder reaction, then lithium aluminum hydride reduction.
20:53
Then you have a hydroxymethyl group here.
21:01
He then transformed the primary alcohol by forming sulfuric acid, ASTR, or just CH3, the sulfuric chloride and pyridine as the base,
21:32
forming a leaving group from the primary alcohol,
21:52
and then simply with a cyanide, making nucleophilic substitution.
22:10
So, and here, they had, well, the one carbon more they were in need of.
22:23
85% hydrolysis with KOH and ethylene glycol.
22:56
So, next step is this one, treating this carboxylic acid with iodine, slightly basic medium.
23:20
So, what will happen?
23:23
I think you should be well aware of this type of reaction.
23:42
It is, of course, an iodo-lactonization. 86% yield, no, 68.
24:09
Once again, reduction with lithium aluminum hydride. Well, what do you get? You will get, again, a primary alcohol on this side,
24:35
the secondary alcohol here, and the iodide was gone, reduced off.
24:47
So, 90% yield. So, I think I should go on on the next blackboard.
25:03
Once again, we are at this stage. So, what is to do next? Oxidizing, this one, and forming a leaving group here.
25:26
Maybe one should do that the other round, and we did so. Mesylation here, oxidation there. So, mesyl chloride pyridine, as before in analogy,
25:47
and oxidation, that was a chromic acid oxidation typical for that time. And we get to this ketone, 87%.
26:19
And then, just sodium hydride in DMF was sufficient, forming that one.
26:58
So, it's clear deprotonating here.
27:01
This is the nucleophilic center, this is the electrophilic center. There is that C-C bond formed from here to there. And this is, of course, the same as this structure.
27:32
So, we just have to get rid of that carbonyl group. Well, while 90% of that ketone was obtained,
27:52
Wolf-Kishner reduction, that is hydrazine KOH,
28:01
then gave the stain, unfortunately, in just 23% yield for the final step. I'm sure you can improve that. Well, okay, this was the first example of a twistane synthesis.
28:30
And, well, the next example is from the group of Delong-Champs, a Canadian chemist, to my knowledge, following the Whitlock synthesis five years later
28:56
and choosing the synthesis path derived from vitro synthetic analysis step R2.
29:08
So, having a naphthalene, a hydrogenated naphthalene moiety. And he had the nice idea, why not starting from a functionalized naphthalene,
29:34
the 2,7-dihydroxy naphthalene, and with renin-nickel, hydrogen, ethanol,
29:53
elevated temperatures, 150 degrees, and 100 atmosphere, rather vigorous reaction conditions,
30:14
you get this product with that, right?
30:23
That's stereochemistry because all hydrogens will approach from the same side. So, and a remarkable 63% yield.
30:50
So, first, oxidation with one equivalent of oxidizing agent.
31:09
It was, again, with chromate oxidation. And secondly, making use of an orthoaster with power toluenesulfonic acid as a catalyst in ethanol than the,
31:42
oh, well, I made a mistake. It was not one equivalent of the oxidant. It was enough to oxidize both.
32:00
But then it was, well, more or less one equivalent of the orthoaster in order to get the mono ketone, mono the other ketone protected as the acetal.
32:30
Well, of course, it's difficult to get that in high selectivity. So, the yield given was about 20%. However, I assume that it was a mixture of the diketone plus the bisacetals plus that.
32:53
And then separating those, in the end, they had only 20% yield. However, the byproducts should be able to recover, I think.
33:05
So, now, from here, then, this one was reduced again. So, first, reduction.
33:21
Second, again, a mutilation. And third, hydrolysis of the acetal, 60% yield of that.
34:04
Remarkable is the next step. Sodium hydride deprotonation there to form the enolate nucleophilic substitution.
34:29
So, in dioxane, heating that up a bit. Well, that already formed the twistane known, this one.
34:55
And that step worked quantitatively.
35:03
So, again, the final reduction to the hydrocarbon made some problems. We formed the dithiocetal.
35:30
This is quantitatively. And, again, renin-nickel-ethanol reduction, but only 34% yield than getting to the twistane.
36:05
Next two syntheses we will discuss are from the famous Hans Musso, Karlsruhe University. And he was also involved in the synthesis of various interesting hydrocarbons.
36:28
For instance, in the synthesis of so-called esterrains. First of all, the tetra-esterrain.
36:42
From the Latin word for stars. So, target molecule is this one.
37:05
This is the tetra-esterrain. So, and all those carbons here are part of cyclohexane moiety fixed in the boat conformation.
37:29
So, how to synthesize that one? Well, what would be the retro-synthetic analysis for that?
37:45
Well, obviously, the most straightforward idea would be this one.
38:04
You get that by Burch reduction. Try to irradiate. Hoping for that. Well, I didn't find it in the literature. Didn't find it in the literature. Well, I think it didn't work.
38:20
Otherwise, it would have been published. Okay? But, nevertheless, muscle group thought, well, with some more groups attached, it might work out far better.
38:42
And indeed, I think this one is not made by Burch reduction. But by first Diels-Alder reaction of butadiene with acetylene dicarboxylic acid, ester, hydrolyzing the ester and forming the anhydride then.
39:15
Here, in this case, hydrogenation, no, no, irradiation, photochemical irradiation worked forming this compound.
39:51
Well, unfortunately, several attempts getting into the range of 9 to 10% yield.
40:07
Next step, hydrolysis of the anhydride. First, just sodium hydroxide in water.
40:27
Secondly, adding some acid, Wernstedt acid again.
40:53
The tetra acid was obtained.
41:01
Now, we have to get rid of those four carbons. You can transform normally the carboxylic acid, getting rid of the carboxylic acid moiety, having than a halide sitting at the same position.
41:23
This is a classical Hunds-Dieker reaction.
41:40
So that is done with silver salt as an oxidizing agent. For instance, think silver carbonate in the presence of bromine.
42:00
This is transforming carboxylic acid in the corresponding halide functionality. So they tried it, but it didn't work, unfortunately.
42:20
They then decided to try the so-called Grob decomposition. This is related to the Hunds-Dieker reaction.
42:40
And, well, it's done with another oxidizing agent. Let tetra acetate in the presence of N-chlorosuccinimide, NCS.
43:00
And then you have the tetrachloro-tetra-esterane.
43:27
Most successful attempt was 20%. And just one step to the tetra-esterane itself.
43:44
Just sodium and ethanol and the last step worked quite well with a 74% yield. So a nice synthesis to my knowledge, the only one known up to now.
44:06
And, well, if you summarize the overall yield, it's rather low. So that's the reason why there are no investigations about the reactivity of the tetra-esterane.
44:26
It should be interesting to know to which hydrocarbons it could rearrange, treating it also with Lewis acids. So next synthesis or synthetic approach to an astrain also by the muscle group is targeting this structure.
45:15
That is then, of course, the penta-astrain.
45:26
Of course, somewhat reminding us of the Christmas star. Well, the idea of a muscle group then was, let us try to combine this structure, Tris ketone,
46:22
with this Michael acceptor treating with a base at minus 78 degrees several attempts
47:01
and hoping for that it is deprotonated here. Well, one problem might be that this is, of course, far more acidic than these positions.
47:26
Well, hoping for forming C-C bonds from here to there, from there to there, having an enolate which then will make an aldol addition process to this and then to the other position.
47:43
Not, of course, an aldol condensation because that would be forbidden by Brad's rule. So, target molecule, they were hoping for this one, what that it should be.
48:39
Unfortunately, they noticed that just one C-C bond was formed between those two molecules.
48:52
So, there was a product, but certainly only one C-C bond. This reaction doesn't work and therefore this molecular Christmas star is still waiting for being synthesized.
49:11
Well, Merry Christmas, see you next year.
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