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Lec 09. Pt. 3. & Lec. 10. Migratory Displacements


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Title Lec 09. Pt. 3. & Lec. 10. Migratory Displacements
Title of Series Chem 201: Organic Reaction Mechanisms I
Part Number 13
Number of Parts 26
Author Vranken, David Van
License CC Attribution - ShareAlike 3.0 Unported:
You are free to use, adapt and copy, distribute and transmit the work or content in adapted or unchanged form for any legal and non-commercial purpose as long as the work is attributed to the author in the manner specified by the author or licensor and the work or content is shared also in adapted form only under the conditions of this license.
DOI 10.5446/19348
Publisher University of California Irvine (UCI)
Release Date 2012
Language English

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Subject Area Chemistry
Abstract UCI Chem 201 Organic Reaction Mechanisms I (Fall 2012) Lec 09 Pt. 3 and Lec 10. Organic Reaction Mechanisms -- Addition to Sigma Star (σ*) & Migratory Displacements Instructor: David Van Vranken, Ph.D. Description: Advanced treatment of basic mechanistic principles of modern organic chemistry. Topics include molecular orbital theory, orbital symmetry control of organic reactions, aromaticity, carbonium ion chemistry, free radical chemistry, the chemistry of carbenes and carbanions, photochemistry, electrophilic substitutions, aromatic chemistry.
OK we're going to continue were just going to finish up some little last bits on lecturer 9 on topic 9
of which is editions of Sigma in in concerted displacement reactions and we've been talking about sp to it as 3 hybridized centers and I just want to remind you not to draw as into reactions sp to hybridize centers and I think you know that that you shouldn't do this but I'm going to find that you're doing this every once in a while you'll make this mistake and I'm simply going to remind you it's never easier to attack it as 2 centers into a Dakin sp 3 anything actually extremely dis favored to attack it feeding centers with nuclear files so recall that if you ever have a
choice almost always you a choice on in a case like this the nucleophile displays of preferentially arms here
sp 3 center and so I had drawn for molecules down here so we can try to compare on on some different rates of attacking sp 3 centers in its produce ended up what's actual rate constancy around these solar and started mean right K relative these actual rate constants in Pomona per 2nd on so you can convert them into relative rates if you'd like so the bottom line is of these 4 substrates that I've drawn here at this probe Hodel substrate is the fastest it's gotten P 3 center that's being attacked on there's no steric hindrance from the alkaline and in a way that kind is helping accelerate a century actions because the price system is donating into that P like orbital in the transition state is a musical pieces P character it's increasing at that center the transition state this is a little bit faster then just a simple Howell systems and not a lot about 50 per cent faster and in the case of Al ill you have to worry about the rotational stated this double bond is a twist around this bond right here on this role little line here's a twist around and bond that price system is only activating that that carbon center when it's in a particular orientation was Papa dual it's it's cylindrical asymmetrical you can spin all-rounder in it's always activating attack that center and its lessons of its analysis take a look at these 2 substrates it at the other end over here on your right hand side is a S P 2 hybridized centers and let's see how much slower these are so here we're looking at something on the order of a factor of 10 thousand times slower to attack sp to Ibirite centers and U.S. reactions it's not impossible but shouldn't have a really good explanation before you invoke sp to bursitis in 2 reactions at these kinds of S P 2 hybridize centers and will end of course you're probably not going to do reactions with
this kind of allying all Hale lied more typically you'll be dealing with a vinyl he lied
and so now it starts to look really ugly as far as the choice for what kinds of reactions for good and what kinds of reactions is that so generally don't design reactions that trade will rely on its into reactions of vinyl bromide vinyl don't invoke those kinds of mechanisms were U.S. into reactions because it'll remind you of these rate differences and ask you to explain why you think that's plausible but let me give you a sense of 4 arms and animal 20 draw 20 give you a sense for the kind of penalty that you pay Canadian away estimating this I'm trying to draw up drawing up planar version of methane
obviously you can't plan saying that it's easy to draw out plenary methane in a computer and say Tell the energy of this but what you find is that plane
methane is 130 K cows promote hiring energy than regular attaches he draw on that day an under-strength TD is my abbreviation for territory eagle nesting protect than tipped that's the kind of penalty that you have to pay not not the 430 k Kallstrom or obviously that would be insane but you you're paying some of that price in the transition state for trying to displace this the transition state plenary carbon and there's 1 word but all that orthogonal to the others that doesn't get used in that picture so you'll pay that 430 giggles from orbits some of that penalties included in trying to do a tax dispute 2 were hybridized centers of its I don't want to say that it's
impossible to to react well I don't think it's impossible to do as into reactions at speed to address and shows you it's impossible but if you wanted to take advantage of that there are
reactions where it's very clearly going through this in a while and when the call is innocent to reaction of course all call a concerted displacement so there is a very very cleverly designed systems and what you're doing a concerted displacement administrative center in this case somebody on had nucleophile absolutely poised here 5 Adams away ready to form a five-member ring almost no entropic penalty to this entropy can cost you at 12 K Kallstrom all in the transition state and you could see what's happening here is that this Alcock see group is poised to push out the chloride to type it's not a thing to this and to help requires 2 substrates to collide with each other this is intramolecular so you can't actually call this to reaction and so on you could see how much you have to give
make up your system in order to make these reactions were notice also how cleverly designed this substrate is the God of methyl group here so that you can't do the to eliminations across there that would be a problem if you didn't have
that methyl groups would be a significant side reactions and just to confirm that that's going to a concerted displacement if you make the CIS substrates the other stereo chemistry there's no reaction to this you not get any cycles Asians so alright alright no reaction but what I really need is no cycles Asian with the other geometry really this Claude unity and sort of poised here for this outcome oxidant pushed out out OK so that's an example of what if you have something that's less tricked out in that don't be proposing a concerted displacements sp 2 centers on that's very challenging and not generally plausible the circuit another type of substitution if possible but very rare and
that you'll have a tendency overuse and you will see used in the literature when there's no mechanistic basis for those
kinds of proposals sought and got talk about to find reactions and I'll explain what that is but just 1 moment this would be a typical case where you have to wonder what's the mechanism for substitution on the system but it's criteria if this is Quaternary center if there's a tertiary center if you substituted it it's very hard and very slow to add that carbon atoms and so what you'll find is in rare cases which you can observe patterns of reactivity that look like this now how do you know but that is not innocent 1
reaction how do you know that the leading group is not popping off to give an al-Qa'eda iron and then in 2nd step slow you can check
for things like solvent polarity dependence does it become much faster Minneapolis that suggests innocent wanted reaction on of just give you some raw numbers here if you compare rates of attack of a nucleophile on just a simple a chloride with nothing else on there and you compare the rates of edition for here on this primary center it's got no and this would be the Essen to pathway 1st serious into prominence and this direct pathway mimic my long pier bigger on the direct pathway where I attacked directly here will call at the Essen to pathway that sent to Prime pathway is intrinsically Over a thousand times slower In
hearing in this case here you're not worried just about and there's a huge entropic penalty that's temperate a temperature dependent Robert penalty it's not just that you're worried about having
the correct alignment between the nuclear file and the carbon quarrying bond now we have to worry even when these 2 molecules collide with each other is the pipe bomb perfectly aligned with the dividing wall below the carbon chlorine bond even more than in tropical climates in the in the transition state so there are cases where it's were reactions are known to go through as into prime substitution for the give you an example and this case they wanted to put on a leading group that was pretty good but not too good so that a knew toss late because they had to be really careful to not get Ehrlich had finds
that 1 put too good a leading group appear because they didn't want 2 formal Academy they want us to go through some sort of substitution process
and so what they did is they did this In meet could on this right on the stroke the structure for so that was the solvent for the reaction said the cramming leading group here this is not a fast reactions to the using of very high concentration of the nuclear fell to drag it's something to go in neck out of it for 3 days so in this particular case they got the substitution product and here's the Pepperdine nuclear file and you can see it is added incentive now again this is a very heavily tricked-out substrate they took great pains to design something that wouldn't go through as someone reactions notices methyl group on here in a way it's kind of cool because it allows you to see that the nuclear file and we'll talk about that in just 1 moment here that the nucleophile added from the same faces the leaving innocent prime reactions that nuclear power plants from the same faces the leading and moreover you can see that this methyl group allows you to tell that the nuclear fallout from the sea bass but that also makes it very hard for the nuclear file to attack here because the methyl group hysterically getting in the way that means you're not directly attacking here that isn't too if you're attack near it into primary if you're attacking the double bond issue to focus when eagle drop the orbital interactions here on analytics system where there's some sort of a leading group and so put that actually I want to draw the leading group pointing out and make a little extra room here before you copy that OK so on England dropped my leading Group here and also a picture of the orbital interactions Inc there involved when you do this destined to take process we got
some sort of a leading group here and 1 to phase this orbital on so that all I want to phase this arm I want a phase sort of into
bonding here so what we want to do is we want to donate electron density into this this is my picture of a Sigma star warble maybe I should make this low little on a little smaller on the inside so another words if you want to somehow displaces leading the after addressing How does it help you if you have a Pisces when would sketch out priced off and will try to imagine what would happen if we filled pies With electron density normally pie stars empty but if was started dumping electron density piste are but you'll find is you can make that overlap and you have to have the phasing correct otherwise you'll get no significant double bonding interactions is facing tells you that is as we say Bill normally empty pasta with electron density what happens is that electron density will appear on the opposite side this is a general principle
enterprise systems will talk about this war later there an electron density by overcoming the
nuclear file here the electrons occupancy will tend to appear on the into pure playing aside it's the reverse of an elimination in a way OK so what that in order for this this warbles symmetry to work out the nuclear file has to come in and attack from the same faces leaving as you add as you as you donate electrons into his orbital here they start to appear on his backside hope you displaced from the other side if you don't see the stereo specificity you have no idea that wasn't you have no evidence that it was to prior to notice that this is a fundamental requirement is that the nuclear power has to add in from the same face but that's a scary a specific requirement destined to primary actions you'll see people invoking into prime reckons all over the literature and in most cases there is no evidence for that just trying it because they don't have rules Ferrero pushing they're just trying to show some changes in bond OK so let's at 4
4 s and type concerted displacement reactions and so were slightly going to
switch gears here and talk about nuclear files for concerted displacements on literal lot closer than this minute about nuclear positively right next door intramolecular relative to the leading groups there are all kinds of named reactions in organic chemistry Pinnacle rearrangement Wolf rearrangement Beckmann rearrangement courteous rearrangement on the list goes on will arrangement the list goes on on many of them the world categories of this something called a migratory displaced it's physically the same idea that's been used over and over and over again and maybe they haven't covered every single possible variant on this all these users switch 1 atom out and put a new 1 anybody remained rearrangement summit taking back to us 1 of the oldest examples of this in this dates back to 1860 very urgent origins organic chemistry on the pinnacle the arrangement was 1st demonstrated with this Diehl called called you make pinnacle I'm trying to draw the somersault horse representation so that this group is specifically ante to this so that there's a bond tainty to the which group visit a you take acetone you dime rises with a reducing agent and you get the so-called dirt-cheap very common very easy to access to 1960 and when you exposes the sulfuric acid which was 1 of the few regions they had back in 1860 on something happens that needed some product that doesn't have the same carbon skeleton anymore and what's going on is that this is rearranging arm ultimately initially to give the Sox Sonia With the TV will group on it and of course you lose the proton and this is now a on just a simple he tone ,comma they call this act alone because classical you make it through a pinnacle rearrangement of Pinnacle Kanako alone to Quito you know it doesn't have the same carbon backbones pinnacle OK so this is a pinnacle rearrangement what's going on here the way you think about this is that of the actual leaving group in this case is probably needed OH its water is the leading group and so what is it it's going to make that act as a leading group resisting Mista warble on the back and if this is going to leave something is going to have to donate electron density that Sigma or normally 4 Cobble Kanye information it's the CAT bonds next-door will look at this bomb that drawn right here when it's empty plane of the electrons in signal bonded donating in the intervening or they're helping to push out this water Leading Group and it turns out that this bond is weak that bond is weak because there's a lone pair and we no longer have donors that donating Sigma star for this bond and weakening it making it a better nucleophile so you can see by having this lone pair here we we can respond and make it a better nucleophile weaker bonds are more nucleophilic was electrons in the lower bills are higher hiring energy focus when I see a bunch of reactions that look like this I'm just gonna come change nitrogen carbon switch oxygen every possible variant on reactions that over and over again so that saw the pinnacle of how do you know that this is not just going to a cobbled can for the moment
we in some way to draw up a slightly modified substrate here but where I've got family groups on each cartridge in the dial 999 Adam methyl group and the other side of the proton now this were going through a cargo Kanye and you'd be totally correct in believing that well it I'd be easier for mecarbil can center right if this is just cobble Kanye information than what's going to happen is this 0 8 is going to lead as water the former cobbled that I'm here and 1 of these 2 groups will migrate but you don't lose this war that's not the 1 over here the Treasury that you lose this water this OH group as water so when you look at the product for this reaction on the sum sulfur needed copper sulfide gas address doesn't matter just a solid phase version of sulfuric acid for this coordination on the end product of this but you can see is that the methyl groups they've bonded to the same carbon atom that had only child what's happened is this final group over here has migrated
over so if we draw this out with some of the facts in this Red you can see what's happening here is
that the lone pairs are donating weakening that bond and that's migrating over now there were 4 by of the war independent possibilities here could have been a mouthful of migrated over the fennel here than on this side behind right on that side of all those were possible in this case it shows you fit in in the pinnacle rearranges the migratory aptitude and you can run through a series of these in order to gage which groups migrate faster and if you measure that will find is that Errol migrates the fastest that's greater than CC DoubleLine's that's faster than hydrate 0 groups and migrate faster than tertiary which is faster than secondary which is faster than primary numbers you're not going to hysterics to argue
what migrates vast area you might look at the fact that there's electron deficiency in this group here and the better
it is able to accommodate that the better able in the better you'll be migrating over so why is it that ,comma if you want some sort of our reasoning for why is it that found to migrate faster when you look at 1 2 cargo Kanye migrations it turns out the Cobble Kanye migrations are faster and again this is not a couple can with fennel rather than help fuel because the double bonds here can donate at the same time that the signal bond might be saying Wait a 2nd you're saying that a signal bond can donate into moral at the same time that apply but yes yes yes if I had an anti-war orbital in summer except the system more than 1 component can donated at or below the same time that's an old calculations take all that stuff you can if you drew some sort of a resident structural describe underneath
kind of like cycle operable combined that's why Finland vinyl migrate so quickly in the transition state for migration looks kind of like separable provide because not only is a single mom donating their
apply bond is also donating OK so cynical everything I'm going to show you is basically the pinnacle rearrangement ,comma some sort of variation Celestica look at some common variants but for so this first one will will go through is called the tiffin OH Danny not reaction of things very easy to make medicinal hydroxy means so now they have these Bosnian catalyze
reactions to make those for Internet nitro methane into a Aqaba Neil and then reduce the nitro group that's how you make
methamphetamine and of course that the trick here you need to convert that Amin into a leading group and the best way to do that is with something called nature's acid chemically usually chemistry right HON no that's not it looks like an acronym is not an acronym it's a molecular formula is nature's acid were there and so that's what they're using in order to convert the gaming group into it into what's called a dies in leading Group and initially you get intermediate there is an extraordinary Leading Group on there I can't think of any better meaning that converts nightdress acid converts and means into dies only in groups right nitrogen gas is now leader and you did better than that very hot and could see this system is perfectly set up about Bonds here depending on how I feel this Niger does nitrogen I can just depending on how I rocked this back-and-forth at any point in
time 1 of these 2 bonds here will be online is
indeed to this bond in cages shift right on over his alleged draw that helps announced having water is a leading group I've got a vastly better leaving guys only so you can imagine it's just migrating over and what is it that makes this bond good it migrating was being weakened what's weakening this bond holders long pairs here on this OH group that are donating into into binding model it's like the OH long there's almost doing to attack breaking the CEC bond which we considered it migrates over better focus that's what happens you can see what's going to happen years you'll end up with a ring expansion and I'm not sure how good a job I'll do here withdrawing this out but you end up with a seven-member rain on and that's traditionally what-if in Odem
in office used for delivering expansions and key towns and you end up with it with an extra methylene groups there whenever you need that yes I would look like
this in the end product or at the end of this so I'm leaving at a step sorry what proton still in the country and then you can be prove on so again you don't buy you can't buy Niger's acid there's no bottle of nature's acid in the lab but you do you take sodium nitrite and hydrochloric acid to that and I'm not going to go through the mechanism exists at 5 or 6 steps Aveiro pushes basically you can prove meet major gas water I'm sorry this is nature's Asotin get water that is leaving as part of the dies only formation mechanism to make nature's acid by permitting sodium nitrite ,comma and that reacts in Aceh catalyze reactions and it's OK so you can see the analogy here just took
H 2 and replaced it with nitrogen gas is a leading the same idea because let's extend this idea
from a signal bond here would happen if I replaced this single bond you with a double 1 will still work yet they're both getting protonated rapidly proton transfer the faster the button on the loss corporate and on blogs to capital so little that there is rapid and reversible from nation that's occurring in this reaction so it's not that you're not appropriating their suspicious that you don't get migratory displacement until you prove it this way it's faster that's the limiting step the 2 of them this it was we OK so this is an alpha Daiei's carbon yield compound on and this is kind of a worthless structure to draw doesn't give us any insight into reactivity excellent change this I'm going to draw and is a more popular residents formed by is still worthless Ferrero pushing his forests thinking about the activity by John all draw different resonance structure for this little help you more clearly see on what kind of reactivity you should expect for this system 10 until you draw this alternative resonance structure don't feel like it's entirely clear what you Jordan the drawing with the start of doing this but take these electrons here in this nitrogen donate them here move those over and that all hope you know more clearly see what kind of reactivity to expect from this system so that's really the best residents structure to help you think about what's going to happen when you eat this or if you hit it with a photon of light and Jackie and ATK Cal's from all of energy on so under those kinds of conditions heat or light diesel rearranged to give key teams and in the leading group you can see is going to be nitrogen gas of this sort of sketch that in a case that has we think about the things or arrangement here that allows us to rearranged to give the crime while once again I can see it's the AA group that migrated over so this is the leading group that's pretty clear why that leaning misleading because the AA group is pushing it out it's like the AA group is the nucleophile here and I say a crappy nucleophile why would that pushing thing out well there's a lone pair here is always a wine intake it is always aligned to 2 donated to the into here that weakens that our common bonds that are common bond is nucleophilic because of that lone pair which is donating into that and that allows it to migrate over until you can keep lighter or the common ways to do that reaction can never understood in this example you never know the impact of organic chemistry around you you look at all the microchips in your computers and cell phones etc. video projectors the major organic chemistry so it turns out that the photo resist resins that used a pattern of microcircuits organic compounds organic photo chemistry is driving all of that and I'll show you 1 of the earliest versions of a photo resist that used to follow pattern of integrated circuits that process called photolithography this is called noble act Dianchi residence and Q stands for Daiei zone after O'Quinn and that's this will free arrangements substrate that goes through this mechanism here somebody sat in their assault and their organic chemistry mechanisms class and heard about this war 409 guess they thought they were going to apply the assault phone type group there that helps modulate the properties in this case the EU's liked to have to put in the energy that allows this rearrangement to occur on and the Mecca I'm not going to draw through the entire mechanism here but in this case when you do this rearrangement what happens if you go from this water insoluble organic on groups that they spread on microchips and wherever you shine light it does this photochemical version of the Wall rearrangement and then you get a key team insulin and exposes the aqueous sodium hydroxide this gets converted into a water soluble sodium carboxyl late I'm not going to show you all this the steps for Attack of hydroxide anarchy team but it's like a three-step thing going on there Denson now wherever you shined light those little parts of your Goodby film become water soluble and can be washed away to leave these patterns these microcircuits patterns on the much more sophisticated photochemical resist resins nowadays the pace and catalytic Proton generation this is 1 of the earliest versions on the photo resists this DVDs these Deion contenders is noble act is just a polymer you need to know about that not that it's not cool but you don't need to know about it OK so Hoffman and courteous rearrangement of switch from carbon to nitrogen the book of
the 4 of us can do a quick and comparison this season for the last 10 is better I think that's a little better focus so of a hot but classical Hofmann rearrangement you can see the analogy here to this To this will free range I'm simply going to replace this Adam right here with a nitrogen atoms and the leading group is not that important in this particular case of Hoffman it's a bromide on and in order to make this work better on you typically have to have this way with the negative charge so let me go in residents or magic taking Enbrel image
and deeper meeting the Proton from and indelible decent make and the emoluments of the conditions in just a moment and what
I'm going to do is going to draw resonance structure once again that this 1 this is not a really good resident structure but as soon as I draw this I can see how much it resembles a wolf rearrangement thing over there and look at that looks just like the wall not exactly but very close to that wall range so now you can imagine OK bromide is the leading group but why is going to leave something is going to push that out of this Order appears willing to push their group out and why there are groups of nucleophilic it's because his lone pairs donating to the into binding work it cannot be Tommy hitting the lone pairs overlapping in space with the antibody model is our carbon carbon and so the products of Hoffman rearrangements initially are ISO signing and usually you do something with those on
most and interestingly what you do is you hide relies them down to a means so there's another version of this reaction you could do with a Zeitz and
so let and dropped below allow you to imagine if you will a side that's an entry group here is the more common way people draw a sides and 3 but if you draw and trading clearly see that it looks a lot like that will freely that a side group right there and strong and good residents structure that OK so same idea whether it's nitrogen gas is a leading group Fernando Miami on typically have you use this to make a billion dollars is 1 way of he take is so this is the way you do a arrangements it used
to be called a Hoffman degradation because the end result is you're remove this carbon so this car is not directly connected to
the nitrogen atoms so initially what happens is that in the presence of base forming nitrogen bromine behind you you did probe made here you attack bromine and you make this week display Seibel nitrogen bromine bond here in Rome on it set in an initial intermediate and then the sodium hydroxide beaches during running deep wrote makes this and that's what initiates this whole Hoffman business so the end result in this case but I will draw the whole species shall destroy the ice signing and so in the presence of sodium hydroxide you can't stop you you can't isolate this if stirring around cinema drops at this end up idolizing I want you to
give you something called phentermine so back in the 1990's there was this diet pill called
fen-phen was a prescription diet pill aren't so half of it was phentermine the other half was son of course as it always has some derivative of speed methamphetamine on sold and why there's made billions of dollars off of that until people started getting harder Jackson and they had their ass assumed office billions of dollars so that's why most companies very scared of making diet drugs now a days because they're worried about the will some of the courteous rearrangement this is a side business here there's a nice things for it's the same idea but it's mom I think conceptually it's easier to think about making any side from the Sony Classical courteous rearrangement of you start with an acid chloride or some sort of activated yesterday and then you have as an a I I'm floating around you can literally added sodium a side docent chlorides In again this is the common resident structure draw from his I Salemme draw the more useful resident structure some just going to start by drawing up a resident structure for this allows me to see the relationship between this and that but end Brohm only ended up above and I'm not going to draw the whole nitrogen leading group but again you can see the arrangement of a speech here long periods on this minus look under
filet that is donating the intervening orbital beginning this our carbon Vermont so that our common bond is weaker nucleophilic and look at that its anti-terror pleaded to the
leading group you can't get better than that and I just pushes out the leading the slog of sort of shifts over said it's now bonded to the to the nitrogen atoms on and so that's called the courteous rearrangement and it's just like that of the Hoffman degradation Hofmann rearrangement OK so very easy to make on the side or give you 1 more practical example of this reaction of one-step reagent if you like making massive chlorides this that's very common for doing this courteous rearrangement demands just going to put a bar group here doesn't matter what it was the Brady couldn't take this and acid chloride very easily you'd end up with Parliament for some sort of psychic sulfide Esther there which would be very good but believe In this particular case this is and I dedicate these pieces right here just 1 moment here so you can see they're replacing this is Valdes carbon-carbon bonds to that carboxyl with a carbon nitrogen on so there was a lot and I still signing intermediate involved here and the reagent that use for this is diphenyl fast for Lizzie instead of making an acid chloride diphenyl fast for elicited some kind 280 ppm expand
0 phosphate leading group here and in the 80's I'd leading group from this coming back in and displaces the
phosphate leading group so there's an intermediate that's involved in this reaction that looks like this and then the phosphate and iron gets displaced and and again I'm not going to draw the Esther exchange mechanism here on so that's the leading group and then this undergoes that courteous rearrangement and the hydroxy groups cycle on the ice signing on just a very common 1 step way to make ice assignments from carboxyl Acosta it's pleasing no 1 stepped in all regions for the house Palestine make a billion dollars and with concerted rearrangements and but I'm going to users of the board said the agency the lesson here the G I can take a 2nd
row Adam and 1 of these arrangements and replace it with a different second-rower Adam and works pretty much the same and that's true for all of them we want to work for the people
going to start off by drawing on a very big natural product I mean you're not going to have room to drop this whole matter but I'm going to draw a derivative that is so this this in and of itself is not a billion-dollar drug this is called an IOC units it's made by simply treating at the tone on With hydroxyl amino proxies usually crystal and in the old days people used to make melting point derivatives of everything that melting points for we don't do that anymore we have a mark on so this is the boxing that's derived from half a billion dollar pharmaceutical and then you have to draw all the stuff down here below this is
maybe top 3 items it's not really all that interesting at least from the standpoint of of chemical mechanism be what I'm drawing out as a wreath from license cement
about Akemi taken at the old spiritual version of this is callbacks and sold as bait but sold by Bear it's expressed in bacteria and they make this on the kilo timescale they can express this that's why everybody wants to use public key tied biosynthesis because on this is the example that everybody uses to show that once you get the genes for natural product biosynthesis into an organism you can grow up Hewitt on quantities that the cost of growing up feces it's very very sound technology so of course bear sold this isn't about backs and they wanted to protect their market share so what they do they do it every company has attended every single conceivable derivative of the starting material anything you could possibly think of the patented except for this this I'm interested in this year correctly but they didn't have was the rain expanded version of this and is drawing the top India from surrender of source of from here right over they missed something you may think you cover everything that year ingenious enough to everything but they didn't cover this and of course by the thought of that and so what they realize G whenever I have a key town maybe there's some way to insert nitrogen atom they're using migratory displacement reactions and so that's where they do well basically all I did you take the Tetonia make the hydroxyl Amin and then you make the whole tussle derivative that key tone and it does something called the
Beckmann rearrangement and makes this intermediate and again I'm not going to draw the whole on the whole
rigmarole thing Indiana you don't need to see everything that's involved but you can see happened is that somehow or another this carbon atoms used to be right here has now shifted up and formed a bond with nitrogen and see this hydroxyl group over here it's like lies around onto all draw the mechanism old more detailed testimony but this is the intermediate and this is basically an image they reduced that down and methylated in order to make on Zithromax side of others now formulations of this on this race Heathrow so maybe veneer infection or some sort of bacterial infection on Zithromax took over market share come from theirs by accident focus was to draw
out there pushing for this Beckmann rearrangement and look something like this an important
point to remember about the Beckmann rearrangement all dropped the old toss intermediate is isn't its stereo specific when you make a not seen you get the NCI isomers and you don't easily control that unfortunately usually did you get mixtures of using and it'll rapidly interchange and all the only migration that you get is the group and the 2 the 0 tosser leaving group and so what happens is this group is oriented here to displace out that phenomenally good toss locks leaving group and the intermediate could you get looks kind of disturbing it looks kind of like any silly online and from elective Ilic aromatic substitution would call it a nite Trillium it's not that bad you may think that this looks bad to you but at least every single 2nd row Adam has a filled out of electrons so it's no big deal to make this nite trillium and usually when you expose the water water will come in attack the war in order to make enamored group I'm not going to draw the steps in that mechanism on the of analysts said are prime here from which all the steps involved in that attack but in the case of the In the case of a week from mice and when they did this rearrange it was an intramolecular hydroxyl group that attacked initially the Beckmann rearrangement and it's the same kind of idea but you got his orbital rearrangement here that allows a group that immunity to displace leading and these are always aligned with each other this carbon bond is always aligned with the old tussle into bonds that nitrogen oxygen into bonding orbital look at last example all migratory displacement in the
that's not a lasting till the last 1 that I'm going to cover sure there's many
many more examples of things that go with this is a really kind of 2 related reactions I guess I would call the the rearrangement itself create sharing arrangement and here's the idea the idea is that you got some sort of Keatonâ Aqaba neon and when you treaties with peroxides will talk about this more than the later peroxides found to be very very on nucleophilic functional groups more so than a regular alcohol so initially you'll get an ad out and all drawn a very suggestive way here here's my proxy can he asks italics what I would call that led to oxygen is bonded to a carbon called it an acid tell this is any Assadullah because so it can dry suggested leaders you can see this round is completely week oxygen oxygen bond right that a weak bond it's easy to break but if you wanna make explosives while you on the plane next time take some hydrogen peroxide and acetone and that's why you have to check all your liquids now because of this reaction so the town in this particular case again we've got this lone pair that's donating that's weakening that bond makes it easier to the act as a nucleophile so this week nucleophilic bond and his shift right on over it overlaps with the antibody marble and there you lose that Leading Group and oftentimes will run the center slightly acidic conditions where you can probably guess and make it an even better leaving so you can see what
happens is you clean the carbon-carbon bond in essence and you end up with Ernesta
so where used to before have arm of carbon are attached directly to the Kerviel now there's an ester There's an oxygen atom has been inserted in so it's a great way to during expansions and here's something you couldn't have known with respect migratory aptitude is that if you have 2 very similar carbon substituent 1 of them is more substituted it's the more substituted side the reacts in preference so 1 version of a reagent that you can use for this type of Bayer villager reaction as a proxy assets not not a peroxide but a proxy acid is a very common for this reaction so provides an acid and provides all week oxygen oxygen bond and the end product for this bear villager reaction now has an extra Adam inserted and there's 2 different products but the major product involved oxygen being inserted on them were substituted side and this is completely general and the ratio this will give you a sort of a typical ratio on the use of isolated fields 87 per cent and 5 per cent focus a week oxygen oxygen bonds on you can just replace carbon with oxygen there must be a zillion other variations on this and I would
think they then tried to this stuff's been going on for 100 40 years or something like that in another's you propose
that's always a cover for right now all I can remember what we're going to cover only get back we're done talking about in addition to Cigna stalwart also divine nucleophile the coming intramolecular providing neighboring bonds
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