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E
FUNCTIONAL GROUPINTERCONVERSIONS
GARETH J ROWLANDS123.
312
functional group interconversions
CHapter one - introduction
CHapter two - Alcohols
CHapter three - functional group group ... .........interconversions & alcohols
CHapter four - protecting groups
CHapter five - carboxylic acids & their their ...... .....derivatives
CHapter six - oxidation & reduction
CHapter seven - reduction
CHapter eleven - aldol rct & conjugate conjugate .......additions
CHapter eight - C–C bond formation introduction
CHapter nine - c–c bond formation: enolates
CHapter ten - C-C bond formation: other other ...... ...nucleophiles
functional group interconversions
CHAPTER oneintroduction
recommended book...
other useful books...
in the beginning...
in the beginning, man used natural products to treat illness.
willow bark has been used in the treatment of pain and fever for
centuries
in the beginning, man used natural products to treat illness.
OH
OH
Othe active component is salicin and its metabolite
salicylic acid
©Gustty@Flickr
OH
OH
O
unfortunately, salicylic acid is too corrosive to the walls of the stomach
for prolonged use
O
OH
O
O
Aspirin treats inflammation & is not corrosive (but is more dangerous than you think)
©Chaval Brasil from Flickr
how is aspirin related to salicylic acid?
chemical synthesisor an increase in complexity
some quick revision should make things easier to understand...
Bn H
OBn
H Br
SiMe3
Fu (jacs 2008, 130, 12645) needed one of his students to perform the following transformation:
©David Reeves from Flickr
how would/could they do it?
the first step is nucleophilic attack
Bn H
OBn
H Br
SiMe3
H SiMe3n-BuLi
Bn
H OH
SiMe3
here we are adding a group or building the
molecule
Bn H
OBn
H Br
SiMe3
H SiMe3n-BuLi
Bn
H OH
SiMe3
imidazolePh3PBr
step two substitutes a bromide for an alcohol
we are not building the molecule, just
altering it...
Bn H
OBn
H Br
SiMe3
H SiMe3n-BuLi
Bn
H OH
SiMe3
imidazolePh3PBr
step two substitutes a bromide for an alcohol
this is a functional group interconversion
a potent insect antifeedant & potential natural insecticide
OHOH
HO
AcOMeO2C
O
OO OH
CO2Me
O
O
O
azadirachtin
an alcohol
what is a functional group?
a group of atoms that (chemically) behaves the same in every molecule
OH
both alcohols share very similar chemical
properties
what isfunctional group interconversion
(FGI)?
Text
©dmcneil@flickr
OHOH
O
altering group but not increasing molecular
complexity
how could we achieve this reaction?
OH
R1 HH
OH
R1 R2R2
we cannot add two R2 groups directly to
alcohol
OH
R1 HH
OH
R1 R2R2
PCCoxidation
O
R1 OH
CH3OHH+ O
R1 OCH3
First we have to perform two functional group interconversions to prepare for addition...
we haven’t increased complexity or built
molecule...
OH
R1 HH
OH
R1 R2R2
PCCoxidation
O
R1 OH
CH3OHH+ O
R1 OCH3
R2–MgBr
...Now we can add the two R2 groups
8 lectures look at FGI and reactions that
increase complexity...
...then, when we have the tools, we will look
at retrosynthesis
before we go any further...
the next few slides are only in the notes...I will not be going through it in
the lectures.
a quick look at the basics...
key to organic chemistry is...
...the “curly arrow”...
...you do not have to remember all this...
...if...
...you know how to use...
the “curly arrow”...
...you know how to use...
the “curly arrow”...
you’ve been putting off learning this for three years! but now is the moment of
truth...
a bond (line) is two electrons.
C C
the electrons are not evenly distributed...
Clelectrons are attracted to electronegative elements or groups
the most electronegative elements attract electrons
...top right...
some examples...
Cl O
SiMe3 MgBr
R
RR
I hope you rememberthat the arrow points in the direction the electrons are
attracted (or the cross is the +ve end!)
polarisation occurs in conjugated systems...
Oδ+ δ–
δ+ δ–
this is due to resonance...
O O O O
Oδ+ δ–
δ+ δ–
O ≡
a reaction is the movement of electrons...
electron rich
electron poor
new bond
Nuc Elec Nuc Elec
common nucleophiles include...
NHH
H
H3C MgBr
LONE PAIRS
HIGH ENERGY BONDS (HIGH HOMO)
common electrophiles include...
empty atomic orbital
H F BFF
empty molecular
orbital
polarised bonds
(low LUMO)
CO
HO
H
FB
F FO B
H
H F
FF
so a reaction goes a little something like this...
electron rich
electron poor
new bond
8 is themagic number for valence electrons
remember the octet rule
Cl
so, if i see the following...I’m allowed to deduct marks?
RN
HRR
NucRN
RR
NucH
X
10electrons not allowed
RN
HRR
Nuc NRR
R
H Nuc
...is the correct reaction.
another common mistake...
RN
HRR
Nuc
...”curly arrow” always starts from most electrons
X
electrons do not like other electrons. So...
...is very rare and...
Nuc R
...never happens!
Nuc R X
if you are unsure of any of this material...revise!
E
FUNCTIONAL GROUPINTERCONVERSIONSCHAPTER 2
123.
312
functional group interconversions
CHAPTER twoalcohols
alcohols are found in many natural products...
OHOH
HO
AcOMeO2C
O
OO OH
CO2Me
O
O
O
azadirachtin
Text
O OH O NH2O
OH
HO
OH O
discodermolide
alcohols increasesolubility & hydrogen
bonding allows interactions with enzymes & proteins
Alcohols are very useful starting materials...
R OH
R O
H
R O
OH
O R2
OR Cl
R
R OR2
R2
O O
R O R2
R R
R
Alcohols are also the product of many reactions...
R OH
R O
H
R O
OH
O R2
OR Cl
R
R OR2
R2
O O
R O R2
R R
R
need to knowabout the reactivity
of alcohols
Alcohols are one of the cornerstones of synthesis
C OH C XC OH C C
©cornerstones of ny@flickr
B C BAA C
the basis of alcohols utility comes from...
substitution
Text
©Aidan o’sullivan@flickr
some revision!
Two important substitution mechanisms (but there are more)
R LG R R NucSN1
R LG R NucSN2
R LGNuc
R Nuc
R LGstep 1
R LG
the SN1 reaction...
...2 step process
step 2R Nuc R Nuc
R LGNuc
R Nuc
R LGstep 1
R LG
the SN1 reaction...
...2 step process
step 2R Nuc R Nuc
rate only depends on1st step. Thus substrate
strucutre important
the rate of Sn1 reaction depends on the stability of the cation...
R R
R
R R R> >
...and...
remember resonance can stabilise cation
as well
LGleaving group (LG) ability.
the more stable the anion the better.
the Nucleophile is not important (to the rate of reaction)
NucX
R1 R2
H LG Nuc
R1 R2
H Nuc
a consequence of the mechanism of Sn1 reactions
racemisationthe reason for this should be obvious...
trigonal planar carbocation
HR1R2
nucleophilecan attack from either face (top or bottom)
all moleculesinvolved in mechanism so all control rate
R LGNuc
R Nuc
R LGNuc
R Nuc
the SN2 reaction...
...1 step process
controlled by the substrate...
R LGsterics etc will affect reaction
LGleaving group (LG) ability.
the more stable the anion the better.
the Nucleophile is important
Nuc
R1 R2
H LG Nuc
R1 R2
H Nuc
A consequence of the mechanism of the Sn2 reaction is...
inversion
Text
©e-magic@flickr
why are these mechanisms important?
hypothetical example...©hurleygurley@flickr
You have been asked to perform the following transformation...
OHN3
conditions
N3
You have been asked to perform the following transformation...
OHN3
conditions
N3
you need to control stereochemistry
OHHN3
N3
lets say we could achieve this by an SN1 reaction...
?
Sn1H
R1R2
racemisation
fail
Sn2
inversion
H
R2 R1LGNuc
δ– δ–
Textsuccess
Textsuccess
but...
N3
OH N3
can this happen...
?
question 1is HO– a good leaving group?
question 2what about
chemoselectivity?
©oberazzi@flickr
Text
question 1is all about leaving group
ability...©mag3737@flickr
H2O H X H3O XKa
base acid
you will remember that...
the more stable X- the more X- we have...
...and...
Ka = [H3O ][X ][H–X]
pKa = –logKa
...therefore...
Xsmall pKa
high concentration
of...
Xsmall pKa
good leaving group
H–X has large pKa H–X has small pKa
H–X is weak acid
X– is strong base
H–X is strong acid
X– is weak base
Xis a poor
leaving group
Xis a Good
leaving group
pKa is a very useful guide to reactivity... a table of values can
be found at:
http://www2.lsdiv.harvard.edu/labs/evans
h2o pKa 15.7
HO- is a poor leaving group
Text
©alexanderdrachmann@flickr
question 2chemoselectivity is also an issue!
Nuc HO
R Nuc H O R
most nucleophiles also act as bases
and thesolution?
Text
©pal berge@flickr
functional group
interconversion