OC II (FS 2013) Lecture 1 Prof. Bodenielssi/download/4. Semester/OC II...OC II (FS 2013) Lecture 1...
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OC II (FS 2013) Lecture 1 Prof. Bode 1 Oxidation 1 Oxidation state of carbon Oxidation is a process in which a chemical species loses electron. Reduction is a process in which a chemical species gains electron. 2 Functional group interconversion Key to organic synthesis is the interconversion of functional groups. Oxidation and reduction allow for the change up and down the oxidantion ladder. Part of organic chemistry is learning how to master the manipulation of oxidation state and knowing the appropriate reagent for the desired transformation. 3 Oxidizing agents Oxidizing agents increases the oxidation state of the substrate but itself undergoes a reduction. The net process is called a redox reaction. There are many oxidants available in the “tool box.” Here we are categorizing them based on their mode of action (mechanism). H 3 C H H 3 C OH H 2 CO CO HO H CO O most reduced most oxidized R X R Other functional groups with equivalent oxidation state R OR' R OR' R O X = halide, OH, or OR N R NC R O NC R N R C O N H R R' SH R methane methanol formaldehyde formic acid carbon dioxide alkene thiol alkyne acetal epoxide amide nitrile isocyanate R OR' OR' OR' orthoester OC R N cyanate carbodiimide C S S carbon disulfide OH oxidant B O oxidant C O OH oxidant D H oxidant A For example: Some class of oxidizing agents: [Metal] O N H Cr O O Cl O PCC: MnO 2 RuO 4 KMnO 4 CrO 3 "X-Y" Me 2 S Cl O O Me Me DMDO: HO OH Br 2 I 2 Cl 2 NaClO 2 O O I O OH IBX: O O N N Cl Cl organic oxidant DDQ: N O Me Me Me Me TEMPO:
Transcript of OC II (FS 2013) Lecture 1 Prof. Bodenielssi/download/4. Semester/OC II...OC II (FS 2013) Lecture 1...
OC II (FS 2013) Lecture 1 Prof. Bode
1
Oxidation
1 Oxidation state of carbon Oxidation is a process in which a chemical species loses electron. Reduction is a process in which a chemical species gains electron.
2 Functional group interconversion Key to organic synthesis is the interconversion of functional groups. Oxidation and reduction allow for the change up and down the oxidantion ladder. Part of organic chemistry is learning how to master the manipulation of oxidation state and knowing the appropriate reagent for the desired transformation.
3 Oxidizing agents Oxidizing agents increases the oxidation state of the substrate but itself undergoes a reduction. The net process is called a redox reaction. There are many oxidants available in the “tool box.” Here we are categorizing them based on their mode of action (mechanism).
H3C H H3C OH H2C O C OHO
HC OO
most reduced most oxidized
R
XR
Other functional groups with equivalent oxidation state
R
OR'R
OR'
R OX = halide,OH, or OR
NR
N CR O
N CR N R
CO
NH
RR'
SHR
methane methanol formaldehydeformic acid
carbon dioxide
alkene
thiol
alkyne
acetal
epoxide
amide
nitrile
isocyanate
ROR'
OR'OR'
orthoester
O CR Ncyanate
carbodiimide
C SS
carbon disulfide
OH oxidant B O oxidant C
O
OH
oxidant D
H oxidant A
For example:
Some class of oxidizing agents:
[Metal] O
NH
CrO
OClO
PCC:MnO2
RuO4
KMnO4
CrO3
"X-Y"
Me2S Cl
OO Me
Me
DMDO:
HO OH
Br2
I2
Cl2
NaClO2
O
OIO OH
IBX:
O
O N
NCl
Cl
organic oxidant
DDQ:
NO
MeMe
MeMe
TEMPO:
OC II (FS 2013) Lecture 1 Prof. Bode
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3.1 Oxidation of alcohol to carbonyl compounds 3.1.1 TEMPO oxidation
3.1.2 Swern oxidation and other variants
Mechanism
OOMe
HOMe
HO
NO
MeMe
MeMe
OOMe
HOMe
OH
NaOCl [O](catalytic)
NO
MeMe
MeMe
oxidation
NO
MeMe
MeMe
base
R OH base
base-HN
OMe Me
Me Me
OR H
H
NOH
MeMe
MeMe oxidation
NaOCl
PhMe
OH
(COCl)2DMSOEt3N
CH2Cl2-78oC
PhMe
O
Swern oxidation:
SO
Me Me SO
Me Me
O
ClO
Cl S O
Me
Me
O
O
ClCl-
CO2 + COS Cl
Me
MeR OH
H HSMe
MeR O
H H
H
basebase-H+
SMe
CH2R O
H H
H more acidic
less acidic
baseS Me
CH2
R O
H HS Me
CH2
R O
H H
ene-like
R O
H SMe Me
Mechanism:
Other varients
Moffatt oxidation:
HN
Et
OHDCC
DMSOcat. H+
HN
Et
ON C N
HDCC acitivation
S OMe
Me
OC II (FS 2013) Lecture 1 Prof. Bode
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3.1.3 TPAP oxidation
Other metal oxides oxidation (i.e. Cr or Mn) have similar mechanism.
3.1.4 Dess-Martin and IBX oxidation
Corey-Kim oxidation:
Me
Ph
OH
NCSMe2S
Me
Ph
O
NCS acitivation
SMe
MeN
O
O
Cl S Cl
Me
Me
Et OHO
Ru OO
OO
Et OO
Ru OHO O
O
OH
Et OO
RuO O
OH H
Et OO
RuO O
OH
H2ORuO O
O
O N OMe
O N Me
Ru OO
OO
Et OHO
Pr4N RuO4 (TPAP, 5 mol%)
O N OMe
(NMO, 1.5 eq.)
CH2Cl2, 4Å MSEt O
O
Mechanism
catalystreoxidation
A special feature of MnO2 oxidation is a mild and selective oxidation of unsaturated system.
OHCl
Cl 20 equiv. MnO2
CH2Cl2room temp
OCl
ClH
OBnO
OH
MeEt DMP
OBnO
O
MeEt
H
IBX:
OIO OH
O
Dess-Martin(DMP):
OI
AcO OAc
O
OAc
OC II (FS 2013) Lecture 1 Prof. Bode
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3.2 Oxidation of aldehyde (or equivalent) to carboxylic acid derivative 3.2.1 Pinnick oxidation also sometime known as Lindgren oxidation
3.2.2 Oxidation by N-heterocyclic carbene (NHC)
3.2.3 Oxidative amidation This reaction is mechanistically similar to other metal oxides with the Ru cat performing two oxidations: first on the alcohol to aldehyde and second on the hemiaminal to the amide. It is a nice example of catalytic amidation reaction – a problem with few satisfactory results (See Milstein Science 2007, 317, 790).
Mechanism:
OI
AcO OAc
O
OAc H HR
OH
OI
AcO
OAc
O
H
H
RO
OAC
OI OAc
OH
RO
I5+ I3+
O
OHOMe
NaClO2NaH2PO4tBuOH/H2O
HClO or 2-Me-Butene(as scavenger)
O
OHOMe
OH
Mechanism
ClO2 + H2PO4
ClOOHR
O
H ClO
OHR
O
H R
OHOHClO
2 ClO2
2 ClO2 + Cl + OH
ClO
O
R
O
H
H
Ph+
S N Bn(5 mol %)
H
O
1.0 equiv [O]MeOH
Et3N (7.5 mol %)Ph OMe
O
Ph
OH
N
S
BnBreslow intermediate
Ph
O
N
S
Bnactivated carboxylate
[O]Ph
O
N
S
Bn
H
H+ transfer
SET?
+ MeOH
Common oxidant:
MnO2tBu
tBu
tBu
tBu
OO
S N Bn
OHR2 NH2 R1
R2NH
ORu
N P tButBu
NEt Et
COH
1 mol%R1reflux-tol
C6H13BnN
H
O96%
C5H11PhN
H
O58% N
H
O
OMe
99%
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3.2.4 Formal oxidation of aldehyde to nitrile This is technically an elimination reaction with the net outcome of oxidation of C=O to CΞN bond
3.3 C-H oxidation 3.3.1 Radical halogenation
3.3.2 Dehydrogenation: alkane to alkene
3.3.3 Allylic C-H oxidation
3.3.4 Benzylic C-H oxidation Many strong oxidants such as KMnO4, IBX or H2O2 may be used for benzylic oxidation
RuN P tBu
tBuNEt
EtOC H
O
R1
OR1
RuN P tBu
tBuNEt
EtOC H
H
- H2Ru
N P tButBu
NEt
EtOC H
OR1
NHR2
OH
R1 NHR2
RuN P tBu
tBuN
Et EtCO
H R1R2N
H
O
R2 NH2H
Mechanism
hemiaminal
O
NH2OHNOH
oxime
N
nitrile
OHSO
OCl
elimination
H Cl2 Cl Hhv Cl - HCl Cl
Cl
mechanism:
Pt
Δ
β-pinene
MeMe
SeO2, H2O2
tBuOH, H2O40 - 50oC
trans-pinocarveol
MeMe
OH
Mechanism
R
SeOO
R'
H
R
SeOO
R'
H
R
SeOO
R'
H
R
OH
R'
Hartshorn and Masamune Org. Synth., 1988, 6 , 946.
hydrolysis
OI
O OH
ODMSO
Nicolaou JACS 2002, 124, 2245Me Me
KMnO4 / MnO2
O
Shaabania Tetrahedron, 2004, 60, 11415
O
OC II (FS 2013) Lecture 1 Prof. Bode
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3.4 Alkene oxidation 3.4.1 Epoxidation by mCPBA - This reaction is stereospecific
3.4.2 Dihydroxylation - This reaction is also stereospecific
3.4.3 Wacker oxidation - This reaction generally follows Markovnikov selectivity
3.4.4 Ozonolysis
m-CPBA24 h
O
Me Me Me Me
dr > 9:1
OO O
HOH
R
R R
Cl
OH
Me m-CPBAOH
HMe
HOH
Me
dr = 95:5
Me
H
Me
O
Me
120°
A1,3-strain minimized
Preferred reactive conformation
Stereochemistry:
OOsOO
O
OH
RR
HO
R R
OH
2 OH−
2 H2O OsHOHO OH
OH
O
O
2-Os
HOHO O
O
O
O
2-
NMM
2 OH−
OsO O
O O
R R
Me
Me 1 mol% OsO4
NMO, H2O Me Me
HO OH
mechanism
NMO
RPdX2
OH
H
R
PdXOH
H2O
PdX2
β-hydride elim.then tautomerization
R R
R R
R R
O
PdXH
HXPd0
H2O, O2
10% Pd(OAc)2CuCl
R RR R
O
Cu+ + O2
Markov-nikov
OC II (FS 2013) Lecture 1 Prof. Bode
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3.5 Baeyer-Villiger oxidation This reaction is stereoretentive
4 Heteroatom oxidation 4.1 Borane oxidation (in hydroboration sequence)
4.2 Fleming-Tamao oxidation
5 Other functional groups and their oxidation state
Me
Ph 1) O3 CH2Cl22) PPh3or Me2S
mechanism
Ph
Me
PhPhO O
H
Me
PhPh
OO O
Ph PhMe H
OO
O
Ph PhMe H
OO
O =
Ph
PhMe
H
O
OO
Ph
Ph
Me
H
O
OO
reduced
primary ozonide secondary ozonidePh
Ph
Me
H
O
HOO Me
Ph
PhO
OH
mCPBA
mechanism
HO
HOMe H
Me OO
O
Me
HO
HOMe H
Me OO
O
O
Me
PhO
O
O
O
Me
HO
OHO
OPh
OHNH
Ph
O
OO
Me
O
OMe
H H
Taxol
steps
Ar
O
O O H
O
RSRL
Ar
O
O OORL
RS H
RL migrates faster than RS
RL larger than RS
RLO
O
RS Ar
O
OH
mechanism
NBoc
MOMO
Me
9-BBN
NBoc
MOMO
Me BR2
H2O2
NaOH NBoc
MOMO
Me OH
BR2O OHR BR2
R
OOH
BR2RO
BRO OR
OR
H2OROH + B(OH)3
mechanism
N
PhO
SiMe
Me 1) BF3-AcOH2) H2O2, NaHCO3
N
PhO
HO
RSiMe
Me E-X
RSiMeX Me Ar
O
OORSi Me
Me
ArO
OO Si Me
Me
Ar
OO
OR
baseROH
OC II (FS 2013) Lecture 1 Prof. Bode
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6 Oxidation used in industrial setting Oxidation is commonly done in and industrial setting. Many of these processes have been performed in large scale. Examples include oxidation of p-xylene to terephthalic acid (44x 106 tons per year), oxidation of cyclohexane to cyclohexanol and cyclohexanone (6 x 106 tons per year), and the synthesis of ethylbenzene hydroperoxide (6 x 106 tons per year). A few examples are shown here:
7 Biological oxidation
Organosulfur reagent
R SH RS SR S O S OR
R
most reduced most oxidized
R
R
O
thiol disulfide sulfoxide sulfone
Organophosphorus reagent
R P
most reduced most oxidized
phosphine phosphonic acid
phosphate
R
R R P OH
ROH
O
RO P OR
OR
O
Nitro compound
R N
most reduced most oxidized
amine hydroxylamine
R
RR N
OH
R
nitroso
NO
R
nitro
NO
OR
nitrite
NO
RO
Halogen
ClO ClO2 ClO3 ClO4
hypochlorite chlorite chlorate perchlorate
most reduced most oxidized
MeO
Me
ClOH
O
HOO
OH
OH
or
OHNO3
adipic acid
O
OH
O
HOMe
Me44x 106
tons per year
Cu(NO3)2
Me CHOCH2O
terephthalic acid
air
Me
CHOaldolO2
Me
COOH
BASF's methacrylic acid process:
Cavani ChemSusChem 2009, 2, 508
OC II (FS 2013) Lecture 1 Prof. Bode
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Similar to organic chemists, biology utilizes many oxidation strategies (radical peroxide, metal oxide, etc) for synthesis of important metabolites and for regulation processes.
7.1 Cytochrome P-450 Cytochrome P-450 is a family of enzymes that catalyzes the oxidation of many metabolic intermediates:
7.2 Oxidation of phenylalanine to tyrosine
7.3 How does biology stores energy? Trapping energy released from oxidation in the form of ATP
O
O MeMe
Me
H
H
H
O
O OH
Me
Me
H
H
H
Net reaction: RH + O2 + NADPH + H+ ROH + H2O + NADP+
cytochrome P-450 oxidase
progesterone deoxy-corticosterone
Mechanism
Heme Fe3+OH2
S Cys
RHH2O
Heme Fe3+
S Cys
+ 2e
+ O2Heme Fe4+
S Cys
OROH
+ H2OHeme Fe3+
OH2
S Cys
COOH
NH2O2
biopterinphenylalaninehydroxylase COOH
NH2HO
NH
NN
N
OMe
OH
OH
NH2
Mechanism
O2
biopterin
N
NHN
NH
OMe
OH
OH
NH2
OHO
COOH
NH2
COOH
NH2O
COOH
NH2HO
H-Enz
COOH
NH2HO H
Enz-Base
COOH
NH2HO
glyceraldehyde-3-phosphate
OH
O
POO
OHOH
H
NAD
HPO42oxidative
phosphorylation OH
O
POO
OHOH
H
O3PO2
NADH
+H
dephosphorylation OH
O
POO
OHOH
H
HO
ADP ATP
