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Retrosynthesis Putting Reactions Together (more...)

• A large part of organic chemistry involves building more complex molecules from smaller ones using a designed
sequence of reactions, i.e. chemical synthesis. Especially in more complex cases, synthetic problems are often
best solved BACKWARDS in a process know as retrosynthetic analysis

1 Retrosynthetic Analysis : The Synthon (more...)

The most important concept from First Semester Organic : Lewis Acid/Base reactions
• explains bond formation in products
• Lewis Base provides the electrons and Lewis Acid accepts the electrons to make the bond
X Y X Y
L Base L Acid
New concept : the Synthon
• explains bond formation from reactants
X Y X Y
synthon synthon arrow means
provides electrons accepts electrons "comes from"
• the synthons indicate where the electrons come from to make the bond
• the synthons are usually not "real", and have to be converted into "real" reactants
• one synthon must temporarily carry an electron pair, the other often needs a group that "leaves" as the new
bond is made

Example 1
• disconnect the O-C bond
• "put" the electrons on the synthon where they would be most "temporarily" stable
• the other synthon is chosen to have a suitable "leaving group" the other

electrons lower
in energy on O HO HO
compared to C synthon
synthon
add a leaving group in the real reactants here to generate an "effective" positive charge
• convert to "real" reactants (synthetic equivalents), the following reaction makes the provided alcohol
Br SN2
Na HO + HO

reactant reactant
• the benzyl bromide reactant, has a weak bond to Br– leaving group

Example 2
• disconnect the indicated C-C bond
• one of the carbons must carry the electron pair, one the leaving group, which is best?
H2
N C H 2C C
CH CH3 H2 H2
CH3 C C
OR C CH CH3
N
H2 CH3
N C H2C C
CH CH3
better synthons CH3
• convert to "real" reactants (synthetic equivalents)
Br H2 H2
H2 C C
C Na SN2
N + H2C C C CH CH3
CH CH3 N
CH3
CH3
Retrosynthesis 1 Copyright, Arizona State University
Example 3 : disconnect the indicated bond (this is a reaction you have not yet seen)

O
H3C
O
OR
CH3
O
H3C
better synthons
• convert to "real" reactants (synthetic equivalents)
O Li
nucleophilic O
H3C Li
addition
CH3
• in this case the "leaving group" is the C-O pi-bond
• synthon reterosynthetic strategy is an advanced organic chemistry concept
• however, we don't analyze every forward reaction in terms of Lewis acid/base, we don’t have time, we just
know the reactions forwards!
• similarly, we won’t analyze every reverse reaction in terms of synthons, we won’t have time, we will just know
the reactions backwards!

2 SN2 Reactions Revisited : Practice Doing Reactions in Reverse (more...)

• how would you make the following molecules using the SN2 reaction??
• emphasis is on recognizing which bond you can make, and identifying the synthons and thus reactants...
Example 1
disconnect A disconnect
CH3 bond A CH3 bond A CH3
B
H3C C H3C C O H3C C O
O
CH CH3
CH3 CH3 CH3 3 CH3

synthons BETTER synthons

Y CH3 CH3
3 halide no SN2 here
Na X H 3C C O H3C C O H3C Br
CH3
CH3 CH3 Na Y
H 3C C Br Nuc. CH3 1 halide
O
SN2 allowed, thus better synthons, only way to do the reaction
CH3 X CH3

Example 2

A Na
Make bond A B S
OTs Na S S Make bond B

OTs
Y
1 tosylate
preferred method

• 2Y tosylate better than 2Y halide, but still not as good as 1Y anything!

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 Copyright, Arizona State University
Retrosynthsis PROBLEMS Identifying Synthons
In each case identify the best synthons for disconnection of the indicated bonds
Ph
1 Answer
(standard) HO C Me Correct Y / N
H
MeO OH
2 Answer
(challenging) C Correct Y / N
Me Me
H3C O
3 Answer
(challenging) C Correct Y / N
Ph Ph
O O
4 Answer
(challenging) H Correct Y / N
H
5 O Answer
(challenging) Correct Y / N

Doing problems is the only way that you will learn organic chemistry. You should do problems in the notes, from
the textbook and from problem sets.

It is CRITICAL that you keep track of what you know and what you don't know. Each notes problem has a
"Correct Y / N" box. When you are PROPERLY CONVINCED that you can do a problem, circle "Y", if you can't
do the problem circle "N". Keep coming back to those problems with the circled "N", until you can circle the "Y".

Here are some ways NOT TO DO PROBLEMS (and when NOT to circle "Y")...
1. You do them in a group, someone else in the group gets to the answer before you, you understand why the
answer is correct, you therefore assume you can do that problem, you check "Y"
2. You do them on your own, you are not sure about the answer, you check it to see if you are right, you are, you
check "Y"
3. You do a problem, it is similar to the one you just did, you look at the answer, you understand the answer, you
check "Y"
4. You can't do a problem, you ask for help, you understand the answer, you check "Y"
5. You do a problem, you get it mainly correct, but a little bit wrong, you understand what you did wrong, you
check "Y"

UNDERSTANDING is different from DOING. In each of the above scenarios you have not proven that you can do
the problem, rather you have proven that you CAN'T do the problem without help from others, or without
"cheating" on the time it takes to do a problem, or without proving that you can do the problem 100% correct.

Retrosynthesis 3 Copyright, Arizona State University

Example 3

O TsO
DMF O
Na

Y
• if it MUST be 2 , better use tosylate as best possible leaving group! also use a polar aprotic solvent

Example 4
A
Make bond A B
Na X O
Br
O

Nuc. Make bond B

preferred
2
SN2 not possible at sp carbon
Na
TsO Y
must be 2 again,
O
better make tosylate!
Example 5
Br
NH2 "backwards"
DMF
NH2
Na
• you can "make up" your own SN2 reaction, just look for obvious bond to make, do reaction "backwards" to get
the synthons and reactants

3 Putting it all Together : A Retrosynthesis Strategy (more...)

• look for the reactant "in" the target molecule
• identify the required Functional Group Interconversions (FGI) and C–C (C–X) bond making reactions
• generally, try to make C–C (C–X) bonds first, or do an FGI that will allow you to do so
• if your first route doesn't work, go back a step and change the approach
• DON'T look at the starting material (at first), it doesn't help you!!
• You MUST know the reactions forwards and backwards, and practice, practice, practice, practice......

The Problems: Synthesize the (target) molecule on the right from the starting molecule the left. This cannot be
done in one reaction. Give reagents and conditions and the intermediate molecules at each step. Do not show
any mechanisms or transient intermediates.

Example 1
from the
starting Ph Ph
HO Ph
structure
NC Ph N C Ph
Ph
synthons
think about this
C-C bond first +–
Na CN / acetone
conc. H2SO4
heat
Ph NBS, hν Ph

Ph Br Ph
• look for the starting structure in the target molecule
• identify the new C-C band that has to be made, do this first (step 3)
• identify the FGI that you can and need to do, in this case make the allylic bromide (step 2)
• identify the FGI you can and need to do, in this case dehydration of an alcohol to make an alkene (step 1)

Retrosynthesis 4 Copyright, Arizona State University

 Copyright, Arizona State University
Retrosynthesis PROBLEMS SN2 Reactions in Reverse
In each case identify the reactants that can be used with an alkyl halide in an SN2 reaction to synthesize
the provided structure
Answer
1
Me O Ph Correct
(standard)
Y/N
Answer
2
O CH3 Correct
(standard)
Y/N
Answer
3
H3C C C CH3 Correct
(standard)
Y/N
O Answer
4
Correct
(standard) H3C C O CH2 CH CH2 Y/N
Answer
5
CH2 NH2 Correct
(standard)
Y/N
Answer
6
(standard) S Correct
Y/N

Doing problems is the only way that you will learn organic chemistry. You should do problems in the notes, from
the textbook and from problem sets.

It is CRITICAL that you keep track of what you know and what you don't know. Each notes problem has a
"Correct Y / N" box. When you are PROPERLY CONVINCED that you can do a problem, circle "Y", if you can't
do the problem circle "N". Keep coming back to those problems with the circled "N", until you can circle the "Y".

Here are some ways NOT TO DO PROBLEMS (and when NOT to circle "Y")...
1. You do them in a group, someone else in the group gets to the answer before you, you understand why the
answer is correct, you therefore assume you can do that problem, you check "Y"
2. You do them on your own, you are not sure about the answer, you check it to see if you are right, you are, you
check "Y"
3. You do a problem, it is similar to the one you just did, you look at the answer, you understand the answer, you
check "Y"
4. You can't do a problem, you ask for help, you understand the answer, you check "Y"
5. You do a problem, you get it mainly correct, but a little bit wrong, you understand what you did wrong, you
check "Y"

UNDERSTANDING is different from DOING. In each of the above scenarios you have not proven that you can do
the problem, rather you have proven that you CAN'T do the problem without help from others, or without
"cheating" on the time it takes to do a problem, or without proving that you can do the problem 100% correct.

Retrosynthesis 5 Copyright, Arizona State University

Example 2
think about this
C-C bond first
from the
starting
structure
CN
NBS, hν +– C N
–+ Na CN
t-BuO K
DMF
NBS, hν
DMF
Br

need to add –Br Br

need to add C=C need to add –Br
need to add C=C

• look for starting structure in target molecule and for any new C-C bonds
• make the C-C bond first
• identify FGI's, in this case making an allylic bromide is the obvious one
• making an alkene must be next step
• making the bromide must be the first step

Example 3

OCH3 need to make

C-O bond
H2
OH
Pd/C +–
Na OCH3
conc. H2SO4 DMF
heat OCH3
+– Br
Na OCH3
DMF
H2
NBS, hν
Br Pd/C

• there will often be more than one way of solving a synthesis problem
• in this class we look for the shortest number of steps!

Example 4
need to make C-C bond
CH
Ph Ph C

Ph Ph
Na C CH
DMF
NBS, hν Ph C CH
Ph
Ph Br
Ph obvious synthons

• We will return to the synthon concept repeatedly throughout the semester!

Retrosynthesis 6 Copyright, Arizona State University

 Copyright, Arizona State University
Retrosynthesis PROBLEMS Retrosynthesis Practice
Synthesize the (target) molecule on the right from the starting molecule the left, this cannot be done in
one reaction. Give reagents and conditions and the intermediate molecules at each step. Do not show any
mechanisms or transient intermediates (problems from last semester)
Answer
1
Correct
(easier)
Y/N
2
CN Answer
Correct
(easier) (±) Y/N
Answer
3 OH Br Correct
(easier) (±) Y/N

Answer
4 (ignore stereochemistry) Correct
(easier)
OH Y/N
Br
OCH3
Answer
5
Correct
(easier)
Y/N

Answer
6
(standard) OH Correct
Y/N

Answer
7 (±)
Correct
(standard)
Y/N
Br
Answer
8 OH Correct
(standard)
Y/N

9 O O Answer
Correct
(standard)
Y/N
H H
OCH3
Answer
10
Correct
(standard)
Y/N

Doing problems is the only way that you will learn organic chemistry. You should do problems in the notes, from
the textbook and from problem sets.

It is CRITICAL that you keep track of what you know and what you don't know. Each notes problem has a
"Correct Y / N" box. When you are PROPERLY CONVINCED that you can do a problem, circle "Y", if you can't
do the problem circle "N". Keep coming back to those problems with the circled "N", until you can circle the "Y".

Retrosynthesis 7 Copyright, Arizona State University

4 Summary of Synthetically Useful Reactions You NEED to know (more...)
(non-bonding electrons are not shown in this summary for simplicity)
Br
Br2, hν

Br
NBS, hν (±)

Br +– CN
Na CN
SN2
acetone (and analogues)

Ph Ph
Br +–
E2
Na O-t-Bu
DMF Ph
Ph
conc. H2SO4
OH
heat
Br
HBr
(±)
CCl4
OH
1. Hg(OAc)2/H2O
(±)
2. NaBH4
H
1. Hg(OAc)2/EtOH
(±)
2. NaBH4
OEt
Br2 Br
(±)
CCl4
Br
1. BH3.THF D (±)
–
D 2. OH/H2O2 H OH
HBr

ROOR Br
H
H2

Pd/C
H

Retrosynthesis 8 Copyright, Arizona State University

 OH
–
dil. KMnO4/ OH
or OH
OsO4/H2O2 (±)
MCPBA
O

1. MCPBA
+ OH (±)
2. H3O
HO

Retrosynthesis 9 Copyright, Arizona State University