D1
V D. The Retrosynthetic Analysis Approach to Designing Organic Syntheses
A. Introduction:
The retrosynthetic approach to organic synthesis starts from the product and attempts to
determine what reactant molecules might be used to synthesize the target molecule (The desired
product) in one reaction step. We will consider the synthetic utility of Grignard reactions for
synthesizing alcohols. Note that both of the following Grignard reactions form the same product
but use different starting materials.
O
1. Ether
+
a.
CH3
CH2 Mg Cl
H
2. H3O+ H2O
O
H
H
H
O
1. Ether
+
b.
O
Mg Br
2. H3O+ H2O
H
H
1. What bonds are made in reaction a? Mark them on the product structure.
2. What bonds are made in reaction b? Mark them on the product structure.
3. How are the bonds made in the two reactions similar? How are they different?
4. What is the relationship between the C-C bond formed in each reaction and the OH group of
the alcohol in the product?
5. If the new C-C bonds were removed (disconnected), what additional changes would be
required to convert the product molecule back into the starting materials for each reaction?
6. Considering your discoveries in 1->5, suggest structures for starting materials that would
produce the target alcohol given below. Explain the logic you used to devise your starting
materials
H
O
3-ethyl-2-methyl-3-hexanol
V D: Retro Synthetic Analysis
D2
B. Synthesis of Alcohols: C-C Disconnections
1. Retrosynthetic Analysis
Look at the product molecule, find the alcohol OH and identify the bonds around the carbon
holding the OH. These are the bonds that could have been made by a Grignard reaction.
Disconnect each bond (C-C disconnections) in turn to reveal potential precursors for the
product. Then identify the reaction that will reveal the precursors of the Grignard reagent. In
the terminology of Retrosynthetic Analysis, a process such as the formation of the Grignard
reagent is a Functional Group Interconversion (FGI) since it changes the nature of the
functional group but does not change the carbon structure. So the retrosynthetic step for
formation of an organometallic reagent is symbolized by FGI Grig, since it is the formation
of a Grignard reagent.
Full Retrosynthetic Analysis for the synthesis of 3-ethyl-2-methyl-3-hexanol
(Starting materials in bold)
H
O
b.
O
a.
a.
c.
synthon
synthon
C-C
Disconnection
O
Mg Cl
FGI Grig
Cl
+ MgÞ
c.
C-C
Disconnections
b.
C-C
Disconnections
O
O
synthon
O
synthon
CH3
Mg Br
synthon
FGI Grig
Br + MgÞ
CH2
synthon
O
FGI Grig
CH3
CH2 Mg Cl
CH3
CH2 Cl + MgÞ
2. Synthesis based on retrosynthetic analysis b:
O
H
O
Br + MgÞ
Dry
Ether
1. Dry Ether
Mg Br
2. H2SO4/H2O
D3
V D: Retro Synthetic Analysis
3. An Additional C-C Disconnection Example
b.
a.
O
a.
c.
CH3
Mg Cl
FGI Grig
CH3 Cl + MgÞ
C-C
Disconnection
O
H
b.
C-C
Disconnections
c.
C-C
Disconnections
O
FGI Grig
CH3
CH2 Mg Cl
CH3
CH2 Cl + MgÞ
O
FGI Grig
Mg
+ MgÞ
Cl
Cl
4. Synthesis based on retrosynthetic analysis c:
O
1. Dry Ether
Dry
+
Cl
MgÞ
Ether
Mg
2. H2SO4/H2O
Cl
O
H
5. Class Discussion Problem on Alcohol Synthesis:
Use Retrosynthetic Analysis to devise a synthetic pathway for the following compound from
smaller molecules.
O
H
Then write a complete synthetic path, including reagents and reaction conditions based on
your retrosynthetic analysis.
V D: Retro Synthetic Analysis
D4
6. Out of Class Exercises on C-C disconnections in alcohol syntheses.
For our next lab discussion period, use retrosynthetic analysis to devise at least two syntheses
for the following compounds.
H
O
CH3
N
CH3
O
H
Then write complete synthetic paths, including reagents and reaction conditions based on
your retrosynthetic analyses.
Be prepared to discuss both the retroanalysis and the synthesis.
D5
V D: Retro Synthetic Analysis
C. Alkene Synthesis by Dehydration of Alcohols
1. Dehydration of Alcohols:
Dehydration of alcohols is induced by acidic conditions and (as we will see later) usually
occurs by a 2-step mechanism.
O
H
H2SO4
or
H3PO4
a
+
b
Major Product
a. What bonds are made and broken in forming product a? Mark them on the product
structure.
b. What bonds are made and broken in forming product b? Mark them on the product
structure.
c. How do the bonds made and broken in the two reactions similar? How are they
different?
d. What is the relationship between each bond made or broken and the OH group of the
alcohol reactant?
e. If the new bonds were removed (disconnected), what additional changes would be
required to convert each product molecule back into the starting material?
f. Considering your discoveries in 1->5, suggest structures for starting materials that would
produce the target alkene given below. Explain the logic you used to devise your starting
materials
V D: Retro Synthetic Analysis
D6
2. Retro Synthetic Step: FGI-Dehydration
Dehydration is another reaction that changes the functional group without altering the
sequence of the carbon chain. The retrosynthetic step is designated as FGI dehydration.
Usually FGI dehydrations can reveal two possible precursor compounds.
H
O
FGI
Dehydration
OR
FGI
O
H
Dehydration
Potential precursor alcohols can be revealed by adding an OH to either end of the C=C. The
choice of end will depend upon potential competing products.
Sample Retrosynthesis of an Alkene
Cl-Mg
b.
O
a. FGI
a.
C-C
H
Dehydration
H
O
H
C-C
Cl
Mgo
Grignard
FGI-M
Cl
Grignard
FGI-M
b. FGI
Dehydration
MgCl O
O
2 other C-C's
possible
Mgo
3. Out of Class Application:
For our next lab discussion period devise at least 2 different syntheses for each of the
following compounds from simple monosubstituted aromatic compounds and nonaromatic compounds with four or fewer carbon atoms.
Then write complete synthetic paths, including reagents and reaction conditions based on
your retrosynthetic analyses.
Be prepared to discuss both the retroanalysis and the synthesis.
D7
V D: Retro Synthetic Analysis
D. Oxidation of Alcohols to Ketones
1. Introduction:
In the previous section we learned how to use C-C disconnections, FGI’s of Grignard
reagents and FGI dehydrations to synthesize larger alkenes and alcohols from smaller ketones
or aldehydes and organic halides. This unit introduces methods for synthesizing ketones
from alcohols, another FGI, since these reactions change functional groups, but do not alter
the carbon structure of the reactant. The addition of this reaction to our synthetic repertoire
greatly increases our abilities to build larger molecules from a number of smaller molecules.
2. Oxidation of 2˚ Alcohols to Ketones:
Chromium Trioxide (CrO3) in acidic aqueous solution (H2SO4) is a common reagent for
oxidation of alcohols. This metal oxide reagent is a relatively strong oxidizing reagent. It
smoothly converts 2˚ alcohols to ketones.
O
HO H
H2 SO4
+
CrO3
H OH
O
H2 SO4
+
CrO3
3. FGI-oxidation:
The following FGI Retrosynthetic step indicates that the ketone can be synthesized from the
corresponding alcohol by oxidation.
O
H OH
FGI
oxidation
Although this is a simple addition to our reagent list, this oxidation increases our abilities to
synthesize complex molecules from relatively simple ones. Consider the potential synthesis
of the complex molecule shown below. One Grignard C-C disconnection reveals that the
target molecule can be synthesized from phenyl magnesium chloride and 2,5-dimethyl-4heptanone.
Cl
Mg
C-C disconnection
O
Grignard
O
+
H
With only the Grignard C-C disconnection, we were able to disconnect the carbon structure
of an alcohol only once.
V D: Retro Synthetic Analysis
D8
However, we now see that the ketone precursor revealed by the above disconnection can be
synthesized from a 2˚ alcohol as indicated on page 80 and reproduced below:
O
H OH
FGI
oxidation
This FGI reveals a compound that can be further disconnected with a Grignard C-C to reveal
even simpler synthetic precursors.
H OH
O
C-C disconnection
Grignard
Mg
+
Br
H
If we recall that Grignard Reagents can be synthesized from alkyl halides, we can look at the
entire synthetic pathway as a set of disconnections and FGI's. The starting materials are
enclosed in rectangles.
Mg
Cl
O
C-C disconnection
O
+
Grignard
H
FGI-M
FGI
Oxidation
O
H OH
H
C-C disconnection
+
+ Mgo
Grignard
Mg
Cl
Br
FGI-M
Br
+ Mgo
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V D: Retro Synthetic Analysis
4. Out of Class Application:
For our next lab discussion period use retrosynthetic analysis to devise syntheses for the
following compounds from monosubstituted aromatic compounds and non-aromatic
compounds with four or fewer carbon atoms.
OH
O
Then write complete synthetic paths, including reagents and reaction conditions based on
your retrosynthetic analyses.
Be prepared to discuss both the retroanalysis and the synthesis.