basic concepts of retrosynthesis (part1)
TRANSCRIPT
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RETROSYNTHETIC APPROCH APPROCH
TOTOORGANIC SYNTHESISORGANIC SYNTHESIS
Prof. Dr. Shaikh S. NizamiProf. Dr. Shaikh S. NizamiDepartment of ChemistryDepartment of Chemistry
University of KarachiUniversity of Karachi
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BASIC BASIC CONCEPTS
(Part 1)
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CONTENTS
1. Definition of synthesis2. Importance of synthesis3. Polarity of bonds4. Arrow notations5. Basic concepts of
Retrosynthesis
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READINGREADING MATTERIALS
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DEFINATION
The preparation of a The preparation of a desireddesired organic compoundorganic compound from a a readily available readily available starting starting materialmaterial is is known as organic as organic synthesissynthesis
[Synthesis---- singular][Synthesis---- singular]
[Syntheses--- plural][Syntheses--- plural]
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DESIRED ORGANIC ORGANIC COMPOUNDCOMPOUND
The compound we wish to prepare
It is called Target MoleculeDesired Organic Compound is denoted by TM
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STARTINGSTARTING MATERIALMATERIAL
Readily availableCommercialInexpensivecontains five carbon atoms or less apart from aromatic ring ring
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OBJECTIVEOBJECTIVE
To get a pure sample of To get a pure sample of the desired organic the desired organic compoundcompound
To avoid the reactions To avoid the reactions that will produce a that will produce a mixture of productsmixture of products
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PURE COMPOUNDPURE COMPOUND
To studyTo study
1.1. Physical propertiesPhysical properties
2.2. Chemical propertiesChemical properties
3.3. Pharmacological Pharmacological propertiesproperties
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Reasons for synthesizing Reasons for synthesizing Organic CompoundOrganic Compound
1. Proof of structure of a natural 1. Proof of structure of a natural compoundcompound
2. To prepare compounds that are 2. To prepare compounds that are useful to mankind e.g. useful to mankind e.g. pharmaceutical, polymers, dyes pharmaceutical, polymers, dyes etc.etc.
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Reasons for synthesizing Reasons for synthesizing Organic CompoundOrganic Compound
3. To prepare specific compounds to study reaction mechanisms or biological metabolism e.g. labelled compounds
4. For the intellectual challenges – new problems demand new solutions and can lead to the development of NEW CHEMISTRY, reagents, etc.
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SOME FASCINATING SOME FASCINATING COMPOUNDSCOMPOUNDS
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BOND POLARITYBOND POLARITY(Polar covalent bond)(Polar covalent bond)
Most heteroatom are more Most heteroatom are more electronegative than electronegative than carbon carbon i.e.i.e. O, N, Br, Cl, O, N, Br, Cl,
Partial positive charge Partial positive charge appears on carbon (appears on carbon (+)+)
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BOND POLARITYBOND POLARITY(Polar covalent bond)(Polar covalent bond)
Si, Mg,Li are electropositive Si, Mg,Li are electropositive compared with the carboncompared with the carbon
The polarity in these case is The polarity in these case is reversedreversed
partial negative charge partial negative charge appears on carbon (appears on carbon (-)-)
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ARROW NOTATIONARROW NOTATION
Simple reaction arrow “reacts to give”Delocalisation arrow
“two different ways to draw the same delocalised structures”Equilibrium arrow
Curved arrow“two structures are interconverting”
“motion of two electrons”Fish-hook arrow “motion of one electron”Retrosynthesis arrow
“could be made from”
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RETROSYNTHESISRETROSYNTHESIS
It is reverse of the synthetic steps
We have a reliable reaction in mind
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RETROSYNTHETIC ANALYSISRETROSYNTHETIC ANALYSIS
1.1.The process of WORKING The process of WORKING BACKWARD from the TM in order to BACKWARD from the TM in order to devise suitable synthetic routedevise suitable synthetic route
2. Retrosynthetic Analysis can be done by two methods
a) Disconnection
b) Functional Group Interconversion
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DISCONNECTIONDISCONNECTION
1.A paper operation involving an imagined cleavage of a bond.
2.As a result of disconnection usually negative ion and positive ion are formed which are called ‘SYNTHONS’
3.Disconnection is shown by a wavy line like ~ or VVVVVVVV
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JIGSAW PUZZLEJIGSAW PUZZLE(Target Puzzle)(Target Puzzle)
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PUZZLEPUZZLE(Disconnection)(Disconnection)
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DISCONNECTION OF C-CDISCONNECTION OF C-C
R1 C C
H
H
R2
H
H
TM
PATH 1
PATH 2
R1 C
H
H
+ + C R2
H
H_
R1 C
H
H
_+ C R2
H
H+
SYNTHONS
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FUNCTIONAL GROUP FUNCTIONAL GROUP INTERCONVERSION (INTERCONVERSION (FGIFGI))
The process of writing The process of writing one functional group one functional group for another to help for another to help synthetic planning is synthetic planning is known as known as FGIFGI
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FUNCTIONAL GROUP FUNCTIONAL GROUP INTERCONVERSION (INTERCONVERSION (FGIFGI))
FGI can be done by FGI can be done by ADDITION ADDITION SUBSTITUTIONSUBSTITUTION ELIMINATIONELIMINATION OXIDATION / REDUCTIONOXIDATION / REDUCTION FREE RADICAL REACTIONFREE RADICAL REACTION
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SYNTHONSSYNTHONS
These are idealized fragmentsThese are idealized fragmentsSynthonsSynthons are shown by a are shown by a ++ or or
–– sign like anion or cation sign like anion or cation (Not real anion or cation)(Not real anion or cation)
May or may not be May or may not be intermediate in the intermediate in the corresponding reactionscorresponding reactions
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SYNTHETIC EQUIVALENT
The actual compound used The actual compound used toto
function as synthon function as synthon Denoted by a triple line Denoted by a triple line Known as REAGENTKnown as REAGENT
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Retrosynthetic analysis,Retrosynthetic analysis,Synthons & Synthetic Synthons & Synthetic
equivalentsequivalents
R—R ………………………………………………………………………
R+
+
R-
R-
+
R+
TM
RBr,RI,ROMe,ROTs
RMgBr, RLi, LiCuR2
SynthonsSynthetic equivalents
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DESIGNING A SYNTHESISDESIGNING A SYNTHESIS
Recognize the functional Recognize the functional groups in the target moleculegroups in the target molecule
Disconnect by methods Disconnect by methods corresponding to known and corresponding to known and reliable reactionsreliable reactions
Repeat as necessary to reach Repeat as necessary to reach available starting materialavailable starting material
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SYNTHESISSYNTHESIS
Write out the plan Write out the plan according to the analysis, according to the analysis, adding reagents and adding reagents and conditionsconditions
Modify the plan according Modify the plan according to unexpected failure in to unexpected failure in the laboratorythe laboratory
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RETOSYNTHETIC ANALYSISRETOSYNTHETIC ANALYSIS Hawthorn perfumeHawthorn perfume
MeO
O
TM
_
MeO+
+
O
H
MeO
Cl
O
Path 1
---------------------------------------------------------------------
Path 2
+
MeO+
_O
?
?
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EFFECTIVE SYNTHESIS
An understanding of An understanding of reaction mechanismreaction mechanism
A working knowledge A working knowledge of reliable reactions of reliable reactions
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EFFECTIVE SYNTHESIS
An appreciation that An appreciation that some compounds are some compounds are available available
An understanding of An understanding of stereochemistrystereochemistry
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11stst RETROSYNTHETIC ANALYSISRETROSYNTHETIC ANALYSIS CHCH33CHCH22OHOH
CH3 CH2 OH
TM
Path 1
CH3+
+-CH2OH
CH3Br
?---------------------------------------------------------------------
Path 2 CH3-
++CH2OH
CH3MgBr
H2C O
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SYNTHESISSYNTHESIS
CH3MgBr
CH3CH2OMgBr TMH3O
+
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22ndnd RETROSYNTHETIC RETROSYNTHETIC ANALYSISANALYSIS
CH CH33CHCH22OH & OH & SYNTHESISSYNTHESIS
CH3 CH2 OHFGI
CH3CHOreductionTM
SYNTHESIS
CH3CHONaBH4
TM
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33rdrd RETROSYNTHETIC ANALYSIS RETROSYNTHETIC ANALYSIS
CH CH33CHCH22OH & OH & SYNTHESISSYNTHESIS
CH3 CH2 OHFGI
hydrationSYNTHESIS
H2C CH2
H2C CH2H3O
+
TM
TM
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44thth RETROSYNTHETIC RETROSYNTHETIC ANALYSISANALYSIS
CH CH33CHCH22OH & OH & SYNTHESISSYNTHESIS
CH3 CH2 OHTM
FGI
SN2CH3CH2Br
CH3CH2Br-OH TM
SYNTHESIS