a primer to designing organic synthesis
DESCRIPTION
Teaches students to use the language of sythesis directly (utilizing the grammar of synthon and disconnection) rather than translating it into that of organic chemistry Synthesis is the process of making a desired compound using chemical reaction. more often than not, more than one step is involved. The importance of synthesis : 1. Total synthesis of interesting and/or useful natural products 2. Industrially important compounds 3. Compounds of theoretical interest 4. Structure proof 5. Development of new synthetic methodology 6. Importance to other areas of science and technology .TRANSCRIPT
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A PRIMER TO
Prepared by:
Mr: Mohammed H. Raidah
2008-2009
[email protected] 00972599497541
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*Contents:
Introduction to Organic synthesis …………………………………………………3 One group disconnection disconnection of simple alcohol ………………………………………………….12 disconnection of simple olefins……………………………………………………17 disconnection of aryl ketones…………..………………………………………….18 Two group disconnection ……………………………………………………….21 β-Hydroxy carbonyl compounds …………………………………………………21 α-β unsaturated carbonyl compounds……………………………………………..23 1,3-dicarbonyl compounds ……………….............................................................24 1,5-dicaronyl compounds…………………………………………………………26 Mannich reaction………………………………………………………………….28 α-Hydroxy carbonyl compounds………………………………………………….29 1,2-diol…………………………………………………………………………….33 The Pinacol-Pinacolone rearrangement……………………………………………34 Allan-Robinson reaction…………………………………………………………...36 Bischler-Napieralski reaction………………………………………………………37 Bartoli Indol synthesis…………………………………………………………… .38 Benzilic acid rearrangement……………………………………………………….39 Benzoin condensation……………………………………………………………..39 Birch reduction……………..………………………………………………………40
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Introduction to Organic synthesis
Synthesis is the process of making a desired compound using chemical reaction. more often than not, more than one step is involved.
:The importance of synthesis
1. Total synthesis of interesting and/or useful natural products 2. Industrially important compounds 3. Compounds of theoretical interest 4. Structure proof 5. Development of new synthetic methodology 6. Importance to other areas of science and technology
:Basic steps of solving synthetic problems
a. Choice of TARGET MOLECULE (T.M) b. Consideration of applicable synthetic methodology c. Design of synthetic pathway d. Execution of synthesis -- these steps are highly interactive
Approaching the design of a synthesis (part one)
For simple molecules it can be obvious just by looking at the target structure ,for example:
Bromoalkanes are available from alkenes or from alcohols
Esters are available from carboxylic acids by reaction with alcohols ;benzoic acid is available from toluene
Br
bromocyclohexane
HBrBr
OHPBr3
Br
CO2Me
methyl benzoate
-4-
Approaching the designing of a synthesis (part two)
For more complex molecules , it help to have a formalized , logic-centred approach; RETROSYNTHETIC ANALYSIS
Retrosynthetic analysis is the process of working backwards from the target molecule to progressively simpler molecules by means of DISCONNECTIONS and /or FUNCTIONAL GROUP INTERCONVERSIONS that correspond to know reactions . When you`ve got to a simple enough starting material (like something you can buy and usually is cheap) then the synthetic plan is simply to reverse of the analysis . The design of a synthesis needs to take into account some important factors
1. it hase to actually work 2. In general , it should be as short as possible 3. Each step should be efficient 4. Side products (if formed) and impurities (there always are ) should be easily
separable from the desired product 5. Environmental issues may be relevant 6. There's more than one way to skin a cat
Example retrosynthetic analysis Target molecule :
OH
Disconnect
A B
OHSYNTHONS
REAGENTS ? ?
OH
PhMgBr
O
H
SYNTHONS
REAGENTS
CO2H CO2MeKMnO4 MeOH
H2SO4
-5-
Therefore the target molecule could be synthesized as follows :
What is a synthon? When we disconnect a bond in target molecule , we are imagining a pair of charged fragments that we could stick together , like Lego bricks , to make the molecule we want . these imaginary charged species are called SYNTHONS . When you can think of a chemical with polarity that matches the synthon , you can consider that a Synthetic equivalent of the synthon. Thus,
An aldehyde is a synthetic equivalent for the above synthon. There can be more than one synthetic equivalent for a given synthone, but if you can't think of one …try a different disconnection.
Always consider alternative strategies.
Bri) Mg/Et2O
ii) CHO
OH
R H
O
R H
OH
≡ δ+δ-
OH
A B
SYNTHONS
Syntheticequivalents
OH
PhCHO BrMg
OH
Br?
SYNTHONS
Syntheticequivalents
-6-
Besides disconnections , we can also consider functional group interconversion . Our target molecule is a secondary alcohol ,which could be prepare by reduction of a ketone . this is represented as follows:
Ph
OHFGI
Ph
O
DISCONNECT
Ph
O
Ph
O
Br
Synthesis number four
Ph
O i)base
ii) BrPh
OLiAlH4
Ph
OH
T.MTarget Molecule
A second possible synthesis :Br i)Mg/Et2O
ii)PhCHOPh
OH
similary
Ph
OH
Ph
OH
≡ ≡
Ph
OBrMg
thus a third possible synthesis is
Ph
O BrMg
Ph
OH
-7-
There are other possibilities , but let's not bother with any more.
How do you choose which method?
Personal choice .If you have a favourite reagent, or if you are familiar with a particular reaction (or if you have a strong aversion to a reaction/reagent) then this will affect your choice .Also you need to bear in mind the efficiency of the reaction involved, and any potential side reactions (for example ,self- condensation of PhCOMe in method 4 ).
Analysis number five :
Ph
OPh
O
Ph
O
LiCu 2
Synthesis number five :
Ph
Ot-Bu2CuLi Ph
ONaBH4 Ph
OH
T.M
Ph
OH
Disconnecting heteroatoms can also be a good idea:
Ph
OH H2O
Ph
6th approach :
Phi) Hg(OAc)2
ii) NaBH4Ph
OH
-8-
DEFINITIONS What you need to makeTARGET MOLECULE (T.M)The process of deconstructing the T.M by breaking it into simpler molecules until you get to a recognizable SM
RETROSYNTHETIC ANALYSIS
An available chemical that you can arrive at by retrosynthetic analysis and thus probably convert into the target molecule
STARTING MATERIAL (SM)
Taking apart a bond in the T.M to see if it gives a pair of reagents
DISCONNECTION
Changing a group in the T.M into a different one to see if it gives accessible intermediate
FUNCTIONAL GROUP INTERCONVERSION (FGI)
Add a functional group to facilitate bond formation ,FGA especially applies in the case of molecule containing no reactive functional group
FUNCTIONAL GROUP ADDITION (FGA)
Conceptual fragment that arise from disconnection
SYNTHON
Chemical that reacts as if it was a synthon
SYNTHETIC EQUIVALENT
-9-
Some synthons and synthetic equivalents:
synthon equivalent(s)
R
R R
OH
R R
O
R
OH OH
R
O
RCl ,RBr , RI , ROMs , ROTsonly when R= alkyl
Br
R
O
R
O
R
O
R OEt
O
R Cl
O
R O
O
R
O
R(alkyl ; NOT"RH+base")
RMgBr , RLi , R2CuLi , other organometallic reagents
R
O
R
O
R
OCO2Et
make sure you don't lose CH2 group if you represent eg. RCH2 as R
( viz. make sure the product hase the right number of carbon atoms)
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Latent Polarity
Think about some of the reaction we've looked at for carbonyl compounds:
AO OH O
O O
O
O
Nu
Nuδ+
δ−
H baseB
E
E
O
δ+
δ−
δ−
C NuNu
O
E
Nu
O
E
O
δ+
δ−
δ−δ+
ie O
δ+ δ+δ+δ+δ− δ−δ−
δ−
these polarities apply quite generally:
OH
δ+δ+δ+δ− δ−δ−
δ−
δ−
Br
δ+δ+δ+δ− δ−δ−
δ−
δ−
NR
δ+δ+δ+δ− δ−δ−
δ−
δ−
NHR
δ+δ+δ+δ− δ−δ−
δ−
δ−
-11-
The partial positive and negative charges indicate the latent polarity of the bonds in a molecule. They help us choose the synthons for key disconnections in a retrosynthetic analysis . viz.
OH
δ+
δ−
δ−
OH
Equivalents for synthons with reversed polarity
synthon equivalent(s)
R R
OH
R
O
Me
O
O
R RBr
OH,or
RBr
O
,orOO
R Br
OEt+ sec-BuLi
OEt
(VERY strong base)
OEt
Li
E OEt
E
H3O+
E
O
ethoxy vinillithiumEVL
similary from acetylene:
i) base
ii) E
EH3O+
HgO E
OHtautom.
s-BuLi
-12-
1.One group disconnection :nnection of simple alcohol disco**
A + B Cconnection disconnectionA + B
Me OH
Me CN OH + CNdisconnection
Synthesis
O + +H NaCNMe OH
Me CN
mechanism O + H OH
CN
T.M
Example.1.1
Example.1.2
Me COHPh
CH
Ph
MeOH + C CH
SynthesisPh
MeO + H + HC CH base
Me COHPh
CH
mechanismHC CH base CHC
Ph
MeOH T.M
-13-
Example.1.3
Me EtOHPh
OH + H3C CH2
Synthesis
EtBr Mg/Et2O EtMgBr
Ph
MeO + EtMgBr
Me EtOHPh
mechanism
O + H
H +
Ph
MeOH
Et MgBr
T.M
Me Me
OHC
OOEt
+ 2MeMgBr
CO
OEt+ 2MeMgBr
Me Me
OH
CO
OEt CO
Me
Me MgBr Me MgBr
+CO
OEt+
T.M
Example.1.4
Synthesis
mechanism
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Compounds derived from alcohols
alcohol
Esters
OlefinsAldehydes
KetonesAlkylhalids
Example.1.5
Ph Ph
OAc FGIPh Ph
OH
Synthesis:
mechanism:
+ HC OEt
Ph Ph
OHPh2 + HC OEt
O
PhMgBr2
OPh Ph
OH
PhMgBr
HC OEtO
PhMgBr
Ph H
O
Ph Ph
OH
Ph Ph
OH
+ CH3COOH Ph Ph
OAc
T.M
R CO
OH SOCl2 R CO
ClR`OH
R CO
OR`
Reminder:
-15-
Example.1.6
Ph
OH O
H +BrMg
Ph
O
H
FGI OH
H
(aldehyde) (alcohol)
Br+ H C
OH
cyclopentanecarbaldehydeformaldehyde
Br Mg/Et2O MgBr
Synthesis
MgBrH C
OH
oxidation
O
H
O
H +BrMg
Ph Ph
OH
H
cyclopentylmethanol
OH
H
H
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OO
Me
Me
Example.1.7
OO
Me
Me
OH2H HO
OMe
Me
OH
H
HOHO
+ Me Me
O
HOHO
2 H H
O
+ C C HH
Synthesis:
2 H H
O
+ C C HHHOHO
Me Me
OOO
Me
Me
mechanism:
C CH H H
O
C C
HOH H
O
HOHO
BaSO4
reduction
HOHO
HOHOMe
MeOO
HOMe
Me
OH OO
Me
Me
-17-
**disconnection of simple olefins:
Ph FGI OHPh
O
cyclohexanone
+ PhMgBr
Example.1.8
FGI
Ph
OHno helpful disconnection
a
b
Example.1.9
Ph FGI
a
Ph
OH
O+ BrMg
Ph
FGI
Ph
OH
H
O+ BrMg
Ph
b
another analysis for synthesis:in example 1.9 the pathway (a) use Wittig reaction instead of Grinard.
Ph
BrPh3P
Ph
Ph3P H
base Ph
Ph3P
Ph
PPh3O
Ph
PPh3O Ph + PPh3O
R e m in d e r
O H H Ha c id
-18-
**disconnection of aryl ketones:
Example.1.10
PhFGI Ph
OHPh
O
H +Ph3Pa
bFGI
Ph
OH
PhPPh3 +
O
H
Example.1.11
O
MeOMeO
+Cl
O
Synthesis:
MeO
+Cl
OAlCl3
O
MeO
mechanism:
MeOCl
O
MeO
O
H
O
MeO
-19-
Example.1.12
O
O
O
O
O+
O
Cl
O
O
H
H
OH2HO
HO+ H C
OH
Synthesis
HO
HO+ H C
OH + H
O
O
O
O+
O
Cl
AlCl3
O
O
O
Example.1.13
O
Me
MeO
NO2
a ba
Me
MeO
+
O
NO2
Cl
Pathway (b) not occur because NO2 group is electrons withdraw
Example.1.14
O FGI OCH
O+ Me I
O
Br+ HC CH
O
COOEt
+ CHBrMg
a b
a b
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Example.1.15
N
O
NH+
O
HO CO2 +BrMg
Example.1.16
R1R2 R1
R2 R1R2
OH
R1 H
OR2BrMg
+
Example.1.17
OH
MgBr O
Synthesis
+
Br
Mg/Et2Oi)
ii) OOH H3PO4i)
ii) H2/Pd
T.M
Reminder:
C CH OH
C CH H
O
acidheat
heat
LiAlH4 C OHH
+
+
H2O
H2
-21-
2.Two group disconnection
**β-Hydroxy carbonyl compounds
One group disconnections summary
1. alcohols
2. Olefins
3. acids
R1
R3
OHR2 R1 MgBr +R2
R3
O
PPh3 + O
R CO
OH RMgBr + CO2
4. carbonyl compounds
Ar C ORO
ArH + Cl R
O
CH2 CO
RR RBr +
OOEt
OR
OH O
H
Example.2.1
αβ H
O+
O
H
Synthesis:
O
HH Base
O
H
O
HHO H
O
OH O
H
-22-
Example.2.2
Ph
OO
Ph OHα β
OH
+ PhPh
O
O
Synthesis:
OH
PhPh
O
O
Ph
OO
Ph OH
Reminder:
the group is attached to a carbon atom that has at least one H substituent (e.g.-CHCHO,-CHCOR, -CHCO2Et ),then electron-withdrawal by the group results in such H atom being acidic:
CO
CO
C C OH
HHO OH
H2OC C O
H
C C OHα
-23-
** α-β unsaturated carbonyl compounds
H
Oα
β
Example.2.3
H
OOHH
O
H3C H
O+
H3C H
OBase
H2C H
Oα H
O
H2C H
O H
OOH
H
OOHacidheat
H
Oα
β
T.M
Synthesis:
Example.2.4
Ph CO2H
Oβ
α Ph CO2H
OH O
Ph H
O+ H3C CO2H
O
Synthesis:
H3C CO2H
Obase
H2C CO2H
OPh H
O
Ph CO2H
OH Oacidheat Ph CO2H
O
T.M
Example.2.5
R
Oβ αR
OHO
O+
R
O
Synthesis:
R
Obase
R
OO
R
OOH
acidheat R
O
Example.2.6
α
β
O O
OH
O
O
-24-
** 1,3-dicarbonyl compounds
O O
δ+ δ−δ−
δ−δ−
δ− δ+
Ph Ph
O O
Example.2.7
Ph
O
Ph
O
Ph
O
Ph
O
OEt+
Synthesis:
O
Ph
OPh
Base
NaOEtPh
OOEt
Ph Ph
O O
T.M
PhO O
OEtPha b
PhO
PhO
OEt
+O
OEtPh
O
OEtPh
a
b
O
OEt+ Ph
O
Ph
O
OEtPh
O
Ph
Example.2.8
EtO
Example.2.9
Ph
O
O
OEt
OEt
Ph
OOEt + OEt
O
Ph
OOEt
OEt
O
EtO
-25-
Example.2.10
Ph
CPhO
OEt
Ph
Br+ CPh
OOEt
Synthesis:Ph
Br+ CPh
OOEt
Base T.M
mechanism:
CPhO
OEt
Ph
Br T.M
Example.2.11
H
OO
δ+
δ−
Me
OMe
+ H
O
OMe
EtO H
O
Synthesis:
OMe
EtO H
O
+ baseNaOEt T.M
-26-
** 1,5-dicaronyl compounds:O O
δ+ δ−δ+ δ+
δ− δ−
δ− δ− δ−
Michael addition
PhPh
O
H
Oβ
αPh 1 2
O
34
5H
Ph
O
Ph
O
HPh
OH
+EtO
R R`
OO
Example.2.12
β
α
a b bR`
O
R
O
H
+ R
O
R`
O
+
a
R
O
R`
O
+
Example.2.13
OCO2Et
O
1
23
45
O
CO2Et
+
O
H
O
CO2Et
+
O
Example.2.14
EtO
OO
CN
Ph
a b EtO
O
CN
Ph O+
EtO
O
CN
Ph O+H
b
a
EtO
O
CN
OPh+EtO
O
CN
OPh+
-27-
Example.2.15
Ph Ph
CO2EtO
β
α
Ph Ph
CO2EtO
HO1
2
3
45
Ph
CO2Et
O
O CO2EtO
+ Ph
O
Example.2.16
O
Oαβ
1 2
3 4
5
O
OO
O
O
+O
12
3
45
OO
OMe
O
OMe
+
O
Example.2.17
Example.2.18
O O
O
H
O
O
H
+
-28-
Mannich reaction:
R CH3
O+ C
OH H
formaldehyde+ R'2NH
HR N
OR'
R'
mechanism:
R'2NHH
H OH
R'N
R'CH2 OH2
HR'
NR'
CH2
R CH2
O
CO
RCH2CH2NR'
R'
I Me
C
O
RCHCH2NR'
R'
Me HR
O
was attacked by N thus N bearing +ve charge make easy removeI Me NR'
R'
Me
Application for mannich reaction
O
+ R'2NH+ CH2O H
O
N R'
R'
O
mechanism:
R'2NHH
H OH
R'N
R'CH2 OH2
HR'
NR'
CH2
O
CH2NR'
R'
I Me
CH2NR'
R'
Me
O
OH O
-29-
** α-Hydroxy carbonyl compounds
Example.2.19
O
Ph 1O
2
345
O
PhO
Ph +
O
O O
+ CH2O
remember Mannich reaction
O
NR3
Example.2.20O
NR2
O
+ NR2CH2
O
+ CH2
OH
CH2 NR2HO
H
CH2 NHR2HO
O
+
O
+
O
+ CH2O + R2NH
NR2
Ph
PhCO
OH
OHα
Ph
PhO + COOH
or CN
Synthesis:
Ph Me
OCN
H
Ph
Ph
OH
CN
NaOHH2O
Ph
PhCO
OH
OH
T.M
-30-
CEtO2C
OHO
OH 12
C3
O
H + COOH
or CNOEtO
O
HCOEtO
COEtO
+
+ EtO H
O
COEtO
Br + CH2COOEt
Example.2.21
Synthesis:
OEtCH2C
C
O
O
OEt
OEt
CH2C
C
O
O
OEt
OEtOEt
EtO OEt
O+ C
H2C
OOEt
CH2C
OOEt Br
CO2Et
H
CO2Et CO2Et
HH CO
OEt
O
CN
HO/H2OCEtO2C
OHO
OH
OEt
-31-
Example.2.22
PhOH
OH
Ph OHOH
OH
O
EtO + 2PhMgBr
OH
O
H + CN
Synthesis:
CHO
CH2 O
CO
H
OHK2CO3
CNC
CN OH HO/H2O
HO
OH
OH
O
HO
EtOH/HOH
OH
O
EtO2PhMgBr
PhOH
OH
Ph OH
T.M
H
RCHO R CH
NH2CN R C
H
NH2COOH
mechanism:
R C HNH3
NH3
R C
OH
H
NH2
R C H
NH
CN RHC CN
NH2
HO/H2O RHC COOH
NH2
O
NH3
CN
Reminder:
HOOC NH
H
NHH+ CN
Example.2.23
OH+ NH3
-32-
Reminder:
O
COH
HLiAlH4
Example.2.24
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
HO
HO
OPh
Ph O+
Ph
Ph
O O
FGI
Ph
Ph
OHEtO H
O
+2PhCH2MgBr
Synthesis:
Ph C HO
CN Ph HOHC
OHOHO/H2O
Ph MgBrOHPh
Ph O
CrO3 OPh
Ph O
H CO
OEt + 2PhCH2MgBr
Ph
Ph
OHCrO3
Ph
Ph
O
OPh
Ph O
Ph
Ph
O
Ph
Ph
Ph
Ph
HO
HO
Hacid
heat
Ph
Ph
Ph
PhO
T.M
+
-33-
** 1,2-diol
KMnO4
or OsO4
OHHO
hydrationOHOH
OHOH Al2O3
Reminder:
One useful radical reaction is the pinacol reduction:
OMg - Hg
benzene
OHHO
OHHO FGI O+
PPh3
remember Witting reaction
Example.2.25
Ph
OHOH
Ph O +Ph3P
Ph
Example.2.26
O
O
H
H
CO2Me O HO
HO
H
H
CO2Me+
CO2Me CO2Meα
β
α−β unsaturated carbonyl
+
-34-
rearrangementPinacolone -The Pinacol**
R1
R2
R4
R3
OHHOH
R1
R4
R3
O
R2
mechanism:
R1
R2
R4
R3
OHHO HR1
R2
R4
R3
OH2HO R1
R2
R4
R3
HO
R1
R4
R3
O
R2
Example.2.28
OOH OH
OH
reverse -pinacol
rearrangement
pinacol
reduction2
O
O Mg - Hg
benzene
OH OHH+
OH2 OH
Synthesis:
T.M
Example.2.27
CO2HCO
H + Ph3P CH2 CO2H
+ CO
Hα
β
OHOH
FGI
-35-
(CH2)n
CO2Et
CO2Et
Na
Xylene(CH2)n
C O
CHOH
A closely allied reductive linking of carbonyl groups is an intramolecular version with esters, called the acyloin reaction, which again gives a 1,2-dioxygenated skeleton:
Example.2.29
O
OH
CO2Et
CO2Et
2 +
CO2Et
CO2Etacyloin Diels–Alder
-36-
Example.2.30
OMe
CO2Et
CO2Et
OMe
CO2Et
CO2Et
OMe
+C
C
CO2Et
CO2Et
Synthesis:
CH3
OH
Br2/light
CH2Br
OH
Me2SO4
CH2Br
OMe
i) Ph3Pii) Baseiii) Ph CHO
HC
OMe
Ph3P
Ph
CO
H
OMe
OMe
C
C
CO2Et
CO2Et
OMe
CO2Et
CO2Et
T.M
OMe OMe
HO
CH2Br
OH
+
Ph
CO H
-37-
:Robinson reaction-Allan**
Synthesis of flavones
Example.2.31
CO2Et
CO2EtO
CO2Et
CO2EtO O +
C
C
CO2Et
CO2EtSynthesis:
OC
C
CO2Et
CO2Et
CO2Et
CO2EtO
T.M
O
OH
R
R' O R
O O
R'CO2Na
O R'
RO
mechanism:
O
OH
R
H R'CO2Na
O
OH
R
R' O R
O O
O
OH
R
R'
O
O
O
HOR'H
R
O
O
R'
R
-38-
Napieralski reaction-Bischler**
Synthesis of dihydro isoquinoline from β-phenylethylamide using phosphorus oxychloride.
HN
R O
POCl3N
R
mechanism:
HN
RO
Cl2PO
Cl HN
R OPOCl2
N
R OPOCl2
H NH
R OPOCl2
H
N
RExample.2.32
H2CFGI
H3COH O
+ Ph3P CH2
Synthesis:
Br CH3i) Ph3Pii)base Ph3P CH2
O PPh3
CH2
O PPh3CH2
-39-
Bartoli Indol synthesis **
Synthesis of 7-substituted indol from Ortho-substituted nitro benzene and vinyl Grignard reagent.
Example.2.33
N N
HOH
NO H
+
Synthesis:
NO H
+
N
HOH acid
heat
N
mechanism:
NO
O
MgBr
N
O
O
MgBr
N
O
MgBrN
O
MgBr
NO
H
MgBr
NO
H H
H
MgBrH HO
NH
NO2R
NH
MgBri)
ii) H3O
-40-
** Benzilic acid rearrangement
Rearrangment of Benzil to Benzilic acid via aryl migration.
Benzoin condensation **It's a cyanide-catalyzed condensation of aryl aldehyde to Benzoin.
ArC Ar
O
OKOH Ar
C OH
OH
O
Ar
mechanism:
ArC Ar
O
O
OH
Ar C O
O
ArOH Ar
C OH
O
O
ArAr
C O
OH
O
Aracidicworkup
ArC OH
OH
O
Ar
a proton transfer leads to formation of carboxylate anion
Benzil Benzilic
HAr
O
CN ArAr
O
OH
Benzoinaryl aldehyde
mechanism:
HAr
O CNAr
CNH
OAr
CNH
OHAr
CN
OH Ar H
O ArAr
O
OH
CN-H+H
Protontransfer
ArAr
OH
O
CNAr
ArO
OH
Reminder:
Ar
CN
HOH
such H bond to Carbon connect with two electron withdrawal groups thus this H is Acidic.
-41-
Birch reduction **
The reduction of aromatic substrates with alkali metal, alcohol in liquid ammonia , known as “Birch reduction”
.Benzene ring with an electron donating substituent )1
:Benzene ring with an electron withdrawing substituent)2
W
W=CO2H,CO2R,COR,CONR2,CN,Ar
Na,liq,NH3
+e-
W W W
H H NH2
W
H H
+e-
W
H H
H NH2
WRadical anion
W
X
Na,liq,NH3
ROH
X
X=OR,R,NH2
Single Electron Transfere
SET
X X
H
H
Radical anion
H ORH
H
H
X
+e-
X
HH
H
X
H OR
X
-42-
:References
1) Stuart G. Warren; designing organic synthesis , John Wiley,1978
2) CM3001 Dr.Alan Ford (lab 415) ,text :Willis&Wills organic Synthesis (OUP)