Finishing off the reactions of carboxylic acid derivatives (well the substitution reactions) and introducing oxidation and reduction. Then looking at the oxidation of alkenes (epoxidation and dihydroxylation) and alcohols (the usual suspects).

1. 123.312FUNCTIONALGROUP previously...
INTERCONVERSIONS
O
functional group we have looked at
CHAPTER6
functional group
interconversions interconversions... R Cl
O O
R OH
R OH R NH2
CHAPTER six
oxidation and
O
reduction ...& then alcohols,
carboxylic acids & their
derivatives...
E
R OR2
1 2 3
©jspace3@flickr
oxidation: PERMITS THE but its formal
INTRODUCTION OF FUNCTIONALITY definition is...
tion: on
Oxidaally, o xidatcitrons
form s when ele m a
look at oxidation
of organic compounds first (&
not inorganic compounds like
R H
oxidation
R
Y
H
M
M
22+ occur emoved fro
e- aremrpound
co
the rust shown here!) to the organic chemist
oxidation is the addition of
now turn our attention to oxidation electronegative atoms
& reduction
4 5 6
A more useful definition: reduction is the opposite... reduction : PERMITS THE removal
OF FUNCTIONALITY
Oxygen is gained
Hydrogen is lost Y reduction
R H R H
or
electrons lost
electronegative element
gained removing an
electronegative
atom/bond...
©David Reeves from Flickr ©smig44 uk@flickr
7 8 9

2. the formal A more useful definition:
oxidation
definition is...
tion: n
Reduc lly, reductio
R H Cl R R N O C O
formas when a s
O O O
Oxygen
-
is lost R OH
occur ound gain R1/H
R R OH H2N NH2
Hydrogen is gained
2 comprons
M2
Cl Cl O Cl Cl
e- M R NH2
elect or
electrons gained
R R R
O
OR1 Cl Cl
R1O OR1
electronegative element R Cl
lost R R R NH2
a generalisation...
Reduction
©David Reeves from Flickr
10 11 12
a simple method to oxidise electron
neutral or rich alkenes is with a
peracid
Text
O
O
oxidation of O
alkenes
O R O H
R O H peracids are often
unstable/explosive
13 14 15
meta-chloroperoxybenzoic acid electrophilic Epoxidation with reaction proceeds with retention
(mcpba) peracid of stereochemisrty
O
R2 O R2
OH RCO3H RCO3H
O O
O
H
O
R1 R1
O
RCO3H O
Cl
most common
reagent normally sold as
reaction is concerted R1 R2
(bonds made & broken at same
Cl 70% in water (still a white time), which has an important
start with a cis alkene R1 R2
powder) get a cis epoxide
consequence...
16 17 18

3. antibacterial: O OH
epoxidation in nucleophilic Epoxidation with
indolizomycin total synthesis peroxide
N OH OH
H O
O H O O
mCPBA O H O
N N R R2 NaOH R R2
H 84% H
TEOC TEOC
O still explosive...still
SiMe3 sold in water very different
©http://www.flickr.com/photos/ajc1/534413333/sizes/o/
O mechanism...
19 20 21
nucleophilic Epoxidation with ...reaction is stepwise so... chemoselectivity
peroxide
H O O O
O H O O
O H O O R R2
O H O R R2
R R2 NaOH R R2 free rotation in this
intermediate means there is no
A reaction that you control of stereochemistry
(trans predominates) O hydrogen peroxide only peracid reverses this
have/will do in the 312 lab. it is O reacts with activated selectivity (only reacts
very different to the previous (electron poor) alkenes with electron rich alkenes)
epoxidation R R2
very different ...no control of
mechanism... stereochemistry ©gillonde@Flickr
22 23 24
epoxides are useful intermediates
OH
O
Nuc R examples
R
Nuc
what is all the fuss about ring strain makes
epoxides? normally get good
epoxides very reactive stereo- & regio-control
on addition of a
©ultrabobban@Flickr
nucleophile
25 26 27

4. reaction with reducing agents... madagascar periwinkle use of epoxides in total synthesis
OH NsHN
O
Ns
O LiAlH4 N
OH
Et
Et K2CO3
N
OH
Et
82% N
R R H
N H
N
Boc
MeO2C
Boc
MeO2C
N TBDPSO OTBDPS
H
H MeO2C Et
OAc
formation of an alcohol MeO large (& medium) rings are normally hard
with control (retention) of H
NOH to form due to both entropic & enthalpic
stereochemistry Me CO2Me factors
vinblastine ©TusharKumar@Flickr
28 29 30
use of epoxides in total synthesis dihydroxylation of alkenes concerted reaction...
O O O O
Os Os i. OsO4
ii. NaOH / H2O HO OH
NsHN Ns O O O O
O
Et K2CO3
N R R
OH
NaOH R R
N 82% N
Et
H2O i. OsO4
Boc Boc R ii. NaOH / H2O HO OH
MeO2C MeO2C
OTBDPS
two oxygen atoms can be
TBDPSO added to an alkene
OH R R R
...as a results we
note retention of observe retention of
stereochemistry at oxygen stereochemistry start with a cis alkene
centre OH get a cis epoxide
31 32 33
3
how many compounds?
OH OH
OH OH
OH OH
osmium tetroxide is vile!
volatile & toxic at levels below that which
can be smelt. it also stains the cornea OH OH
©cayusa@Flickr
not four
34 35 36

5. OH OH OH OH OH OH
! ! !
OH OH OH OH OH OH
meso meso these two are
identical due to a
plane of symmetry
enantiomers
37 38 39
4
how many compounds?
OH OH
OH OH
OH OH
broken the
OH OH symmetry
©arkadyevna@Flickr
40 41 42
how would you make the two the cis compound is easy... trans isomer...
different diastereoisomers?
O
OH OH O O OH
O
Os O
OH
O O OH
OH OH Cl
simple...just takes more than
just worried about the one step
...
relative stereochemistry dihydroxylation but what about epoxidation first
the other then...
diastereoisomer?
43 44 45

6. Ring open epoxide we can fully oxidise an alkene by
breaking the double bond
OH
KOH OH
!
O
OH
how would we form
OH just one enantiomer?
©wonderferret@Flickr ©e-magic@Flickr
46 47 48
ozonolysis: reductive work-up other reagents can also achieve mechanism can be
this transformation a little daunting!
O3 then
Me2S or Ph3P CHO
CHO
ozonolysis: oxidative work-up
O3 then
H2O2 / HCO2H CO2H
CO2H
©clappstar@Flickr ©Jasoon@Flickr
49 50 51
mechanism... mechanism... mechanism...
O O this then O O O O
O O fragments O O O O
before...
O O O O O O
cyclisation to give a
compound called an
first step is a ozonide
cycloaddition O O O
O O O
O O O O O O
O O O O O O
52 53 54

7. Reductive work-up: oxidative work-up: oxidative work-up:
H2O2
O H+ O
O O OH O
O H O O O H O H
O O O H
O O
OH
O OH H O H O
O O mechanism isn’t so O
O S clear...I’m ok up to the H H
O S aldehyde then made it up ...
O H H H
O O O OH
H O H O
O H
O O repeat O H
O
O O CO2H CO2H
OH
the ozonide is then OH OH oxidation could occur via a
broken down on hydride shift or it could
work-up be radical
55 56 57
Care must be taken in the Chromium-based oxidation
oxidation of alcohols... reagents: Jones reagent
always goes to
carboxylic acid
H H [O] H [O] OH CrO3,
H H H2SO4 OH
R OH R O R O
oxidation of R OH R O
R H [O] R
alcohols often hard to stop
oxidation at aldehyde CrO3,
R OH R O
stage R H H2SO4 R
R R
X
[O] R OH R O
probably should
have a bottle of can oxidise tertiary alcohols
vinegar here... R OH but it requires C-C bonds
to be broken harsh, acidic conditions limit its use
58 59 60
Chromium-based oxidation Cl
Chromium-based O O
reagents: Pyridinium oxidation reagents:
Cr O Cr O Cr O
chlorochromate O O N Pyridinium N
O H Dichromate O O H 2
H H PCC H H H
PDC PDC
R OH NO H2O R O DCM R OH DMF
H OH
R H PCC R
R O R O
R OH R O
many chromium reagents are
less acidic (but still acidic!) carcinogens mild & interesting selectivity
61 62 63

8. Mechanism of chromium oxidations fragmentation common to most
oxidations
O
O
H H O H H O O OH Cr
H O H H O O Cr OH
Cr Cr O O
R O H O
R OH O O OH R H R
OH
R H
OH
H Y
general mechanism for
all these reagents O H Mechanism for
aldehyde O
remember, if
X
HO
Cr
OH R O
oxidation
(normally
needs water)
R OH R
something is oxidised
something is reduced O
©nesster@Flickr
64 65 66
the Swern oxidation the Swern oxidation
Text
dmso is methyl
sulfoxide
DMSO,
H H (COCl)2, Et3N H
R OH R O
one example of a class of
mild & selective oxidations...
never goes to the acid
©natashalcd@Flickr ©rantz@Flickr
67 68 69
complex mechanism mechanism of the swern oxidation: mechanism of the swern oxidation:
O O
H H H
Cl H H :NEt3
S O H H
Cl H H
S Cl S S
O O R O
R O
O
O Cl
S CO2 H
CO S
H H
Cl
R O
only two problems: the
H H R OH Cl smell of dimethylsulfide &
S S the potential racemisation
R O of alpha stereocentres
70 71 72

9. fragmentation common Activated DMSO reactions... you do not need to
to many oxidations Text remember names just
Swern
the general principle
O
O
Cl Et3N
S Cl
H H O H H O
Pfitzner–Moffatt
Cr O H H
R O S O N
OH S
C TFA / pyridine
R O N
organic chemistry is just a few basic parikh-doering
concepts repeated over & over. It’s what you O N O
can do with those concepts that is so S
Et3N
fascinating S
O O
©Graham Johnson, Graham Johnson Medical Media, Boulder, Colorado
73 74 75
Aldehydes readily oxidised to acids:
Jones reagent
CrO3,
oxidation of H H2SO4 OH
aldehydes &
ketones R O R O
already seen this
reaction during the many reagents
oxidation of alcohols can promote this
©nezume you@Flickr
tranformation
76 77 78
The baeyer-villiger oxidation mechanism mechanism
O O O O
H a 1,2-shift then occurs to
H
HO
O O
O O O R R O
O insert an oxygen HO O C-C R R
O into a O
RCO3H RCO3H
O
RCO3H bond
O
HO HO
R2
R R2 R O
first the ketone is
O activated by protonation &
O then undergoes nucleophilic
addition of the peracid
RCO3H H H
O O
O O O
O O O O
ketones can also be
oxidised but this involves
breaking C-C bonds
79 80 81

10. the more substituted side migrates the more substituted side migrates
X
O O
R R
Ph Ph
O O O O O !– O O
O O
RCO3H !+ RCO3H
Ph HO O HO O O Ph
!+
Ph O Ph O
there is a build up of methyl group least stable
O positive charge (2e shared +ve so benzylic group O
question over 3 atoms) so the group that can migrates
stabilise a positive charge note: retention of
which product is stereochemistry
©carbonnyc@Flickr
formed? migrates
82 83 84
what would happen in what would happen in what would happen in
the following the following the following
reaction? reaction? reaction?
? ? ?
O O O
RCO3H RCO3H RCO3H
under acidic conditions
carbonyl protonated & get
question of baeyer-villiger otherwise
chemoselectivity epoxidation
85 86 87
madagascar periwinkle the baeyer-Villiger N
OH
Et
oxidation in total H
synthesis
N H
N
H Et
MeO2C
OAc
MeO
N OH
H
Me CO2Me
OH O O
Et
N Et O Et
mCPBA,
H
AcOH
N H
N
H OH OH
MeO2C Et
OAc
MeO
N
H OH OTBDPS note: retention of OTBDPS
Me CO2Me stereochemistry
vinblastine ©TusharKumar@Flickr
88 89