Modern Organic Chemistry and terms used in Retrosynthesis

1. RETROSYNTHETIC APPROCH
TO ORGANIC SYNTHESIS
[CHO- 353] [Part – B]
Prof. Gaikwad Abhijit A.
M.Sc. B.ed. SET, TIFR.
Department of Chemistry
N.V.P. Mandal’s College Lasalgaon

2. BASIC
CONCEPTS
(Part 1)

3. CONTENTS
1. Definition of synthesis
2. Importance of synthesis
3. Polarity of bonds
4. Arrow notations
5. Basic concepts of Retrosynthesis

4. READING MATTERIALS

5. DEFINATION
The preparation of a desired
organic compound from a readily
available starting material is known
as organic synthesis
[Synthesis---- singular]
[Syntheses--- plural]

6. DESIRED ORGANIC
COMPOUND
The compound we wish to
prepare
It is called Target Molecule
Desired Organic Compound
is denoted by TM

7. STARTING MATERIAL
Readily available
Commercial
Inexpensive
contains five carbon atoms
or less apart from aromatic
ring

8. OBJECTIVE
To get a pure sample of the
desired organic compound
 To avoid the reactions that
will produce a mixture of
products

9. PURE COMPOUND
To study
2. Physical properties
3. Chemical properties
4. Pharmacological
properties

10. Reasons for synthesizing
Organic Compound
1. Proof of structure of a natural
compound
2. To prepare compounds that are
useful to mankind e.g.
pharmaceutical, polymers, dyes etc.

11. Reasons for synthesizing
Organic 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.

12. SOME FASCINATING
COMPOUNDS

13. BOND POLARITY
(Polar covalent bond)
 Most heteroatom are more
electronegative than carbon
i.e. O, N, Br, Cl,
 Partial positive charge appears
on carbon (+)

14. BOND POLARITY
(Polar covalent bond)
 Si, Mg,Li are electropositive
compared with the carbon
 The polarity in these case is
reversed
 partial negative charge
appears on carbon (-)

15. ARROW NOTATION
Simple reaction arrow “reacts to give”
Delocalisation arrow
“two different ways to draw the same
Curved arrow
delocalised structures”
Equilibrium arrow
“two structures are interconverting”
Fish-hook arrow
“motion of two electrons”
“motion of one electron”
Retrosynthesis
arrow
“could be made from”

16. RETROSYNTHESIS
It is reverse of the synthetic steps
We have a reliable reaction in mind

17. RETROSYNTHETIC ANALYSIS
1.The process of WORKING BACKWARD
from the TM in order to devise suitable
synthetic route
2.Retrosynthetic Analysis can be done
bytwo methods
a) Disconnection
b) Functional Group Interconversion

18. DISCONNECTION
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

19. JIGSAW PUZZLE
(Target Puzzle)

20. PUZZLE
(Disconnection)

21. H H
TM
PATH1
H H
R1 C C R2
PATH 2
R1
H
C+
+ C R2
H
H
_
H
H
R1 C
H
_
+
H
H
C R2
+
DISCONNECTION OF C-C
SYNTHONS

22. FUNCTIONAL GROUP
INTERCONVERSION (FGI)
The process of writing
one functional group for
another to help synthetic
planning is known as FGI

23. FUNCTIONAL GROUP
INTERCONVERSION (FGI)
FGI can be done by
 ADDITION
 SUBSTITUTION
 ELIMINATION
 OXIDATION / REDUCTION
 FREE RADICAL REACTION

24. SYNTHONS
These are idealized fragments
Synthons are shown by a + or
– sign like anion or cation
(Not real anion or cation)
May or may not be intermediate
in the corresponding reactions

25. 25
1. Introduction
• Synthon term was coined by Prof. E.J.Corey in mid 1960’s
• Elegant and more systematic approach
• .
• Depends on perception of structural feature in the reaction product and manipulation of
structures in the reverse synthetic sense.
• Designate ‘structural units within a molecule which are related to possible synthetic
operations’.
• Helps in eliminations of low probability variants.

26. Target
Molecul
e
Disconnect
ed
Precursors
• This process of analysis produces simple starting material and shows different
pathway.
•From this precursor the cheap starting material has been selected for the synthesis
of the target molecule or desired molecule.
26
Process called
Analysis

27. 27
-
•Synthon can be divided in to following two types – They
are derived from a reagents with functional groups
1. Donor Synthon eg. - C2H5 is ethyl donor synthon from - C2H5Li
2. Acceptor Synthon eg. - C2H5 is ethyl acceptor synthon from – C2H5I+

28. 28
2. Definition of Terms
a. Disconnection :
It is an imaginary process in which the bonds are broken to get simple possible starting
materials. This is also called as "transform". A curred line is used at the pointof
disconnection of bond and a double line arrow (=>) is used for representing
disconnection.
b. Synthon :
It is an idealized fragment obtained by disconnection and may or may not be
involved in the reaction but helps us to work out reagents to be used.
Example – R X => R+ + X- (Synthon)

29. Chemical bond can be cleaved :
29

30. a. Functional Group Identification :
It is the operation of changing one functional group to another either by interconversion,
substitution, elimination, oxidation or reduction, so that the disconnection becomes easier.
Example :
NO2
NH2
FGI
H3C COOH H3C CN
FGI
30

31. 3. Basic Rules In Disconnection
•When one thinks of retrosynthetic analysis of a target molecule, it is a question ‘where
the disconnection is to be done?’. This is generally governed by certain rules:
Rule -1
Disconnection of a bond should be done in such a way that it produces stable fragments.
While carrying out a disconnection the molecule is broken down by one bond at a time.
e.g. O2N
R
-C NO2 +
31
C R+

32. Rule -2
The number of fragments generated by disconnection should be as small as possible. So,
the synthesis of target molecule can be carried out in possible steps.
e.g.
O O O O
32
+

33. Rule -3
A bond joining a carbon to a hetero atom always broken with the electron pair onhetero
atom. e.g
Rule -3
Sometimes a disconnection carried out does not generate sufficient stabilised fragments,
but such fragments can be obtained by using FGI or by introducing an additional electron
withdrawing group and then removing it after synthesis.
C N C
+
+ N
-
33

34. 34
Guidelines For Disconnection :
(i) Make the analysis in such a way that the synthesis become as short as possible.
(ii) Use the only disconnections corresponding to known reliable reaction.
(iii) Disconnect C-X bonds especially two group disconnections.
(iv) Choose the disconnection corresponding to the highest yielding reaction, if known.
(v)Disconnect back to recognisable starting materials or to compounds which can be
easily be made.
(vi) Disconnect C-C bonds according to the functional groups in the molecule , if possible
- disconnect at the middle of the molecule.

35. 35
Guidelines For Good Synthesis :
In retrosynthetic approach, there are usually more than one way to synthesize a
compound. But the selection of a best desirable route is important. Thereafter the
following factors are considered in order to decide which one of the routes is safe and
simple to employ.
(i) Availability of starting material.
(ii) Which route involves the least number of separation operations ?
(iii) Which route gives the highest overall yield ?
(iv) How expensive are the starting materials and reagents ?
(v) Which route includes least time and effort ?

36. Retrosynthetic pathway : Benzocaine from
toluene
4. Use of Synthon In Synthesis of Some Medical or Organic
OEth
O
H2N
C-O
H2N
OH
O
FGI
O2N
OH
O
2O N
Me
C-NMe
Benzocaine :
• Toluene is readily available starting
material
• Me is activating and ortho-/para-
directing
• We know reagents for the synthon NO2
36

37. Me H2SO4
HNO3
CH3
O2N
KMnO4
Oxidation
2O N
OH
O
H2Pd/C
Oxidation
H2N
O
OH
EtOH/H
+
H2N
OEt
O
Synthesi
s :
37

38. SYNTHETIC EQUIVALENT
 The actual compound used to
function as synthon
Denoted by a triple line 
Known as REAGENT

39. Retrosynthetic analysis,
Synthons & Synthetic equivalents
………………………………………………………………………
R+
+
R-
R-
+
R+


R—R 
TM
 RMgBr, RLi, LiCuR2
Synthons Synthetic equivalents
 RBr, RI, ROMe, ROTs

40. DESIGNING A SYNTHESIS
Recognize the functional
groups in the target molecule
Disconnect by methods
corresponding to known and
reliable reactions
Repeat as necessary to reach
available starting material

41. SYNTHESIS
Write out the plan according
to the analysis, adding
reagents and conditions
Modify the plan according to
unexpected failure in the
laboratory

42. RETOSYNTHETIC ANALYSIS
Hawthorn perfume
MeO
O
TM
_
+
+
O
H
MeO
Cl
O
Path 1MeO
+
Path 2MeO
+
O
_
?
?

43. EFFECTIVE SYNTHESIS
An understanding of
reaction mechanism
A working knowledge of
reliable reactions

44. EFFECTIVE SYNTHESIS
An appreciation that
some compounds are
available
An understanding of
stereochemistry

45. 1st RETROSYNTHETIC ANALYSIS
CH3CH2OH
CH3 CH2 OH
TM
Path 1
3CH +
+
-
CH2OH
3CH Br
?
Path 2 CH3
-
+
+
CH2OH
CH3MgBr
H2C O

46. SYNTHESIS
CH3MgBr
CH3CH2OMgBr TM
H3O+

47. 2nd RETROSYNTHETIC ANALYSIS
CH3CH2OH & SYNTHESIS
FGI
CH3CHO
reduction
CH3 CH2 OH
TM
CH3CHO
SYNTHESIS
NaBH4
TM

48. 3rd RETROSYNTHETIC ANALYSIS
CH3CH2OH & SYNTHESIS
FGI
hydration
H2C CH2
SYNTHESIS
H2C CH2
3H O+
TM
CH3 CH2 OH
TM

49. 4th RETROSYNTHETIC ANALYSIS
CH3CH2OH & SYNTHESIS
FGI
SN2
CH3CH2Br
-
OH TM
CH3 CH2 OH
TM
SYNTHESIS
CH3CH2Br

51. BASIC
CONCEPTS
(Part 2)

52. CONTENTS
Examples of Retrosynthetic
analysis of:
 1-Phenylhexanol (TM 1.1)

53. RETROSYNTHETIC ANALYSIS
1-PHENYLHEXANOL
Ph CH3
OH
Ph CH3
O
FGI
(TM 1.1)

54. 1st RETROSYNTHETIC ANALYSIS
1-PHENYLHEXANOL
TM
Path 1
+
+ CH3
?
CH3
Br
Path 2
OH
Ph
+
CH3-
+
Ph H
O
CH3
BrMg
Ph CH3
OH
-
OH
Ph

55. SYNTHESIS
CH3
Br Mg
CH3
BrMg
Ph H
Et2O
O
CH3Ph
OMgBr
H+
/H2O
TM

56. 2nd
RETROSYNTHETIC ANALYSIS
1-PHENYLHEXANOL
Ph CH3
OH
TM
Path 1
Path 2
Ph+
+
-
OH
CH3
?
Ph-
+
+
CH3
OH
PhMgBr
PhBr
CH3H
O

57. SYNTHESIS
PhBr + Mg
Et2O
PhMgBr
PhMgBr +
CH3H
O
H+
/H2O
TM

58. 3rd
RETROSYNTHETIC ANALYSIS
1-PHENYLHEXANOL
OH
Ph CH3
Ph
OH
+
+
CH3
-
O
Ph
BrMg CH3
TM

59. SYNTHESIS
O
Ph
+
BrMg CH3
Ph CH3
OMgBr
H+
/H2O
TM

60. 4th
RETROSYNTHETIC ANALYSI
1-PHENYLHEXANOL
Ph CH3
OH
TM
FGI
CH3
O
Ph CH3
O
-Ph
Ph
O
+
+
CH3
Ph CH3
O
Br CH3

61. SYNTHESIS
Ph CH3
O i ) -
OEt
ii)
Br CH3 Ph CH3
O
LiAlH4
TM

62. 5th RETROSYNTHETIC ANALYSIS
Ph CH3
1-PHENYLHEXANOL
O
+
Ph
O
+
- CH3
Ph
O
2
LiCu(
CH3
)

63. SYNTHESIS
Ph
O
+ CH3
)
2
LiCu(
Ph CH3
O
TM
NaBH4

64. 6th RETROSYNTHETIC ANALYSIS
1-PHENYLHEXANOL
Ph CH3
O Ph
O
+
-
CH3
+
Ph
O
LiCu(CH3)2

65. SYNTHESIS
Ph
O
+
LiCu(CH3)2
Ph CH3
O
MeOH
NaBH4 /CuI
TM

66. What is the best
synthesis?
Availability of the reagent
Synthetic step should be
kept minimum unless there
is an advantage of FGI
Disconnection of C-C bond
should be in the center of a

67. Help Tim to get a nibble
of the Birthday Cake!

68. Help Tim get a nibble of
the Birthday Cake!

69. Help Tim get a nibble of
the Birthday Cake!

70. Help Tim get a nibble of
the Birthday Cake!

72. FUNCTIONAL
GROUPS
INTERCONVERSIONS

73. CONTENTS
 Definition of Functional Group
Interconversion (FGIs)
 Importance of FGIs
 Functional group containing
heteroatoms
 Unsaturated hydrocarbons
 Removal of Functional Groups

74. Definition of Functional
Group Interconversion
The process of writing
one functional group
for another to help
synthetic planning is
known as FGI

75. Definition of
Functional Group
Interconversion
 FGI can be done by
 Substitution
 Addition
 Elimination
 Oxidation
 Reduction

76. Why FGI is needed?
 A TM containing more than
one functional group, one
functional group may interfere
with desired reaction on
second functional group during
a synthesis.

77. Why FGI is needed?
 This problem can be solved
into ways
 a) Use of protecting group
 b) Change in synthetic strategy
(using FGI)

78. Importance of FGIs
 It helps in identifying suitable
disconnection.
 Consider the synthesis of
ketone containing a double
bond.
 Alkenes may be prepared by
the dehydration of alcohol.

79. Importance of FGIs
O
Ph Ph
TM
First step in the retrosynthetic
analysis of TM could be functional
group interconversion to an alcohol
But which alcohol ?

80. Importance of FGIs
Ph Ph
O
FGI
i
FGI
ii
Ph Ph
O OH
Ph
OH
Ph
OTM

81. RETROSYNTESIS
Ph Ph
O
FGI O OH
_
Ph
+
Ph
+
OH
Ph
O
H Ph
O
TM
O
Ph Ph
Matched Latent Polarity
(Consonant)
i

82. RETROSYNTESIS
Ph Ph
O
FGI
ii
Ph
OH
Ph
O
Mismatched Latent Polarity
(Dissonant)

83. Functional group
containing heteroatoms
For convenience these
functional groups will be
initially divided into three
major classes depending
upon their oxidation level

84. a) Carboxylic acid and their
derivatives
 Compounds in this class are the highest
oxidation level of organic compounds
 It includes
 Carboxylic acid (RCO2H)
 Esters/lactone (RCOO2R)
 Amide/lactam (RCONHR)
 They may be interconverted by a series
of simple reactions

85. Transformations of
carboxylic acid derivatives
R OH
O
R Cl
O
SOCl2
or PCl5
H2O
R NH2
ONH3
R OR'
O
H2OH2O
H+/
R’OH
RO-
R C N2H O
R O R'
O O

86. b) Aldehydes, ketones and
their derivatives
 Functional groups in this class
are at lower oxidation level
than class (a)
 It includes the features C=X in
which the carbon atom is
bonded directly to either
hydrogen or carbon.

87. b) Aldehydes, ketones and
their derivatives
 The group includes
 Aldehydes (RHC=O)
 Ketones (RR’C=O)
 Imines (RR’C=NR”)
 Hydrazones (RR’C=NNHR”)
 Oximes (RR’C=NOH)

88. Transformations of
aldehydes
O
R H
N
aldehyde
R' R’=alkyl, aryl,(imine)
R’=NMe2 (hydrazones)
R’=OH (oxime)
H2O R’NH2
S
H
S
H
2 3HS(CH ) SH/H+
H
R H
OR'R'O
R
2R’OH/H+

89. c) Alcohols and their
derivatives
 Apart from Alcohols (ROH)
themselves, this class includes
 Amines (RNH2)
 Thiols (RSH)
 Disulphides (RSSR)
 Ethers (ROR)
 Alkyl halides (RX)

90. Interconversions of
alcohols and halides
R OH R Cl
SOCl2 or
PCl5
HO-
R Br
HBr
HO-

91. Use of a sulphonic ester
as a leaving group
R OH R OSO2R'
R’SO2Cl
Nu-
R Nu + R’SO3
-

92. Interconversions between
the three oxidation levels
a,b & c above
 To move between groups
classified in the previous
section, it is necessary to
perform a reduction or
oxidation at some stage.

93. Oxidation
 Many methods have been
developed for the oxidation of
organic compounds.
 It is possible to transform a
low oxidation level FG into any
group of higher level.

94. Oxidation
R OH
H
O
Primary alcohol
PCC
or PDCR R OH
O
CrO3 /H+
Secondary alcohol
R R
OH
R R
O
PCC or PDC
PCC= pyridinium chlorochromate
PDC= pyridinium dichromate

95. Reduction
Esters
R OR'
O
R OH
LiAlH4
+
R’OH
Amides
R NH2
O
R NH2
LiAlH4
Nitriles
R CNR
LiAlH
NH2
4
H
O
1 eq.
DIBAL-H
Low temp. R

96. Unsaturated
Hydrocarbons
HO OH
CHO
CHO
OH
OH H
H2,Pd/C
OsO4
O3
HBr
Br
RCO3H
BH3,NaOH/
H2O2

97. Removal of Functional Group
Alcohol to corresponding hydrocarbon
Alcohol
Dehydration
Alkene
Hydrogenation
Alkane

98. Removal of Functional Group
R R'(H)
O
R R'(H)
H H
Wolf-Kishner
Zn,HCl
NH2NH2,KOH
Aldehydes/ ketones to hydrocarbons
Clemmensen