advanced organic synthesis chem 640 dr. nabila al-jaber [email protected] 1431-1432
TRANSCRIPT
9 .Latent PolarityThink about some of the reactions we've looked at for carbonyl compounds:
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10. Latent polarity in bifunctional compoundsConsider a 1,3-disubstituted molecule, e.g.
O
Ph
OH
Latent Polarities:
starting from C=O
starting from C
O
Ph
OH
O
Ph
OH
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O
Ph
OH
O
Ph
OH
+ PhCHO
O OH
Ph
O
Obase
O
Acidic protne
Cross Aldol
PhCHOO O
Ph
Thus
H3O+
Na2SO4
- H2O
O
Ph
TM2 TM
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R R
O O
R R
O O
e.g.
R
O
+R
O
NaOH
R
OR R
O O
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But what about 1,4-disubstitution?
O
O
O
O
O
O
O
O
O
?
+ base
synthons
equivalents
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O
base
O
O
Br
O
BrO
O
O
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The German word UMPOLUNG, meaning polarity reversal is used to describe the situation where the polarity in a compound is deliberately changed to facilitate a particular reaction.
example:
H
O
H
SS
Li
SS
+
+
reacts withnucleophiles
reacts withelectrophiles
acidic proton(pKa ~ 32)
HS SH
cat. BF3·OEt2
n-Butyllithium
H
SSH
OH
- H2O
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11. Strategy in retrosynthesis
1) Consider different possibilities. 2) Try a number of disconnections and FGI's. 3) Try to keep the number of steps down, and stick to known & reliable reactions. 4) In real life, a synthesis has to be economically viable. 5) Whenever possible, go for a convergent route rather than a linear one, as this will lead to a higher overall yield
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Let, 2/11-10-201011
ABCDEF ABCDE + F
ABCD + EF
AB + CD , E + F
A + B , C + D
ABCD + E
ABC + D
AB + C
A + B
linear
Linear vs. convergent synthesis assume 80% yields (optimistic!)
eg.
A AB ABC ABCD ABCDE ABCDEF A...K A......Pstep 1 2 3 4 5 ...10 ...15
approxoverall yield: 80% 64% 51% 40% 32% ...10% ...3.5%
A AB
E EF
C CDABCD
ABCDEF
80% 64%
G...K
L...P
A...KA......P
51% 40% 32%
Linear:
Convergent:
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12. Aim for the greatest simplification
1. make disconnections towards the middle of the molecule (this is more convergent anyway)2. disconnect at branch points3. use symmetry where possibleeg. (towards the middle)
Ph
O O
Ph
O O
Ph
O
base
MVK Ph
O O
O
methyl vinyl ketoneMVK
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eg. (at branches)
Ph
O
CO2EtPh
O
CO2Et
Ph
O
CO2Et
NaOEt
Br
Ph
O
CO2Et
Ph
O
CO2Et
?
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eg. (look for symmetry)
O O
HO
O
HO
NaOEt
self -condensation
H2O
OO
O
O
HO
O
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Alternatively, potentially reactive groups can be protected or masked so they don't react, eg. reduction of an ester in the presence of a ketone
Ph
O
CO2Me
HO
OH
cat. TsOH
OO
Ph
CO2Me
Ketal(stable to bases and
nucleophiles)
OO
Ph OH
LiAlH4
Et2O
H3O+
Ph
O
OH
Note that protection strategy requires two extra steps (must be efficient); better syntheses minimise the use of protecting groups.
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OEt
O O
O
Sometimes it helps the retrosynthesis if you add a functional group to facilitate bond formation (Functional Group Addition, FGA). An example of this is acetoacetic ester synthesis:
Thus:O O
CO2Et
Bu
FGA
CO2Et
O
CO2Et
Odiscon. discon.
SM, Ethylaceto acetate
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The synthesis therefore is
O
Bu
O
CO2Et
Bu
CO2Et
O
NaOEtBuBr
NaOEt
O
CO2H
Bu
H3O+
CO2
CO2Et
O
MeICO2Et
O
Acidic proton
TM
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13. Ring Closing ReactionsSynthesis of carbocyclic moleculesSame approach as to acyclic systems. The probability of reaction between two functional groups is higher if:
a) reaction is intramolecular (faster reaction)b) the distance between the two groups is shorter
e.g. Intramolecular alkylation:
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EtO2C CO2Et EtO2C CO2Et EtO2C CO2Et
X
EtO2C CO2Et
NaOEt
BrCH2CH2CH2CH2Br
EtO2C CO2Et
Br
NaOEt
EtO2C CO2Et
H3O+
heatCOOH
Cyclopentanoic acid
e.g. Intramolecular alkylation:
Intramolecular acylation eg. the Dieckmann cyclisation; especially good for 5-membered rings:
NaOEt
O
CO2Et
O
CO2Et
EtO2C
CO2Et
NaO OEt
CO2Et
O
CO2Et- NaOEt
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Condensation:
O O
OH
O
OH
O O
t-BuOK
O
OH
O
1-(2-methylcyclohex-1-enyl)ethanone
nonane-2,8-dione
acidic proton
- H2O
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MeO2C(CH2)7CO2MeNaH
ester added overnine days
(CH2)6
CO2Me
O
EtO2C(CH2)14CO2Et (CH2)13
CO2Et
O
"
14. Medium and Large Rings (8-11 membered and 12+)Intramolecular reaction is less favoured with bigger rings. Often, high-dilution conditions and slow addition can be used to suppress intermolecular reaction and hence promote ring closure.
eg.
similarly
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15. Cycloaddition reaction (Diels-Alder)Generic reaction (in retrosyntheic terms):
XX X = EWG(CHO, CO2R, CN)
electron rich electron pooreg
CO2Me CO2Me
concerted reaction
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Unsymmetrical Diels-Alder reactions:
R' R'
R
+
RR
R'
Major product Minor product
R'
+
Major product Minor product
R R
R'
R R'
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note that the 1,3-disubstituted product is the minor product in both cases
CO2Me CO2Me
CH3
+
CH3CH3
CO2Me
61% only 3%
16. Disconnections & Functional Group Interconversion in Aromatic SystemsSome reactions used in aliphatic systems don't apply for aromatic systems (SN1 and SN2 reactions, for example, are extremely unfavourable for ArX.
R
O O
R PhH + RCOCl + AlCL3
Friedel-Crafts acylation
eg.
RCOCl AlCl3
R
O
R
O
H
RCO
RCO
i)
ii)
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In planning synthesis of polysubstituted aromatics, the order of reactions is important to ensure that the reagents are compatibleand to take advantage of the directing effect of existing substituents:
Group Directs Activation
NH2, NR2OH, O-
NHAc, ORalkyl/aryl/vinylCO2
-
X (halogen)CO2HCNCOR, CHOSO3HCX3NO2
ortho/para-*
meta-
activating
neutral
deactivating
(more)
(more)
note that ortho/para- mixtures can be formed and may have to be separated
*
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Examples
CO2Et
H2N
benzocaine (painkiller)
f rom toluene
H2N
CO2H
O2N
CO2H
H2N
HNO3
H2SO4
KMNO4
NO2
CO2H
NO2
H2 Pd/C
CO2H
NH2
EtOH
H+T.M.
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CO2Et
H2N
benzocaine (painkiller)
f rom toluene
H2N
CO2H
O2N
CO2H
H2N
HNO3
H2SO4
KMNO4
NO2
CO2H
NO2
H2 Pd/C
CO2H
NH2
EtOH
H+T.M.
17. Birch ReductionPartial reduction of aromatic systems by (usually) sodium in liquid ammonia. It's an example of dissolving metal reduction.
Such methods used to be quite popular but most applications have been replace by modern hydride reagents.
Dissolving metal reduction does still have it's uses thoughand the Birch reduction is one of them, . (also recall the specific reduction of alkynes totrans-alkenes).
The typical conditions involve liquid ammonia (bp. −33 °C) and sodium metal,in the presence of a proton source (usually an alcohol, EtOH).
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EWG
EDG EDG
EWGNa, NH3 (l), EtOH
"
eg EWG = CO2H, NO2
eg EDG = Me, OMe
18. Fusing Rings onto aromatic systems
The classical Hayworth naphthalene synthesis. The fused aromatic system is formed by dehydration of a tetralin intermediate, which is prepared from an existing benzene ring and succinic anhydride.
O
CO2H
discon.
FGI
O
O
O
+
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Thus:
33
AlCl3
O
HO2C HO2C
Zn-Hg/HCl
Clemmensen
OOO
i) SOCl2ii) AlCl3
O
tetralone
RR
i) RMgx
ii) H3O+
Pd/C
via enamineRBr
O
R
i) LiAlH4
ii) H3O+
R
Pd/C
R
1-subtitution (aka -)
2-subtitution (aka -)
intramolecularFC
Dehydrogenation
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19. Blocking positions in aromatic rings19. Blocking positions in aromatic rings
Functional groups that are introduced reversibly, or can be easily Functional groups that are introduced reversibly, or can be easily cleaved under mild condtions, can be used to access otherwise cleaved under mild condtions, can be used to access otherwise hard-to-make compoundshard-to-make compounds
Et Et
SO3H
Et
SO3H
Br
Et
BrSO3
H2SO4
Br2
FeBr3
dil.
H2SO4
NH2 NH2
Br
Br Br
Br
Br Br
Br2NaNO2/HCl
H3PO2
1-bromo-2-ethylbenzene
1,3,5-tribromobenzene
TM
TM
N2+
Br
Br Br
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You have to know the terminology of You have to know the terminology of stereochemistrystereochemistry
a) Chiral, achiral compoundsa) Chiral, achiral compounds.. b) Stereogenic, nonstereogenic centersb) Stereogenic, nonstereogenic centers..
c) Enantiomers, diastereomersc) Enantiomers, diastereomers.. d) Prochiral, prostereogenicd) Prochiral, prostereogenic..
e) Enantiotopic, diastereotopic atoms and facese) Enantiotopic, diastereotopic atoms and faces . . f) Ways of drawing stereochemistryf) Ways of drawing stereochemistry..
g) For two adjacent stereocenters, we can useg) For two adjacent stereocenters, we can usei. (R) and (S)i. (R) and (S)
ii. For cyclic structures, cis and transii. For cyclic structures, cis and transiii. threo and erythro (very old-fashioned)iii. threo and erythro (very old-fashioned)iv. syn and anti (for a chain drawn in zigzag fashion)iv. syn and anti (for a chain drawn in zigzag fashion)v. like and unlike (only Europeans use this one)v. like and unlike (only Europeans use this one)
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