Lecture Designing Organic Syntheses 21 - 07.01.15
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Human body temperatureRing strainChemical structureChemical reactionCupcakeSetzen <Verfahrenstechnik>CarbeneBenzeneBiosynthesisRearrangement reactionIsomerCubaneSea levelPhotochemistryLecture/Conference
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MyeloperoxidaseStarvation responseIceChemical compoundMoleculeRearrangement reactionPhenobarbitalRing strainBenzeneChemical reactionChemical structureDörrenWursthülleLithiumColumbia RecordsPenning trapLithium chlorideFunctional groupCryogenicsButcherMethylgruppeMethanisierungSynthetic oilDichloromethaneYield (engineering)CyclopentadienePharmacyAromaticityLecture/Conference
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Functional groupChemical reactionAdenineTrivialnameSetzen <Verfahrenstechnik>IsotropyDyeingWursthülleGap junctionReaction mechanismAcidMoleculeAageBenzodiazepineChemical structureDiazoCarbeneValinePhenyl groupTetraederstrukturSubstitutionsreaktionDicarboxylic acidImideLecture/Conference
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WalkingRearrangement reactionDipol <1,3->Yield (engineering)StuffingHydrolysatAzofarbstoffDyeingRadioactive decayCopper(II) chloridePhotochemistryMolecularityStickstoffatomButcherChemical compoundGemstoneStop codonLecture/Conference
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Puff pastryWine tasting descriptorsLactitolFunctional groupFenton's reagentChemical structureCycloalkaneDyeingLeadBiosynthesisBenzeneHydrocarbonPenning trapChemical reactionCarbon monoxideSolutionCombine harvesterRadical (chemistry)Adenomatous polyposis coliPhenyl groupYield (engineering)PolymerCubaneIonenbindungElimination reactionWalkingPedosphäreHeterodimereLecture/Conference
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GesundheitsstörungZunderbeständigkeitAddition reactionChemical reactionGrowth mediumWalkingBromideSolutionAzo couplingWursthülleKetonePenning trapElimination reactionSurface scienceRearrangement reactionChemical structureThermoformingFunctional groupRadical (chemistry)MoleculeDoppelbindungDicarboxylic acidAllylHalideCubaneBase (chemistry)Fermentation starterAlpha particleAqueous solutionTriethylaminBromineCycloadditionBiosynthesisChemical elementChemical compoundProcess (computing)Yield (engineering)KaliumhydroxidLecture/Conference
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MethanisierungChemical structureSandHydrogenAcidComplication (medicine)WaterfallÖlChemical compoundFunctional groupGeneKohlenstoff-14River sourceLeadRing strainMixtureWursthülleRearrangement reactionIonenbindungIsomerBiosynthesisLecture/Conference
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Yield (engineering)PalladiumGesundheitsstörungInsektengiftChemical reactionLithiumMoleculeChemical compoundWalkingTeaChemical structureDoppelbindungSystemic therapyAluminium oxideCycloalkanePenning trapCarbon (fiber)BiosynthesisHydrogenBenzeneVancomycinZincPropionaldehydHydrocarbonBromideDyeingIonenbindungAddition reactionRearrangement reactionHexachlorocyclopentadieneFunctional groupStuffingDienePhotochemistryZunderbeständigkeitProcess (computing)ElephantiasisCyclopropaneBiomolecular structureCycloadditionButanolEthaneBromineLecture/Conference
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OxideFunctional groupCoalDiet foodTerrasse <Geologie>DyeingÖlBiosynthesisChemical reactionWalkingRearrangement reactionZigarettenschachtelElimination reactionStereoselectivityHydrideAcidChemical structureBody weightCarbon (fiber)ChromerzSetzen <Verfahrenstechnik>Set (abstract data type)BisacodylHydroxideDieneDiazoAlkeneAlcoholAcid anhydrideMethanolEsterEthyleneDiolWursthülleChromatierenProcess (computing)Ford TempoHydroborierungLecture/Conference
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GesundheitsstörungCarbon (fiber)Functional groupIonenbindungOrgan donationSynthetic oilReactivity (chemistry)MetalMoleculeMethylgruppeLithiumCarbeneX-ray crystallographyPolymerSteric effectsChlorideBiosynthesisButyllithiumHydrogenRetrosynthetic analysisNuclear magnetic resonanceSeleniteAgeingCobaltRadical (chemistry)MatchActivity (UML)Lecture/Conference
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Functional groupGrowth mediumBiosynthesisHydrocarbonYield (engineering)Drop (liquid)WursthülleNaturstoffButyllithiumPropeneBase (chemistry)Lecture/Conference
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Computer animation
Transcript: English(auto-generated)
00:05
Happy New Year everyone and welcome to part 21 of the lecture on designing organic synthesis. The subject of today are carbon frameworks which resemble polyhedrons.
00:25
Most of what I will tell you today is nicely presented in the marvelous book of Henning Hopf, Classics in Hydrocarbon Chemistry. And first of all let's talk about the so-called prismains.
00:46
So a prism, how does that look like? It's a drawing of a prism and if this is meant as
01:11
the structure of a hydrocarbon then this is prismain and especially this is the three prismain.
01:33
Closely related is this structure, a cube. And this cube, well, straight forward name of that hydrocarbon
01:54
would be cubane. But nevertheless it is also a prismain, the four prismain. There are of
02:12
course even more prismains. What about the five prismain? So a drawing becomes a bit more
02:28
complicated like this. And while I won't draw the six prismain, we'll just write that down.
02:53
We can now have a look at the steric strain energies of each molecule. 320 kcal per mole
03:26
for the three prismain. While at 90 degrees it has a half time of about 11 hours. But it is
03:56
all stable, completely stable at room temperature. Even though it is that highly strained. Strain
04:12
energy of cubane 172 kcal. It withstands higher temperature up to 200 degrees. So also stable
04:32
until 200 degrees. And the five prismain, 144 kcal. This is the most stable of all prismains.
04:56
With the six prismain and even more with the seven prismain the strain energy goes up again.
05:05
Here we have 164 kcal. In all of those of the synthesis that have been planned and have been
05:23
performed for these structures, one of course had the idea you have to put in somehow the energy. You can do that if you have intermediates on a high energy level like carbenes or you put
05:46
in photo energy. Photochemical reactions are regularly very important for synthesizing this type of products. So if we have a look at that three prismain first.
06:09
And as I said at 90 degrees it has a half time of about 11 hours. What will be the product of rearrangement of this compound? Well it is an isomer simply of benzene. And indeed it reacts
06:35
to give benzene. In fact the original name of the three prismain is the lardenburg
06:47
or better lardenburg benzene. Since the chemist lardenburg suggested in the year 1869
07:13
that this is the structure of benzene. So he was wrong but nevertheless lardenburg benzene
07:24
is well symbolizes the high interest into this isomer of benzene. So it has been synthesized
07:48
by the group of cuts in 1973 at the Columbia University in New York. Well we don't do a retro synthetic plan in that case because we wouldn't get the idea.
08:12
Some strange reactions have been applied there. They found some interesting reactions forming highly strained molecules and then thought well maybe we could start with these
08:28
strained molecules and build an even more strained one the lardenburg benzene. Okay so the cuts group started with cyclopentadiene treated that with methyl lithium and it's clear
08:54
what will happen methane will be formed and of course the aromatic cyclopentadienyl anion
09:12
with the lithium counter cation. Then dichloromethane is slowly added in dry dichloromethane
09:29
of course lithium chloride is formed and this highly sensitive compound treating that at low
10:02
temperature with the second equivalent of methyl lithium. Once again methane is formed and once again second equivalent of lithium chloride and as a main product this one the yield
10:36
obtained 45 plus minus five percent yield. They did it a lot of time and the maximum yield
10:54
was 59 percent but obviously achieved only once. So this is also a highly strained molecule.
11:08
It has a trivial trivial name called benz valine. While in the original publication they didn't make any remarks about the mechanism of its formation
11:31
while later on another group I think from Italy had publication in tetrahedron letters where they
11:41
um discussed mechanism based on uh some uh experiments with certain c marked frameworks and uh well I think the best explanation might be that well whatsoever we get
12:07
as an intermediate this carbene and the carbene undergoing a sheletropic
12:36
reaction which reminds us of a Diels-Alder reaction with this as the diene and that
12:54
as the dienophile. Okay just a suggestion explaining at least the structure.
13:04
So let's call that BV as abbreviation for benz valine. This benz valine is next treated
13:31
with this electrophile with this diazo functionality. This is a diazo dicarboxylic acid
13:53
imide phenyl substituted. All this is well known as a very electrophilic dienophile.
14:03
In this case it will interact with the benz valine and an intermediate like this will be formed first this dipolar intermediate then a lot of rearrangement steps will occur
15:02
each steps these steps are outlined in Henninghoff's book but why you just can't keep that in mind. So I just write down the final result of the rearrangement. It's this one and you see the only thing we
15:47
still have to achieve is forming that bond and get rid of of that stuff there. Well astonishing 60 yield of this product was obtained.
16:06
Then hydrolysis and secondly oxidative workup with our copper chloride as the oxidant
16:31
delivers this azo compound and the final step is photochemical radiation
16:42
molecular nitrogen is formed and the corresponding die radical which combines forming that final C-C bond.
17:05
Okay they got hands on that compound but for these last steps just between four and six percent yield were obtained. So let us then have a look at this special hydrocarbon
17:53
cubane. Well it not only resembles a polyhedron but the specialty is that all sides
18:13
are all planes here are equal. So it is a completely regular polyhedron and complete regular
18:25
polyhedrons are called platonic solids. So this is one example of a platonic
18:40
solid. Well another one is of course the well a dodeca or we call we call it a dodecahedra and dodecahedrine so this is
19:07
a dodecahedra is the hydrocarbon with which is also resembling one of the platonic solids
19:27
having 12 five membered rings so pentagons. 12 pentagons in a complete sphere.
19:42
Well forming a C20 H20 cage. So and of course now the complicate part for drawing these structures begins. We will try
20:00
that. So first pentagon here the second one third one and behind the blackboard
20:45
another one. So here we will have a pentagon there a pentagon and now we have to connect
21:09
these positions. So it should be complete round yeah but ball shaped but
21:23
well I think you got the point okay. So we will later on talk about the synthesis of dodecahedra. First of all let's discuss cubane. So as you already might know
21:44
Eaton's group synthesized cubane. So and one important rather important intermediate
22:08
is this one and as an exercise please just figure out in one or two minutes how did they
22:31
synthesize that one. So every one of you noticed that this is obviously a product of the Diels-Alder reaction a Diels-Alder dimerization of this bromocyclopentadienone
23:00
and as you might know normally those cyclopentadienones are not stable with the exception of highly substituted ones. For instance that so-called tetracyclone with four phenyl group
23:31
which itself is then known. So these should be phenyl groups for Diels-Alder reaction losing
23:45
carbon monoxide and resulting in the hexafenyl benzene in high yield. So that means this is
24:05
so sensitive it reacts to polymers plus that Diels-Alder product you can't buy that you have to generate that in situ. So you might do that by an elimination reaction. Best idea
24:32
is treating this trisbromo cyclopentapentanone for instance with the base
24:51
triethylamine has been applied. So two of those bromines
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bromines you can introduced by a simple addition reaction of elemental bromine to the double bond and this bromide in allylic position you can introduce
25:27
with the well-known method n-bromosocinimide under radicalic reaction conditions with a radical reaction starter. So now back to this structure
25:56
let us draw this one in another perspective then we notice that this double bond
26:44
is in close proximity to that one and therefore a photochemical two plus two cycloaddition
27:02
reaction has been tried it is successful as I started once again yes this is the result okay
28:15
so you see cycloaddition process forms a four membered ring at the same time also here the
28:23
four membered ring is formed one four membered ring and the second one. So we now need a ring contraction and we know as an example for ring contraction the so-called favorski rearrangement
28:45
for which we need ketones cyclic ketones with a halide in alpha position. We already have that here and that means in this case simply treating it
29:03
with koh in aqueous solution will form the cubane dicarboxylic acid in about 30 percent yield and
29:44
this reaction has been performed in a medium scale up to 2.7 kilograms of that product formed in a one-part reaction. So from here once performed 2.7 kilograms.
30:13
Well a couple of more steps then will lead to the cubane. So let's go on
30:34
with dodecahedrine. First that was that molecule was synthesized by Leo Paquette's
30:50
group at the Ohio State University. I think it's Ohio State and this is a somewhat tedious step-by-step approach. On the other hand more elegant is the synthesis by
31:10
Prince Bach from Freiburg University. So first of all the basic idea of his synthesis. He thought
31:39
that this would be an interesting starting compound. Well okay you see here
32:18
we have the five membered ring there also five membered ring and then
32:26
wow these methylene group here the CC single bond connecting the two five membered rings here a methylene group there a methylene group and in the center we have a four membered ring.
32:42
So unfortunately we have to draw that again symmetrically to the plane of that four membered ring. So it wasn't that complicated. This structure he called pagodane and he noticed
33:35
that this is far more strained
33:42
than dodecahedrine. Dodecahedrine is not that strained. So we have a lot of strain energy in here and if we could connect these two carbon atoms these two carbon atoms
34:09
therefore we have to get rid of one two three four hydrogens and we have to put
34:21
these four hydrogens in here using them to cleave this CC bond and that CC bond. Then well we have dodecahedrine. This is an isomer of dodecahedrine and he hoped for
34:45
a rearrangement reaction similar as it was the case as you certainly remember um for the adamantine synthesis of Paul von Raag-Schleier. Well we tried it
35:07
we tried it a lot of times and well always got a horrible mixture and painfully isolating than dodecahedrine then up to eight percent yield then um using palladium
35:41
on aluminum oxide and of course heating that up. Wow a better yield of the dodecahedrine skeleton much better yield they achieved than
36:05
adding one equivalent of bromine to that single bond of course it's symmetrically or that that means we have cleaved the central four membered ring we leave out the other stuff
36:31
that is around there having this dibromide then treating that with zinc having than two elephants
36:52
okay cyclopropanation gave this structure with missing that and that single bond
37:11
and having a cyclopropane here the cyclopropane there and then again similar reaction conditions a far better rearrangement took place forming than
37:32
dodecahedrine the dimethyl dodecahedrine with approximately 30 percent yield so nice synthesis
38:00
however we now have to talk about the problem where to get the pagodane from
38:07
okay there was an additional interesting idea they started with a Diels-Alder reaction
38:27
of this hexachlorocyclopentadiene and norbornadiene forming this strange product
39:16
this was already known this compound isodrine and it was in i think in the late 60s
39:32
a very well known insecticide produced in very large scale again
39:47
again and Diels-Alder reaction now with that double bond here losing
40:15
so2 since benzene ring is formed than here so and now
40:37
you already notice that rather nicely one part the bottom part
40:57
of the upper part just it's a choice of the pagodane is already established
41:10
ah sorry nope there's a mistake this is formed after the Diels-Alder
41:29
reaction and so2 is uh evolves making that uh diene actually i'm not quite sure anymore
41:43
has this been isolated at all because now a very interesting reaction occurs a concerted process where these two hydrogens jump to these two carbons and the aromatic system
42:08
is the result so okay luckily we don't need to go on
42:50
and writing down all those chlorides because in the next step just with lithium in tertiary
43:05
butanol very nice almost clean reaction leads us to the corresponding hydrocarbon
43:25
this one and then similarly in a few reaction steps again with this diene the princebok group
43:53
succeeded in setting up the second benzene moiety these two benzene rings are
44:16
completely parallel and as i told you before photochemical energy photo energy is
44:32
a nice way to get energy into that molecule to build up highly strained systems and
44:42
a photochemical two plus two cycloaddition reaction is possible it's an equilibrium
45:21
the four-membered ring is formed resulting in this structure and another very interesting
45:49
step follows again it is all the reaction now with the well-known dienophile malenic acid
46:05
anhydride it's in this case an axo deals all the reaction because ando doesn't work here and so an axo deals alder reaction with this diene
46:28
forming the olefin here and this olefin then undergoes at the same time again and deals all the reaction as dienophile with this diene so what will be the result
48:07
well okay not bad okay like like that well so we now know what this looks like here
48:30
we will abbreviate that oxidatively one can get rid of this one having now that
48:59
symmetrical setup okay so what do we need we have to eliminate one carbon
49:23
on each side we just need a methylene bridge and not an ethylene diol bridge this has been achieved in a multi-step process
49:47
first hydroboration secondly oxidative workup so hydroboration twice oxidative workup
50:09
then you have an alcohol functionality here and an alcohol functionality there i don't think that there is any selectivity in terms of those stereoisomers but
50:28
it doesn't matter for the synthesis because we make an elimination reaction later on so having two hydroxide groups alcohol here alcohol there then it is oxidized at that time they
50:51
used that oxidation with chromates today we would use a tempo oxidation or something like that
51:06
and after two carbonite groups have been established in the fourth step then diazo dia yes diazo groups are introduced no wrong you've noticed that already right
52:37
so photochemically in methanol a so-called
52:48
wolf ring contraction occurs after a while it's not that difficult anymore to
53:30
draw these types of structures so and as you see with some other methods
53:45
one is then able to get rid of the ester functionality to get to the final dodeca
54:02
to the pagodane and then the rearrangement to the dodecahedrine in the last step with about eight percent well what did they do with the dodecahedrine
54:28
they of course measured NMR spectra right here we would also do so clearly yeah so proton NMR
54:42
one single it at 3.38 ppm that's it it's highly symmetrical it has only one sort of ch bonds the dodecahedrine not the pagodane okay the dodecahedrine and also certain c
55:07
NMR one signal at 66.9 well okay enough about the dodecahedrine
55:34
for the program of today i have one more molecule and i think we should start
55:51
with a retrosynthetic analysis of the one one one proper lane it's this show so just think about for a few minutes how would you disconnect here
56:28
so you should have noticed that this is indeed a very special molecule from the geometry bond geometry at those carbons
56:41
there is no hydrogen sitting here and there otherwise it would have five bonds okay so but all carbon carbon bonds here four have the same direction like an umbrella
57:01
okay so so-called carbons with inverted bond geometry okay so and in retro synthetic analysis we could think of well let's call that r1 disconnect in the center
57:36
homolytically to a diradical like that actually under certain
57:46
moderate conditions this is a stable molecule you can keep that for a while but it has the tendency to polymerize via such diradicals or with a nucleophile butyl lithium
58:08
which you group there lithium there and then polymerization yeah but forming this bond well um a long time it was a matter of debate is there a real bond here or does it have
58:26
diradical character and is somehow with uh sterical hindrance or so on um stabilized um actually it is clarified but i'm not quite sure what is the result they have an x-ray
58:45
structure analysis and it is a very long central bond here so this didn't turn out as the retro synthetic analysis of choice far better is well let's get rid of
59:10
two three-membered rings just leave one three-membered ring leaving group here
59:38
leaving group there and having twice donator reactivity
59:50
wow not i not simply by deprotonation well we would have to make um metal
01:00:00
helite exchange double methylation from something like that
01:00:22
methylation of course maybe stepwise well and this just adding a carbene to volafen
01:01:15
so and indeed at munich university group of professor simies did that synthesis with xr chlorides
01:01:41
making use of bromoform basic medium getting a 45 percent yield
01:02:03
of this and then just treating that with drop wise addition of n-butyllithium at minus 50 degrees
01:02:21
34 percent yield of that 111 propylene was obtained in the next lesson
01:02:42
next tuesday we will again talk about synthesis of first of synthesis of hydrocarbons but these hydrocarbons are natural products then oh thank you for listening for today's see you next week tuesday
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