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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).
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E
FUNCTIONAL GROUPINTERCONVERSIONS
CHAPTER 6
123.3
12
1
functional group interconversions
CHAPTER sixoxidation and
reduction
2
previously...
we have looked at functional group interconversions...
...& then alcohols, carboxylic acids & their
derivatives...
R OH
R OH
O
R Cl
O
R NH2
O
R OR2
O
3
now turn our attention to oxidation & reduction
look at oxidationof organic compounds first (& not inorganic compounds like
the rust shown here!)
©jspace3@flickr
4
R Hoxidation
RYH
oxidation: PERMITS THE INTRODUCTION OF FUNCTIONALITY
to the organic chemist oxidation is the addition of
electronegative atoms
5
formally, oxidation
occurs when electrons
are removed from a
compound
Oxidation:
M2e-
M2+
but its formal definition is...
6
©David Reeves from Flickr
A more useful definition:
Oxygen is gained
Hydrogen is lost
orelectrons lost
electronegative element gained
7
reduction is the opposite...
©smig44 uk@flickr
8
R Hreduction
RYH
reduction : PERMITS THE removal OF FUNCTIONALITY
removing an electronegative
atom/bond...
9
formally, reduction
occurs when a
compound gains
electrons
Reduction:
M 2e- M2-
the formal definition is...
10
©David Reeves from Flickr
A more useful definition:
Oxygen is lost
Hydrogen is gained
orelectrons gained
electronegative element lost
11
R H
R OH
R NH2
R Cl
R
R1/H
O
R
RR
Cl Cl
Cl
RR
R1O OR1
OH
O
R
OR1
O
R
NH2
O
R
NR O C O
H2N
O
NH2
ClCl
Cl Cl
oxidation
Reductiona generalisation...
12
oxidation of alkenes
13
a simple method to oxidise electron neutral or rich alkenes is with a peracid
R O
O
OH
14
Text
R O
O
OH
peracids are often unstable/explosive
15
O
O
OH
Cl
meta-chloroperoxybenzoic acid (mcpba)
most commonreagent normally sold as 70% in water (still a white
powder)
16
RCO3H
O
O
O
H
Cl
O
electrophilic Epoxidation with peracid
reaction is concerted(bonds made & broken at same time), which has an important
consequence...17
RCO3H
RCO3H
O
O
R1 R2
R1
R2R2
R1
R1 R2
reaction proceeds with retention of stereochemisrty
start with a cis alkene get a cis epoxide
18
antibacterial: indolizomycin
©http://www.flickr.com/photos/ajc1/534413333/sizes/o/
N
OHO
H
19
N
OH
TEOCH
N
OH
TEOCH
O
mCPBA
84%
O
O
SiMe3
epoxidation in total synthesis
20
R R2
OO
OHH
NaOHR R2
OO
very different mechanism...
nucleophilic Epoxidation with peroxide
still explosive...still sold in water
21
R R2
OO
OHH
NaOHR R2
OO
very different mechanism...
nucleophilic Epoxidation with peroxide
A reaction that youhave/will do in the 312 lab. it is very different to the previous
epoxidation
22
R R2
OO
OH
R R2
OOO
H
R R2
OO
...reaction is stepwise so...
...no control of stereochemistry
free rotation in this intermediate means there is no control of stereochemistry
(trans predominates)
23
chemoselectivity
hydrogen peroxide only reacts with activated (electron poor) alkenes
peracid reverses this selectivity (only reacts
with electron rich alkenes)
©gillonde@Flickr
24
what is all the fuss about epoxides?
©ultrabobban@Flickr
25
R
ONuc
OH
R
Nuc
epoxides are useful intermediates
ring strain makes epoxides very reactive
normally get good stereo- & regio-control
on addition of a nucleophile
26
examples
27
R
O
OH
R
H
LiAlH4
reaction with reducing agents...
formation of an alcohol with control (retention) of
stereochemistry
28
madagascar periwinkle
©TusharKumar@Flickr
N
NH
OH
Et
H
MeO2C
MeO
N
N
Et
OAc
HCO2Me
OH
Me
H
vinblastine
29
use of epoxides in total synthesis
NBoc
NsHN
O
Et
MeO2C
K2CO3
82%
N
NBoc
MeO2C
OTBDPS
OH
Et
Ns
TBDPSO
large (& medium) rings are normally hard to form due to both entropic & enthalpic
factors
30
use of epoxides in total synthesis
NBoc
NsHN
O
Et
MeO2C
K2CO3
82%
N
NBoc
MeO2C
OTBDPS
OH
Et
Ns
TBDPSO
note retention of stereochemistry at oxygen
centre31
dihydroxylation of alkenes
Os
O O
O O O
Os
O O
O
NaOH
H2O
OH
OH
two oxygen atoms can be added to an alkene
32
RR
R
R
i. OsO4
ii. NaOH / H2O
i. OsO4
ii. NaOH / H2O
HO OH
HO OH
R R
RR
concerted reaction...
...as a results we observe retention of
stereochemistry start with a cis alkene get a cis epoxide
33
osmium tetroxide is vile!volatile & toxic at levels below that which can be smelt. it also stains the cornea
©cayusa@Flickr
34
how many compounds?
OH
OH
OH
OH
OH
OH
OH
OH
35
not four3
36
meso
!OH
OH
OH
OH
37
meso
!OH
OH
OH
OH
these two are identical due to a plane of symmetry
38
!OH
OH
OH
OH
enantiomers
39
OH
OH
OH
OH
OH
OH
OH
OH
how many compounds?
40
441
broken the symmetry
©arkadyevna@Flickr
42
how would you make the two different diastereoisomers?
OH
OH
OH
OH
just worried about the relative stereochemistry
43
the cis compound is easy...
Os
O O
O O OH
OH
simple...just dihydroxylation but what about
the other diastereoisomer?
44
O
O
OH
Cl
O
trans isomer...
takes more than one step... epoxidation first
then...
45
Ring open epoxide
O
KOH !
OH
OH
OH
OH
46
how would we form just one enantiomer?
©wonderferret@Flickr
47
we can fully oxidise an alkene by breaking the double bond
©e-magic@Flickr
48
ozonolysis: reductive work-up
O3 then
Me2S or Ph3P CHO
CHO
ozonolysis: oxidative work-up
O3 then
H2O2 / HCO2H CO2H
CO2H
49
other reagents can also achieve this transformation
©clappstar@Flickr
50
mechanism can be a little daunting!
©Jasoon@Flickr
51
mechanism...
O
O
O O
O
O
O
OO
O
OO
first step is a cycloaddition
52
mechanism...
O
O
O O
O
O
O
OO
O
OO
this then fragments before...
53
mechanism...
O
O
O O
O
O
O
OO
O
OO
cyclisation to give a compound called an
ozonide
54
Reductive work-up:
O
OO S
O
O
S
O
the ozonide is then broken down on
work-up
55
oxidative work-up:
O
OO
H2O2
H+
O
OOH O
O
OH
HO
H
O
O
OH
OH H
O
O
OH
OH
HO
OH
O
O H
mechanism isn’t so clear...I’m ok up to the
aldehyde then made it up...
56
oxidative work-up:
oxidation could occur via a hydride shift or it could
be radical
O
OH
O
O HO
O
O H
H
HOH
O
O
O H
CO2H
OH
CO2H
OH
O
O H
repeat
57
oxidation of alcohols
probably should have a bottle of vinegar here...
58
can oxidise tertiary alcohols but it requires C-C bonds
to be broken
R OH
H H
R O
H[O]
R O
OH[O]
R OH
R H
R O
R[O]
R OH
R R [O]
Care must be taken in the oxidation of alcohols...
X
often hard to stop oxidation at aldehyde
stage
59
R OH
H H
R O
OHCrO3, H2SO4
R OH
R H
R O
RCrO3, H2SO4
Chromium-based oxidation reagents: Jones reagent
harsh, acidic conditions limit its use
always goes to carboxylic acid
60
R OH
H H
R O
H
R OH
R H
R O
R
PCC
NO H2O
PCC
Chromium-based oxidation reagents: Pyridinium chlorochromate
less acidic (but still acidic!)
NH
Cl
CrO
O
O
61
many chromium reagents are carcinogens
62
R OH
H H
R O
H
R O
OH
PDC
DCMPDC
DMF
Chromium-basedoxidation reagents:Pyridinium Dichromate
mild & interesting selectivity
O Cr
O
O
O Cr
O
O
O
NH 2
63
Mechanism of chromium oxidations
R OH
H H
OCr
O
OH
R O
H H
Cr
O
O
OH
R O
HO
CrOHHO
general mechanism for all these reagents
64
Mechanism for aldehyde oxidation (normally needs water)
HO
H OCr
O
O
R H
O
RH
OH
OH
RH
OH
OCr
O
OH
O
R OH
O
65
fragmentation common to most oxidations
©nesster@Flickr
R
H
OX
Y
remember, if something is oxidised something is reduced
66
the Swern oxidation
©natashalcd@Flickr
67
Text
©rantz@Flickr
68
R OH
H H
R O
HDMSO,
(COCl)2, Et3N
the Swern oxidation
one example of a class of mild & selective oxidations...
never goes to the acid
dmso is methyl sulfoxide
69
complex mechanism
70
S
O
S
O
Cl
O
O
Cl
O
O
O
ClS
Cl
S
ClR OH
H H
R O
H H
S
CO2CO
Cl
mechanism of the swern oxidation:
71
R O
H H
S
HHH
:NEt3
R O
H H
S
HH
S
R O
H
mechanism of the swern oxidation:
only two problems: the smell of dimethylsulfide & the potential racemisation of alpha stereocentres
72
R O
H H
S
HH
R O
H H
Cr
O
O
OH
fragmentation common to many oxidations
organic chemistry is just a few basic concepts repeated over & over. It’s what you
can do with those concepts that is so fascinating
73
Activated DMSO reactions...
S
O
Cl
O
O
Cl Et3N
S
O NC
NTFA / pyridine
S
O N O
SO O
Et3N
Swern
parikh-doering
Pfitzner–Moffatt
74
Text
©Graham Johnson, Graham Johnson Medical Media, Boulder, Colorado
you do not need to remember names just the general principle
75
oxidation of aldehydes &
ketones
76
R O R O
OHCrO3, H2SO4
H
Aldehydes readily oxidised to acids:Jones reagent
already seen this reaction during the oxidation of alcohols
77
many reagents can promote this tranformation
©nezume you@Flickr
78
The baeyer-villiger oxidation
O
R R2
O RCO3H
R O
O
R2
O
O
RCO3H
ketones can also be oxidised but this involves breaking C-C bonds
79
O
RCO3HO
H
O R
O
HO
HO O
OR
O
O
OH
O
O
mechanism
first the ketone is activated by protonation & then undergoes nucleophilic
addition of the peracid
80
O
RCO3HO
H
O R
O
HO
HO O
OR
O
O
OH
O
O
a 1,2-shift then occurs to insert an oxygen into a C-C
bond
mechanism
81
Ph
O
RCO3H
PhO
O
OPh
O
©carbonnyc@Flickr
questionwhich product is
formed?82
the more substituted side migrates
HO O
O
R
O
O
O O
R
HO!+
!+
!– O
O
there is a build up of positive charge (2e shared
over 3 atoms) so the group that can stabilise a positive charge
migrates83
Ph
O
RCO3H
PhO
O
OPh
O
Xthe more substituted side migrates
methyl group least stable +ve so benzylic group
migrates note: retention of stereochemistry
84
what would happen in the following
reaction?
O
RCO3H ?85
what would happen in the following
reaction?
O
RCO3H ?question of
chemoselectivity
86
what would happen in the following
reaction?
O
RCO3H ?under acidic conditions carbonyl protonated & get baeyer-villiger otherwise
epoxidation87
madagascar periwinkle
©TusharKumar@Flickr
N
NH
OH
Et
H
MeO2C
MeO
N
N
Et
OAc
HCO2Me
OH
Me
H
vinblastine
88
N
NH
OH
Et
H
MeO2C
MeO
N
N
Et
OAc
HCO2Me
OH
Me
H
the baeyer-Villiger oxidation in total synthesis
OEt
OH
OTBDPS
mCPBA, AcOH
O
O
Et
OTBDPS
OH
note: retention of stereochemistry
89
