two unified conferencing
[Music]
the free laminated sheets are here huh
are these ready to pass out yeah Wow
just for them and you got just spoiled
what do we go give these out now or wait
we got five minutes so if you start
user can you adjust the camera to those
right
Alex can you see it
yeah just either wise you handles right
okay
[Music]
ok it's 8 a.m. can you guys hear me in
Florida yes ok great well welcome to
heterocycles 2019 a few notes before we
get started 2019 is the new and improved
version so that there's been many
iterations this has been a class for
over a decade now so a few things we
should talk about before we begin first
is the notes why are we still writing on
a chalkboard
it's obviously harder for me it to be
much easier just to read you bedtime
stories from a PowerPoint presentation
the point is that you don't commit much
to memory if you don't write it so
that's the point of putting the steps
down the other point is a more pragmatic
one when you have the exam which is
quite a torturous event the exam will be
open note so anything you write on paper
you can bring with you so if you want to
take duelin mils and write it the entire
book by hand you're welcome to do that
we haven't anybody do that but you can
do it but the point is just to get you
to learn the stuff so this is a sneaky
way to do that for 2019 we introduced
espresso and you know you can have some
if you want but the rules for engagement
for the espresso or essentially class
participation which can actually earn
you quite a bit of points on your your
exam so to encourage participation and
the lack of yawning by the way if the
tea is catchy yawning it's a it's a -
one espresso credit you have to get
yourself back out of that ditch if you
fall in we're going to assign this year
and you might want to pair up with these
folks for future or class and sit next
to them we're going to have for the
people we're taking the class for a
grade even the auditors will be involved
but the people are taking class for a
grade are going to be in teams that
their goal is to be the heterocycle
master of the particular class they've
been assigned to so done min and Steve
you are now team pyridine
put together Alex Saul and Zheng indole
pyrrol Max and Max imidazoles
Jiang and Nick Quinn Ellen Hannah and
Vincent P Rizal Elena and Lucas we've
got the diazien's so the peretta seems
purines and pyrimidines are going to be
Tucker and Jess and then we've got the
benzo emulated Puran and thiophene
that's going to be Shuang Sarah and Gigi
and we've got oxes ole and thiazole it's
going to be Zoe and Zeki and we've got
ISIL ox is all and iswith is all it's
gonna be Tejo and Han Tyrone's and /
ilium that's going to be Xiao Cohn
now the auditors people are taking this
class for just auditing they're gonna be
the number of police so we've got Tanner
who's going to be in charge of our PKA
values thank you and we've got the
aromaticity police that's gonna be
Khalid and Nicolas
so you two are gonna be in charge of
ever knowing everything about
aromaticity okay great so class turned
oh no nevermind No
so first thing we're going to talk about
the next so next three lectures are all
gonna be about basic reactivity and you
know the goal of the class is really to
get you ready for drug discovery or
maybe you're going to go into a grow
world but we have a lot of stakeholders
that we need to make happy in this class
because some of you are going to go on
to medicinal chemistry we want to keep
you happy
some of you are going to go into process
chemistry we want to keep you happy
some of you may become radio chemists
different logic there and some of you
may say to hell with it I'm going to do
patent law and we're actually going to
have parts in the class that address
that as well to make you happy
we've also got some local heroes from
drug discovery so if you're from a
company can you raise your hand
fantastic what company you from sir Oh
Lilly Wow
what's your name Ren okay and Patrick
right composer so you guys are going to
be in charge of filling those boards
every morning now I know the industry
folks are like wait a minute what we do
is secret we can't we can't do that but
most of the consulting problems you guys
have are actually very generic ones so
whatever you can bring every class and
put it on there doesn't matter what it
is I'll turn it into something which is
appropriate for the lesson it doesn't
matter what my Suzuki Cup Lee doesn't
work I don't care just put it up there
so yeah the goal is one day you'd go on
to the noble mission of doing what
they're doing you know they say you know
those who you can either those who can
do do those who can't teach so that's I
can't do anything but those folks are
the ones who tell you that what we're
actually learning here are our valuable
ideas and people I talked to have gone
on to companies have said this is
probably the most valuable class they've
taken alright so there's four main
classes of heterocycles you've got a
benzene ring which is very boring and
then you add nitrogen and all the fun
starts happening okay so you can take a
benzene ring excise a CH bond and throw
in its place a nitrogen and what happens
from that is you get these pi deficient
heterocycles and the PI deficient
heterocycles come in two flavors you've
got the ones that are just with one
header item and then you've got the ones
that you start twinkling in Moorhead or
atoms two three sometimes even four five
and six we're not going to cover for
obvious reasons unless you go into the
military and start doing energetics okay
now if you take benzene ring and you
take out a CC bond and throw in its
place in hydrogen now you get what's
called pi excessive heterocycles and
these are generally upset with life they
they're often just angry and I'll get
into that in a minute I like to apply
these anthropomorphic characteristics to
heterocycles because it's just a
pragmatic way of remembering how they
react so you can add one header out
and just pyrole or if you're a North
Iovine or you can add multiple we will
cover the a zoals there's teams here
that are now in charge of learning
everything about a zoals and we're also
going to cover
triazoles and yes you will even cover
tet results these are PI excessive the
two types there or one header atom and
then when you start adding more there's
another type so aromaticity is a useful
way to predict everything so if you
understand relative and I don't mean you
need to memorize what is on it would be
helpful to commit to memory the general
features of what is outlined on your
laminated sheet which you can bring to
your exams by the way but if you go to
the book which I think everybody's got
the grad office is kindly agreed to pay
the exorbitant ten dollars to fund all
of the folks access to the book and
within that you've seen the laminated
sheet you've got these heterocyclic
aromatic city values which I have to say
or our cause for come some consternation
and debate and literature
the general trend holds but there are
exceptions for these so the general
trends are pretty intuitive ok and if
you understand aromaticity in a general
sense the idea is that you will be able
to predict reactivity on heteroaromatic
systems that you've never seen before
that's the whole point of the class so
reactivity of course tautomerism what is
tautomerism anybody know what that is
any clue max any clue what that is
that's it so two structures they only
differ by proton position that's it it's
kind of important to know that for
reasons we will get through you'll see
it almost every class the reactivity of
substituents so not all methyl groups
are the same a methyl group on a PI role
big difference and a methyl group on a
pyridine and it's all about knowing the
aromaticity
and then even retrosynthesis what do you
mean by that well now that we have teams
it means we can have heterocyclic UFC
cage matches in this class
what do I mean by that have I lost my
mind well if you look for example at the
book here you see there's this chapter
on five six used header Aryans and the
question becomes we're gonna talk about
the salaat how do you know when you have
a system like this most of you probably
never seen before how do you know which
one to disconnect first do we go this
way or that way well when you guys fight
it out for all it out you're gonna need
to know aromaticity to know which one do
I make first or second okay so not all
nitrogen's are created equal
that's a really important thing to
remember and we're not going to get into
orbitals and homo-lumo coefficients
because that is it's not really needed
and drug discovery that you don't you
can look that up what you really need to
know is the intuitive the hound dog
sense of reactivity and what you need to
know here is that there's two types of
nitrogen's really easy to remember
you've got pyro nitrogen's and you've
got purity nitrogen here they are so
pyrole would love to give away electrons
it's pi excessive and that's why if you
have a PI role it often will just react
with air it will react with protons it
will polymerize we'll see that tomorrow
pyridines however are relatively stable
they're not as aromatic as benzene
obviously but they're closer pyridine is
what I call the schizophrenic
heterocycle because embedded within
there's a lot of things so purity when I
look at P R and I think okay there's
nitro benzene in there so I view this as
a sort of version of this so in my mind
when I see purity and I see that I also
see this and amine what else do I see I
see this
all three of those things together
amalgamate in my head when I see purity
and like nitrogen triethylamine what
does triethylamine do likes to tack
things makes a duck's really well that's
the general base what's it mean well it
likes to take Electrify you can add
things to an immune and nitrobenzene
generally just electron deficient so it
doesn't do friedel-crafts very well all
of those things are inside of a purity
now what happens we somebody and I won't
call them out ask this great question of
this dichotomy that exists so if I add
start adding nitrogen more nitrogens to
pyridine if you look at the aromaticity
values on your laminated sheep if I
start taking purity and adding more
nitrogens to it it becomes less aromatic
that's okay
but if I take pyrole and I add a
nitrogen to that now it becomes more
aromatic and that seems to be like a
paradox right that doesn't make any
sense
but all nitrogens are not quick created
equal and all ring systems are not the
same either there's a big difference
between taking a pi excessive
heterocycle and adding a nitrogen to it
then taking a PI deficient heterocycle
and even more nitrogen to it so as you
can imagine try nitrobenzene not as
stable as nitro benzene and if I take a
nitrogen and added the pyridine twice I
get triazine which it actually is if you
start adding some fishermans triazines
our energetic molecules
some of them like nitro triazines you
know you can use that in propellants as
closer to whatever so why is that well
the reason is clear if you take a PI
excessive heterocycle that has a
different this is a different from an
orbital perspective is a different type
of nitrogen than that type of nitrogen
if you take one it's already not very
happy I told you it's angry now if we
add to this one nitrogen this is a
pyridine like nitrogen and this is a
pyro like nitrogen and the pyridine like
nitrogen stabilizes the pi excessive
character
of a pyro it's that simple whereas if
you take a six-member ring and you start
adding more header atoms it becomes less
and less aromatic so our rotisserie
cannot be viewed as simply the additive
effect of many nitrogen's on the same
ring it's context dependent that's the
key to remember aromaticity and nitrogen
is context dependent and so if you've
got an unhappy heterocycle and you start
adding nitrogen to it it may become more
happy and if you've got one that's kind
of reasonably chilled with its life like
a purity and you start adding nitrogen
to it you're disrupting it a little bit
so it becomes less and less aromatic now
this question also comes up these three
folks which one is the most aromatic in
the literature has got answers for both
but I think that the easy way that I
like to remember it is by thinking about
what they call topological charge
stabilization which is you know probably
you don't need to remember that but if
you want to understand why literature
suggests that perimeter is more aromatic
than pyridine which is more romantic
than for it Azim one way to think about
it is exchange of carbon for a hetero
atom so on pyridine folks which is the
most electron rich carbon let's label
them 1 2 3 and let's go to teen pyridine
ok Dongmin and see which is the most
electron rich hetero atom on pyridine -
if i take nitrogen and put it in place
charge topological stabilization tells
me that this one should be the happiest
because i did that okay team purity and
what is the next most electron rich
and only one left three so that means
this one could be the next most and then
the least aromatic of these should be
the pretty but if you look at your
header of aromatic beta values they're
almost the same if you can look in
literature you'll find it's kind of on
the edge it's you know it's questionable
which one is the most but that's the
general rule in terms of reactivity that
actually helps me understand predict a
lot of reactivity if you just remember
that little rule actually helps it's
really important to remember this we
will get over we will do this over and
over and over again we will be talking
about the different types of nitrogen's
in molecule so you really need to commit
this to memory and try to understand it
really well and to aid us in our
understanding we're going to go through
how our verticity changes a variety of
different things for example let's talk
about the tendency to give addition
rather than substitution which increases
if aromaticity decreases this is
intuitive I think so let's take a look
at problem of the day number one the
problem of the native for one hopefully
someone will solve for us we will pass
the iPad to someone and maybe to start
us off team pyridine do you guys need
coffee okay so David or zero will will
pass out the the iPad to you can just
use your finger to solve it and we'll
all be able to watch in real time as you
struggle bromine and Oh Liam what is Oh
Liam it's really strong h2so4 it's got
fuming so3 it's a disaster it will like
you know it's like battery acid okay
really strong stuff so in your mechanism
you can use protonation or you can use
an addict with so3 either is fine by me
okay
you're just gonna use a proton okay
maybe we should bring a stylus next time
now while they're doing that it would be
nice if the maxes could be thinking
about the alternative case with with
bromine and and maybe also we might use
team in dal Zheng Saul and Alex and
think about the what it would happen
with the same type of conditions with
that alright so what have they done here
they've added B or two okay so that's
oh you're just in for the bro
all right so thanks team eridium so how
about Saul and team and all where first
would you use those conditions for
bromination why not you don't like
battery acid
yeah in fact you don't even need you can
use NBS but here's the funny thing you
can actually use a pyridine based
pyridine tribromide is a roma tinning
agent you know kind of comparable
reactivity to NBS and it can be used to
Roman 8 so it's funny you need to use
these strange conditions to really harsh
conditions to Roman a purity but we can
use a pyridine based halogen any agent
to halogen a indole or viral stall where
does it go with the in dull where's team
pyrrol the maxes where does it go there
and what kind of do I need what would
happen with these heterocycles if I were
to dissolve them in battery acid they
would bloom rise and we'll talk about
the mechanism of that tomorrow because
they are PI excessive and you've exposed
to a situation were highly oxidizing
environment so you don't need that just
need neutral really mild conditions are
fine why does it go C to with PI role
and c3 with an indole
which one are you talking about is kind
of like a vanilla kiss Amin Amin right I
mean you know so I think the waiter you
can commit this to memory but you can
convince yourself of this when you draw
the resonance structures that arrive
from either capturing an e at c2 or
capturing an electrophile at c3 draw
those and you'll find there's more
resonance structures that stabilize C to
capture and in the case of C 3 you have
to disrupt aromaticity 4 indole so it
prefers C 3 to just keep that everything
cool with the benzene ring we don't want
to disturb that if we can avoid it
questions please don't do friedel-crafts
with Puritans we see this every year in
the midterm okay you can do a
friedel-crafts with the purity but you
gotta have a donating group on it like
an amine it's okay some methoxy ones
will do it that's fine but we see a lot
of people taking for instance nitro
pyridine and treating it with NBS and
somehow bromine goes on there you're not
going to get the job folks if you do
that three interview over they just
close the door you go home early don't
do it on the test okay cyclic transition
States reaction so basically just think
a pair of cyclic reactions this one's
easy to remember the rate of those
increases as aromaticity decreases this
is rather intuitive like look if i take
a mixture of all three of these things
and dimethyl acetylene die carboxylate
which one's going to react sorry you
said that
let's see here where you want Oh so-so
max here you're you're on the pyrole
team but you're actually giving an
assist to the different people looks
like the phiren people don't even have a
team
I guess it's a oh yeah they do Shuang
Sarah and ze
so you can think max for that assists
there so if your ends just gonna form
rather quickly and edit in fact if I
continue heating this mixture guess
what's gonna happen the product is just
gonna be this did you expect that max
you didn't expect that all right good I
mean didn't waste your time today how
did that happen
that was the intermediate right max now
when that does the four plus two I can
do a retro 4 plus two because guess what
another lesson here guys header aromatic
systems love more than anything in their
life to be aromatic so if there is a
pathway to restore aromaticity the
driving force is usually pretty low to
do that so this will just you a rebel 4
plus 2 and you'll drive this off with
equilibrium so it'll sometimes do retro
for us to give you back that will
sometimes give retro 4 plus 2 to expunge
acetylene which can be driven off
because gaseous so eventually over time
we're just gonna exchange this
substituents here for this one because
heterocycles love to be aromatic and
you've got the benefit of the gas being
released now pyro will do the same thing
but usually you have to block it so
usually people put at özil or a Bock and
you can get a diels-alder add up to in
doll is just gonna sit there and watch
pyridine maybe if the temperatures high
enough you might get a pyridinium add up
that nitrogen that that that's known but
that's reversible
and that correlates with aromaticity big
important one now is tautomeric
structure as max said the movement of
protons from one place to another you
really need to know this because it also
affects the site of alkylation so Renan
Patrick how often do you have regio
chemical mixtures when you take in
dissolves puresoles and perez loans and
whatever and treat them with base and
alkylating agent or do mitsunobu is this
a problem that occupies your time
sometimes or any of your colleagues
Patrick says yes all right we have one
one taker so at least at Pfizer there's
a problem and actually a very big
problem I get this problem all the time
for people and so understanding
tautomerism is important because it will
also understand help you understand the
real chemistry of alkylation and how to
control it let's first talk about the
general issue so here we've got a
prototypical two hetero atom substituted
purity and you can have here the
corresponding oxygen nitrogen carbon and
so the way I like to think about this in
the case of pure down let's say which is
the dominant tautomeric form in solution
first let's look at the possible
tautomers that exists all of these
structures are just related by the
movement of a proton
you guys give me some thoughts on this
what do you say there thing tell me this
which one of these compounds is not
aromatic awesome not aromatic so we can
just get rid of that don't even think
about that one for now it's definitely
not going to be a dominant one any other
thoughts you're favoring this structure
here yeah definitely a pure tone that's
what it looks like
it definitely prefers to be this form
rather than this form but is this one
aromatic still is
I have p-orbitals all over the place
this one is the one is you correctly
called out not aromatic because I get an
sp3 lurk in there
can't get in conjugation so how to lock
that one this one's also aromatic and so
what drives the solution I mean there's
a few reasons why this one is in the
pyridine form oxygen is very
electronegative and in solution also
exists as the hydrogen bound hydrogen
bond dimer taste with their
stabilization forces that are
intermolecular as well what about the
case of this one
two amino pyridine you take it for
granted the folks in industry know the
answer to this would mean this is very
rarely do people draw this in one form
and not the other we all take it for
granted that to meto pyridine looks like
that and not like that right now the
reason for this also stems from your
inherent knowledge from undergrad days
on the pKa of phenol verses annalen in
the electronegativity of the two atoms
so amino pyridines
they like to be in the dominant dominant
Tana Marik form of the amino pyridine
whereas the two hydroxy pyridines
favored the pyridine form now what about
the case of carbon do you think two
mental pyridine likes to be like that
people are laughing hysterically right
if you're watching the video you can't
hear the hysterical laughter but it
actually exists it's a very rambunctious
crowd we have here at 8:00 in the
morning so yeah two methyl purity and
exists like that but what is the effect
of that methyl group does it make it
more acidic less acidic goong-min
teen pyridine more acidic yeah well
let's go all the way back here like
several hours ago we were talking about
pyridine and I said when I see a purity
and I think of amine and a triethylamine
and nitro benzene well if it's an amine
that means this should be like a methyl
ketone that's what I when I see that I
just see methyl ketone so I can use the
LDA ad protonate no problem
can I use Lda to deprotonate that and in
a much stronger base like almost like
deprotonating Halloween okay great so to
do a little review of aromaticity
why don't we quickly look at probability
number two which hopefully will
illuminate on the screen momentarily
problem of the day number two we need a
couple of volunteers there maybe we can
look at the structures of those
compounds and find who the volunteers
are going to be let's see for the first
one we need help maybe from the bins an
you lated folks so we've got some
Quinlan people here how about let's see
how about Hana and maybe some assistance
from Sara there we go so let's just talk
about a problem that a number one the
top top row here organized the following
molecules in terms of decreasing
aromatic characters so we first need to
identify which is going to be the least
aromatic of these well the analogy I
would reach for is to go to your
laminated sheet and go to the her
aromatic the the aromaticity values and
think about pretend the aromatic because
everything is equal like we just got to
Benz benzene rings fused into all these
things so the trend should be the same
as if I just thought about urine dial
theme chiral and benzene
most that's our that's our starting
point that's our boring benzine yeah
that sounds pretty good
so what hennas saying is that the least
aromatic of see then
[Music]
oh you're joining out okay yeah most
aromatic next most oh I opine versus
pyrole are we happy with that
designation
yeah a few people saying no Maxie what
what what were you what are you saying
they're big Richard shaking his head
glasses almost fell Oh what happened
[Laughter]
saying what do you say okay so if you're
in is least that looks pretty good
ta is are we good alright great okay
fine how about the next one we need do
we have a team file theme let's see
where are these people oh yeah
so how about Shuang or Gigi this is an
interesting one the effect of annulation
and where the annulation takes place so
which one do you think is the most
aromatic where is uh where where is
Shuang and Gigi where are they oh there
they are
okay great so you know feel free to
opine on this topic most aromatic
what do you say there Gigi you just give
me general thoughts by the way in
heterocycles all forms of participation
are encouraged if you like to get up and
do a dance you can do that if you'd like
to raise your hand and you know say
disparaging things about my outfit
encourage anything that keeps people
awake and excited it's encouraged and
you'll get credit for it
but Gigi anything to talk about on this
one just tell us what general feelings
you think seems to be least aromatic
okay that's a good call so you got this
one that's the most important thing to
get is that that I so benzo thiophene is
the worst but after that these other
aromatic rings are kind of bringing
normalcy to the picture
they're bringing civility to the
heterocycle so this one is very aromatic
this one left so and this one least of
those three and then worst so most
aromatic here then more aromatic
then then aromatic and then this one's
pretty pretty disappointed with life you
don't agree so oh you did good that's
boy I'd be in some trouble so the
question I often get let me ask the
folks from industry how often would
someone in your company recommend the
synthesis let's say this compound
oops I so indole have you guys who
nobody what why not why you don't like
that it looks unhappy you know that's
enough
you know you know who recommends this
the computational folks sorry so why is
it you know the same rule remember we
use a little rule over here uncharged
topological stabilization we can talk
about the way I like to explain it is
you've disrupted the aromatic character
here you've just disrupted it in as
Patrick says it makes it unhappy that's
perfectly fine but if you're not
satisfied with that explanation here's
another one and it all comes down to
thinking about the parent so the parent
of indole is in Dane and if we want to
make it totally accurate we need to
think about the in Dane anion so if you
do the computation the in Dane anion is
going to be happier here than here and
that's why in doll is more stable than I
so in doll that's your sort of high
level explanation for something which is
intuitive to all of you you all knew it
that was the first thing he said was I
don't like that one so there's the
reason so mid chemist how do you take
the ISO Windell and make it turns it's
like if the computational guy says or
gal says make that what do you what do
you what do you put in its place
and this all sounds good to me happy
happy compound why is it happy right
over here we talked about it
remember over here pyrole becomes happy
with becoming a midazolam
same thing you can take ISO in dal and
turn into a pretty happy creature lot of
FDA approved drugs with indosoul in them
Oh in dissolves happy how about two
hydroxy Furion now we have a PI
excessive heterocycle it's not happy
with life and we've added a hydroxy to
it so which of these tautomeric forms is
going to be the most aromatic and again
it's on to Sarah Shuang and Gigi you
know we're gonna call on you a lot today
but honestly we don't do a lot of pure
in and dial things in this class because
drug discovery people just don't like
them so much so this will be the only
class we're really picking on you this
much which one do you think they're Gigi
which of these aromatic versus aromatic
these two are not and so if you had to
vote which is going to be the dominant
dominant tautomeric form in solution
wrong
the third one why okay and I said wrong
to the first one so yeah it's definitely
good deductive logic there and indeed
that is the case because this is so pi
excessive that it's just um it's fraught
with unhappiness in its life do not
propose you can use two hydroxy to your
hands as intermediates in a reaction but
you do not want to use them you wouldn't
propose a stable one just like pi rolls
are unless they have electron
withdrawing groups if it's fine right
look at lipitor it's fine you put
electron withdrawing groups it's fine
but Patrick at Pfizer are they going to
let you put PI roles in the modern era
in your structure big no-no is Lily have
the same rule they don't like them even
you can say lipitor all day and they
still don't like them same thing you
can't put your hands you don't put you
don't usually don't put thiophenes bends
without means sometimes but it's rare
and often the thiophene and the bends
without pain in the case of plavix we'll
talk about one day it's a pro drug so as
soon as you add dial bends without beam
to the body it just gets popped open
right away
and so not very happy not aromatic but
this one at least is conjugated so if
that one is okay and that's a dog
dominant tautomeric form now let's take
the lesson we just learned here to talk
about the problem of the day number
three so problem the day number three it
says as a medicinal chemist in 2019
what would you view is a potential
metabolic liability of Vioxx so you can
pass the iPad to someone who is going to
be any volunteers nobody needs coffee
you guys are just wide awake this
morning huh wired you know we used to
have a coffee cart out here that's why
we brought it in here because the coffee
carts Dom this is just to be nice to you
folks I'm paying for it you want coffee
take some anybody all right who needs
the iPad
everybody looks down
mm max to the rescue oh we have okay
fantastic
all right they're clamoring for it
Tucker what do you say there Tucker are
you drawing out there oh yeah oh you're
just saying oxidation okay why he says
the answer is oxidation here why are you
in which group are you in shendi okay I
thought we used to see h-bar I'm
probably on all your committees okay I
mean give me a break there guys I don't
have any hair laughs barely of memory
cells teachers class okay so Tucker
you're saying oxidation and you're
saying how does that happen
teach us oh you think SIPP is going out
there for the action ah do you need sip
for this one I need you to think more
deeply there Tucker sip you know sip is
when you is when biology brings out the
big guns
you think she needs the big guns for
this one perhaps not what tell me what
other tautomeric form of this might
exist
aha maybe there's a bleeding amount of
this stuff and then you said Oh too
and then that compound can either
disproportionate and give you the
hydroxy product or the ketone or maleic
anhydride so in 2005 DJ Khoury published
at it let paper where he took a biopsy
treated it with potassium tert-butoxide
and then Oh - and got these products and
in a sort of two page Tet let said oh
you folks at Merck might want to
consider that the reason your drug
failed or was pulled from the clinic was
because of this now that's if you talk
to the inventor by ox there they debate
about that they not so happy with that
but that that made Seanie news it might
be the only tablet in history that made
it to see any news just one experiment
um I'm I would recommend not doing it
just because usually fluorines directly
connected usually directly connected to
non phenolic actions like to kick off HF
sometimes but we'll leave it up to Renan
Patrick would you put fluorines there
for the same reason okay and so I
remember you
none of you were all I guess in grade
school or something but when vias was
pulled off the market that was like a
big deal it pretty much like if you look
at for one watershed event in the
industry that made everything miserable
for everybody it was Vioxx being removed
for you know toxicity what they thought
was toxicity reasons the reason was
people were giving doses that were way
too high they were doing indications
that weren't necessary it's still a
really good drug
I had colleagues back then that would go
to TJ to get the Vioxx because it was a
really good pain reliever they had
arthritis whatever and they weren't
selling anymore and celebrex Patrick's
compound
you know you need doses that are ten or
a hundred times more this is like five
MiG's was enough and celebrex is you
know we'll talk about celebrex that's
like 300 500 Meg's sometimes a gram a
day so debatable why that's toxic but
one sort of explanation for it that has
been proposed is that and I think these
days probably because of that experience
a 20-19 medicinal chemist would be
unlikely to make a furor known as a lead
candidate but correct me if I'm wrong
Renan Patrick
pretty pretty accurate okay good let's
take a look at this dichotomous behavior
of a hydroxy asel for instance we've got
this hydroxy ice oxes oh and it exists
in possibly three different forms any
suggestions here from anyone how about
Colleen which of these is not aromatic
you think not not aromatic or aromatic
well it's a good thought experiment to
run through but we've got PI electron
here here here here here okay so we're
good on this one how about this one you
say with some separation but if we have
an sp3 Center there and you're right
it's all over how about this one
aromatic because we got PI everywhere
now which one of these do you think is
sort of the dominant tautomeric form
third one sounds good I'm not going to
ask you to articulate exactly why
because it is a slippery situation it is
the daughter Mara dominant tautomeric
form but both are accessible when it
comes to doing a reaction so for example
if I want to make these two Isetta lated
one is it benzoyl Aidid one is a
satellited from the same starting
material let's just call it a what
conditions what I use for each of these
to access this one versus a top one
yeah this MEC said it's all about the
bass no treble
that would have been 22 years ago okay
so you use bass or you don't
so for the top one we're gonna need bass
and that will give us that for the
bottom one we're just gonna cook this
fella up and acetic anhydride and wait
we will do this again and again the
folks from Lillian pies are probably
wondering how do you get regions like
the attack on it MIT is all here is all
in dissolve random zoals and usually it
comes down to this type of paradigm you
do another neutral or weakly acidic or
you do it under strongly basic and you
can get different types of selectivity
well look into it well before the class
ends we'll go into another sneaky way to
control region selectivity known as the
SEM trip we'll get that into that in
just a minute
how about hydroxy Perez loans it's the
same type of rule govern this one as
well Jess what do you think
which one do you think is the dominant
one yeah yeah one is good and this one
here what is the product when we treat
this with methyl iodide and heat no base
just in methanol what do you say there
Hanna
yeah what's the significance of this
well I guess you should know since we're
going to talk a lot about medicines in
this class but that is the first first
drug this was this is called anti pyrene
and it was discovered by Sandoz in 1884
by Ludwig noir of the empanada mmus noir
cyclisation it's marketed by Sandoz and
it you know it basically just took
fevers and it made them go down No so we
could so anti pyrene your kid had a
fever you take this and the fever went
down a little bit any ideas on how we
make this starting material we haven't
talked about ring synthesis yet but this
one is so trivial looking
so met will see to acetate and phenyl
hydrazine and you get out that starting
material now you might be wondering hey
why do we get that regioselectivity the
hydrazine musician we're gonna talk
about that I mean if I tell you
everything in lecture 1 you don't need
to come back to the other 23 lectures it
has to be reason to get you back okay
that's five murmuring tautomerism how
about six-member in qatar ISM what do
you say there Chang on this top one here
which one do you think is going to be
the most happy in solution Hey well
let's first ask you Chiang which one is
aromatic good now which one do you think
is just sort of which one's better
looking yeah he looks good
anybody prefer be salt prefers be
because he likes to be opposite of
everybody or maybe he has a reason there
is that and there's also a huge driving
force of hydrogen bonding in solution
but definitely that that is you know the
the explanation you gave on the NN
bonding sacrifice for the NC bond is
true but also you get a huge
stabilization from hydrogen bonding for
the same reason that pyridine is so
happy so hydrogen bonding can screw you
up and give you a different prediction
than you would have thought how about
this other one same
you you still think uh what did you say
yeah sure I'm I'm always asking your
chain
both aromatic you think a right anybody
I mean you'd have to be insane to think
be anybody think be being solid the
again of course for the same reasons all
brought up about the nn bond and CC bond
yeah B is actually a dog dominant
tautomeric form but I would argue that
the hydrogen bonding component is even
more energetically responsible for this
phenomenon so tautomerism can be quite
sometimes unpredictable unless you
remember this hydrogen bonding
phenomenon so really important when the
computational chemists brings you
structures like this and they say oh I
like this structure because it's got
this nice hydrogen bond acceptor here
and you can go in and say wait a minute
pal it might actually be a donor
so can you recalculate that okay how
about these keto type substrates so in
the case of pyridines
and p resines where X is equal to n you
actually favor that because of this nice
hydrogen bond
so the enol form is favored how do you
like them apples and when this has been
zaniel ated such as Quinlan's and qin ox
lanes
it's favored
and that gets us to the sort of reason
that we're all here today anybody here
in Floyd's group except half of David's
body is employed but he's a TA so he
doesn't count
so yeah the the cause of genetic
mutation is when the normal pairing ATGC
so in this case you've got a T there is
adenine which is a purine we're gonna
have a whole lecture on purines there
are a lot of fun and this one is a
perimeter or perimeter known found in
thymine cytosine sometimes comes out for
Halloween
looking like thymine so sometimes
cytosine will look like this
and that's a bad day for your coding
mechanisms
that's why mutation happens one of the
reasons and when mutations happen humans
formed from amoebas it's all about
tautomerism so nature took heterocycles
now a useful use of tautomerism can
sometimes be in new reactions that come
up that take advantage of these types of
pure down and hydroxy purity and
phenomenon now the normal way of taking
this isoh quinolone and converting it to
the corresponding nucleophile replaced
analog is doing what what would be the
normal way of doing this pocl3 HANA
which is this kind of like med chem
table salt they use it all the time
right
yep yes the both of our industry folks
are shaking their head indeed pocl3 is
really really needed but PI Bravo what's
the structure of Pi drop I mean in case
you forgot what the structure of Pi
braaap is there's a very useful part of
the book that actually has listed out
all of the peptide coupling reagents
that are known so we can go to amide
bond formation and skip over to this
very useful section that's got all the
crazy peptide coupling reagents out
there and mechanisms for it as well
so there's pie drop so if you take pie
braaap and you treat it with the
crinoline or I so quinolone the
tautomeric form that is the hydroxy
version will engage the pie prop and you
get an Opie o P n R 3 + intermediate and
that intermediate is a great leaving
group that can be mildly attacked with
the nucleophile you can use those PI
prop addicts and more than just Smar
reactions you can also do some goodies
with them I don't know if you guys know
about that but it's a useful way of in
one pot you take your ISO quinolone or
related heterocycle that has a potential
to have a small amount of the hydroxy
tautomer in solution activate it with
the veronik acid and palladium and you
get a Suzuki product without doing pocl3
purifying the chloride and then
subjecting it to a second Suzuki
reaction ok questions alright great so d
the facility of unimolecular reactions
increases as aromaticity decreases so in
other words problem of the day number
four
looks like Max has volunteered for
problem they didn't report front row max
I think you can scroll down roll with
two fingers
it's getting fancy with the colored
chalks double espresso for him perfect
you know great great job that's perfect
you know this type of thing would never
happen with a more aromatic heterocycle
for example I've shown the board there
the synthesis of Dewar pyridine so if
you take pyridine very low temperature
and you shine UV light on it you will
get Dewar pyridine the half-life of
Dewar pyridine is like two minutes so
it's been proven you can make it but
that's it's like dew or benzene right
whereas these types of hetero cycles are
sort of you know they're they're not
they're not really very aromatic I mean
they're aromatic but hmm they could do
without it and so these types of
rearrangements can happen and we'll see
these throughout the class any questions
Florida any questions we all good over
there okay
let's talk about the general reactivity
of heterocycles with regards to their
electrophilic attack at nitrogen so as I
remember if the people over there
probably can't see anything there's no
way to make this screen here show up on
that there is okay that's probably
needed so there's really four types of
nitrogen's this is really important to
commit to memory and it's got to be part
of your instinct the way you think about
had a recycler chemistry you've got the
pyrole anion you've got sort of tyrol
that's alkylated you've got a pyridine
nitrogen and then you've got charged
pyridine alkylated that's it those are
the four types you can mix and match
these and put them in an infinite array
of different hetero cycles and their
features are additive as we'll see in
just a moment so pyridine as we all know
forms tons of addicts pyridine can be
oxidized with a pur acid to make
pyridine an oxide
very rarely do purity in oxides appear
in drugs it's pretty rare most people
most modern medicinal chemists will not
put them in a drug or even propose them
but they are SuperDuper useful
intermediates we will see them more
there's a whole chapter in the book on
what you can do on what you can do with
pyridine and oxides they're actually
really useful purity and a cilium
intermediates we use them all the time
any time you slayed something with DMAP
that's the mechanism pyridine lewis acid
complexes that i mean that's all the
time although worthy all the angle
people right I mean that's how ligands
work right yeah a lot of ligand design
is based on that and then you've got
these strange what they call zinc a
salts with the die nitro a die night
traumatic attack there and we'll talk
about what these inkay's salts do but
there are great inroads towards putting
other things at nitrogen that can't
easily be put by simple alkylation
alright let's talk about the curious
case of a Minnesota
so in MIT is all is a pure 18 and it's a
PI role both so when we add an
electrophile on to emit as ol what what
happens if you're an electrophile and
you see a mid is all what are you going
to do
but you're going too quick you don't
just go to c5 okay you're gonna go into
nitrogen so if if I put an electrophile
on just a PI role it's not going to
react at nitrogen but if I put
electrophile on pyridine it's gonna
react the nitrogen so amid is all has
got both creatures here and the only one
the electrophile sees is that which can
then rearrange to give either depending
on the scenario but most often that now
the tricky thing is understanding how to
control read your selectivity in the
system this is something that that
people in med chem struggle with all the
time so one one let's imagine that you
want to take in emitters all and we want
to alkylate
there
can I just take fennel am it is all and
sodium hydride and then the alkyl iodide
and be assured I'm gonna get one rejoice
Murr no so one thing to remember is that
some atoms hetero atoms have a great
effect because of electronics to direct
the site of alkylation so in the case of
chloro MIT is all you almost always get
exclusive or the dominant product being
alkylation away from the chlorine and
then you could do your suzuki coupling
to put the fennel there that's one
workaround there's others for example
this sneaky sem trick that can be used
in a variety of different contexts one
of them is a midazolam because let's
look at the CH bonds this is a great
preview for tomorrow and and Wednesday's
lecture these two CH bonds in indeed
even you know of course this one all
three of these are quite different but
let's talk about these two in particular
whether this one is near a PI role or
near pyridine changes completely how
these two things react so when we put a
sim group on a midazolam and we do some
sort of lit the asian or zinc asian or
something and cross coupling we can get
this add up because a PI role like CH is
going to be more acidic than the
pyridine one we'll talk about that I
think Wednesday but then let's imagine
we want to open up the reactivity here
when you treat this compound with
catalytic amount of some chloride it
does a magical dance and the product of
this is
that and what once was a Puritan like CH
is now a pyro one look at that any idea
how that happened and why you only need
catalytic amount you regenerate say so
you must be regenerated employed what
happens first tucker is looking like he
wants answer this one
and we're good to go
that's thermodynamic product of course
it can go again you can keep equilibrate
but the thermodynamic product is that
one so it just state eventually just
funnels all to that now we are pretty
religious about staying on time in this
class sometimes we go over it's rare and
sometimes we go under and when we go
under we put those minutes in the bank
we have a few minutes left and so there
is enough time to talk about problem of
the day number five probably name or
five is great because it's a great
prequel for tomorrow's lecture we have a
thiazole this is called the Don Dhoni
aldehyde synthesis in the modern era not
a very useful way of making aldehydes
but from the point of view teaching
heterocycles it's a very nice
instructive mechanism so problem of the
day number five do we have a thiazole
team I thought we had a thiazole team oh
yes Zoey and deke where are they Zoey oh
there is Zoey and we have Zeki where
Zeki
and you want anyone tries Oh II know all
right we have let's see we have takers
here who we not
how about Vincent what do you say there
Vincent
all right great I'm gonna help you
so we're just going to take it
elementary steps there Vincent
what are you putting what he's doing
good he's attacking okay great
great don't forget the TMS yeah
well friends
all right now what do we do you're
attacking go one over we don't want to
take the carbon that's going to be a
problem for Baldwin and geometrically is
an issue to attack TMS that's you got it
great perfect
now that's a very happy anti it's a
great preview for tomorrow's lecture
because we learn all about that at least
this week we're gonna learn all about
that
what makes anions happier than others
that one is a particularly happy one now
what do we do with that we need to
eventually make a carbon-carbon bond and
that's not a carbon-carbon bond yet
well you know I'm gonna give you a clue
you're in a soup follow up aldehyde
let's just do another one yeah
how do we go from there to the product
Vincent
we got it brilliant
now this is the Don Dhoni aldehyde
synthesis but I don't see any aldehydes
maybe I didn't squint enough nope
there's no aldehyde there so how do I
turn that into an aldehyde tea bath well
when we say Don Dhoni aldehyde synthesis
what we really mean is that this is
going to become an aldehyde because I've
added one carbon so tea bath is just
gonna remove our TMS proof and
everything's just going to be sitting
there now let's talk about oxidation
state this oxidation state is it at the
oxidation state of an aldehyde or an
acid or an alcohol it's at the acid
oxidation state so I have to take that
thiazole and somehow turn it into the
oxidation state of an aldehyde before i
disembowel it and turn it into an
aldehyde so the first step of taking a
thiazole and dismembering it to a
aldehyde is treating it with methyl
iodide when I treat this with methyl
iodide words are gonna go nitrogen so
first thing that's gonna happen is we're
gonna get this charge intermediate next
thing I'm gonna do is treat this with
borohydride what's gonna happen with
borohydride reduce we're reduce the
amine here you can have a copy to kim
and you know that's gonna give us now
aldehyde oxidation state all i have to
do now is get rid of this thing so back
then they used mercury acetate you can
use p feh
it's ugly right I mean you know you
don't want to do that today but this is
the done donee all died it actually
there's a Merck paper or many years ago
they used it on process scale to make a
sugar so it's not like it was never used
it was actually very useful back in the
day
okay so that leaves us with exactly ten
minutes to put in the bank tomorrow
class begins at 9:00 a.m. instead of
eight because I got to drop a kid off
and then Wednesday will continue with
general reactivity so this week it's
probably the most important week not to
miss just because we're going through
all the general stuff and yeah so see
you tomorrow right nearly if you're here
and you plan on coming and you want to
receive emails about the class and
you're not actually enrolled in the
class piece of paper I'm here and
Porthos textbook from his office but it
isn't fine enough please let us know
oh yeah the DOS I write it on my iPad
handle it okay you look you can do your
notebook the iPad take your coffee
well no your help what can I hurt - no
yeah no yeah but guess me okay okay 100
so if your eye on the iPad and it's fine
okay yeah I know you gotta bring that
and get us a copy yeah yeah
maybe we can buy you
yeah this one's gonna be the most
aromatic oh yeah yeah the it mostly has
to do with but if you look at just so
Thanksgiving most aromatic yeah the
better explanation is that a sulfur is
softer and bigger and so it's gonna act
a little bit it's gonna it's not going
to detract as much
Electronics of the ring as it would it
was something like nitrogen or oxygen
basically you could think of cytokine as
like Isis tier 4 that effectively
electronic
software is just Hollis yeah there's a
part because his electrons are so like
will you seek you to see so it can kind
of take whatever shape the entity I
don't want to confuse you but one thing
I need to mention poking up with you
have absolutely that's not actually you
the aromatic so if you compare - me and
then this'll be the best I think sorry I
Oh what about this one this one yeah the
compute is small and now stream even
though the string is too common to
benzene rings and deeply interesting yes
really depends this is more about it
because Untersee and after II like to
add two benzene rings animated opening
and not quite benzene human race yeah
this is still really complicated we
don't gonna trick you guys
free consulting no boy you should put
that one day
Wow yeah just rewriting all with the
problem yeah it's pretty easy I mean if
you're just gonna put it up there you
can even do from your last term fine
differently or yeah that Li next time