Chapter 11 Lecture PDF

Chapter 11: Synthesis Strategies
H SPh
TBDPSO
O OTIPS
Felkin-Anh 88
H 3CO Addition
S +
H 3CO 84 TESO OTIPS TBDPSO
O
H 3CO
H
O
OH
Hello H 3CO
O N Coupling 87 Br
+
H O
OH O
OCH3 O O O
O
P OEt
O
OH O O OCH2OCH3 OEt
FK-506 (1)
Horner-Emmons 85
O Reaction
OCH3OCH3 +
83 Br
O OCH2OCH3
H
OCH3OCH3
Retrosynthetic Analysis of FK-506
86 OBn
Chapter 11: Synthesis Strategies
Topics:
I. One-Step Syntheses
II. Functional Group Transformations
III. Reactions Hello

that Change the Carbon Skeleton
IV. How to Approach a Synthesis Problem
V. Retrosynthetic Analysis
VI. Green Chemistry
VII. Practical Tips for Increasing Proficiency
2
I. One Step Syntheses
• Solving a synthesis problem (i.e. “providing the reagents”) is

straight-‐forward when only one reaction is needed:
Hello
• Here, we would need Br2.
• You have to master all the reactions, and the reagents required
before tackling multi-‐step synthesis problems.
• Make sure you can do ALL of the practice problems on the next
few “blue slides” before you move forward with your studying
3
O
Br
H
O
OH
Br d. + En
e.
Hello c.
f.
OH
Br
g. OH
a. b. + En
h. OH
l. i.
k. j. OH
+ En
OH Br
Br
+ En
Br
OH
+ En
Answers:
a. Br2 hv h. Br2, H2O

b. NaOEt i. Br2
c. HBr, ROOR j. H2, Pt
Hello
d. HBr
e. 1. O3 k. 1. BH3·THF
2. DMS 2. H2O2, NaOH
f. cat. OsO4, NMO l. H3O+
g. 1. RCO3H
2. H3O+
O
Br
Br Br a.
H
b. d. e.
Hello f.
k.
g. l.
c.
h. m.
Br
j.
i. Br
Br
O O Br
+ Br Br
C
OH Br
O
Br
a. HBr h. Br2 (1 equiv.)
b. 1. xs NaNH2 i. Br2 (excess)

2. H2O
j. 1. O3
c. 1. xs NaNH2 2. H2O
2. H2O
k. H2, Lindlar’s Catalyst
d. HBr Hello
l. H2, Pt
e. H2SO4, H2O, HgSO4
m. Na, NH3(l)
f. 1. R2BH
2. H2O2, NaOH
g. 1. NaNH2
2. CH3I
II. Functional Group Transformations (2-step syntheses)
• Moving a functional group from one carbon to the next:
Br Br
Hello
8
• It’s logical to review the two-‐step synthesis strategies from

previous chapters
• Moving a functional group from one carbon to the next:

Hello
• Here, we need to obtain the Zaitsev alkene, and choose the strong
base used accordingly
• The second step must be Markovnikov addition of HBr

9
• We can layout all the reactions we know where alkyl bromides and
alkenes are concerned, and then choose the reagents needed to
yield the correct regiochemistry:
Hello
10
• A similar, modified approach can be used for the analogous

alcohols
HO OH
Hello
11
• A similar, modified approach can be used for the analogous

alcohols
Hello
12
• Moving an alkyne from one position to the next:
Hello
13
• We also know how to apply a two-‐step strategy to move the
position of a π bond in an alkene:
Hello
• For the 1st reaction, we need to add H and Br to the alkene
• For the 2nd reaction, we need to do an E2 elimination
• Again, the reagents we choose depends on the regioselectivity we
need
14
• You will not have a chance to do this sort of analysis unless you
can quickly recall all the possible reagents and reaction conditions.
Hello
15
• A two-‐step sequence is needed to convert an alkane to an alkene
Hello
• We would then be able to convert the double bond to a single
bond, or a triple bond
16
Propose an efficient synthesis for each of the following
transformations
OH
a. e.
OH
Hello
Br Br
Br
b. f.
OH
OH
Br
c. g.
OH
OH
d. h.
Answers
1 3
4 1. Br2 4
2 1
a. 2. xs NaNH2 2 3
3. H2O
Br2 Hello
1. xs NaNH2
Br 2. H2O
Br
The first thing I would determine is if the alkene and the alkyne are between the same two
carbons. If I am at all confused, I will number all the relevant carbons.
Next, choose the appropriate reagents to make the desired change happen.
In this case Br2 is chosen since it readily adds across the double bond. Then addition of an
excess strong base will cause elimination to occur twice (first elimination forms the alkene,
second elimination forms the alkyne). Water is also required to protonate the alkyne as the final
step since excess base will likely deprotonate carbon 4 leaving an acetylide anion behind.
Answers 1 Br
1. DBU or t-BuOK
2 Br 2. HBr 1
b. 2
DBU
HBr
Hello
After examining the reaction, we notice that the bromine is originally on carbon 1, but ends up on
carbon 2. Whenever we have a functional group moving over one carbon, an alkene (or double
bond) is often required as the first step. In this case, we need to perform an E2 elimination from
the most substituted carbon. At first, you might want to use NaOMe, but it will predominantly give
SN2 since we have a primary alkyl bromide, and we don't want that. Therefore we need a strong
base that is non-nucleophilic. I chose DBU, but tert-butoxide will also work. We typically use these
for deprotonating the least hindered position, but they will deprotonate the more hindered position as
well, I would just expect the rate of the reaction to be very slow. The idea is we do NOT want SN2
happening. Once we have the alkene, addition of HBr will give us the desired product. Mechanistically
the H+ is added to the double bond first leaving the carbocation on the most substituted carbon. The
bromide will then attack as the second step which installs the bromine on the most substituted carbon.
Answers 1
1
1. HBr
2 2. NaOMe 2
c. 3
3
HBr
Hello Br
NaOMe
Whenever a double bond is being moved over from one position to the next, we must strategically
choose a reagent to add across the original double bond so the second step, the elimination to
give the double bond in the proper place, is possible. In this case HBr is used in the first step
since the Br needs to end up on the most substituted carbon (mechanistically the double bond
attacks the H+ leaving the most stable carbocation that the Br- can attack in the second step).
For the elimination step, we need to form the most thermodynamically stable double bond (the
Zaitsev product). This requires a small strong base so NaOMe is chosen. DBU and t-BuOK can
not be used since they deprotonate the least hindered position due to steric and you will end up
with the starting material again.
Answers
1. Br2, hv
2. NaOMe
d.
Br2, hv
NaOMe
Hello
Whenever you are staring with a compound that has no heteroatoms, double bonds or useful
leaving groups of any kind, you will likely need to use radical chemistry to install a bromide at the
most substituted position. This bromide will then give you a handle so you can manipulate the
molecule further.
Step one, radical bromination. Since the most stable radical (in this case tertiary) is formed
during the first step, the bromine will end up at this tertiary position after this radical attacks a
molecule of Br2. The second step is our standard method for making the most thermodynamically
stable alkene (Zaitsev product) by using a small base. Using a large base like DBU or t-BuOK
will give the undesired Hoffman product do to deprotonation at the most accessible position.
Answers 1 1.TsCl
2. NaOEt
2 3. H2O, H2SO4 OH
e. 3 3
2
OH
1
TsCl H3O+
Hello 1 NaOEt
1
2
3 2
3
OTs
In this case the alcohol is moving over one carbon. The problem is alcohols are not good leaving
groups since HO− has an unstabilized negative charge. Therefore we need to make it into a
better leaving group so we react it with tosyl chloride. H2O/H2SO4 might work as well, but
probably not. I would avoid SN1 and E1 mechanims whenever possible since they are difficult to
control and carbocation rearrangements will occur which means you will be making your product
alkene along with many biproducts (poor percent yield)
After OTs is made, treat it with a strong small base to get the most thermodynamically stable
alkene (Zaitsev Product). Once this internal alkene is in hand, treatment with H2O/H2SO4 will put
the alcohol at the most substituted position. Do NOT use HBr, since a Br will be placed at carbon
3 instead of the OH. You need an acid that is non-nucleophilic. HSO4− will not add to anything so
using sulfuric acid is a good choice here for installing an alcohol.
Answers Br
1. NaOMe 2
3 1
2 2. H2O, H2SO4
f. 3 1
OH
NaOMe
H2O, H2SO4
2
Hello 3
1
In this example, a Bromide is being converted to an alcohol. If you number the carbons you will
realize that the alcohol ends up one carbon away from where the bromide started so we need to
make a double bond as the first step.
NaOMe is used first to make the Zaitzev product since it is small and sterics are not an issue. If
DBU or t-BuOK are use, the double bond would end up between carbons 1 and 2 and that would
not be useful to us. The OH is then installed on the most substituted carbon by adding H2O, H2SO4.
Sulfuric acid is used in this case since its conjugate base is highly stabilized and non-nucleophilic.
Mechanistically this reaction works very similarly to the reactions with HBr. First the double bond
attacks the H+, which leaves a stabilized tertiary carbocation. Water will then attack the
carbocation. After proton transfer, an OH will be left on carbon 3. The key is that the OH ends up
where the the most stabilized carbocation forms.
Answers OH
1. TsCl
2. DBU 2
3. HBr, ROOR 3 1 Br
g. 2
3 1
TsCl HBr, ROOR
OTs
2
Hello
3
2 DBU 3 1
1
In this reaction, you have a few options, but some options are better than others. First do NOT
heat the alcohol in concentrated H2SO4. It seems like you may be able to skip right to the
alkene, but once you form the secondary carbocation, this molecule will rapidly rearrange to
give the tertiary carbocation. Instead use TsCl to make the alcohol into a better leaving group.
For the E2 elimination step, any strong base should work. I would prefer that you choose either
DBU, DBN or t-BuOK since they are non-nucelophilic. If you choose NaOMe, you will still get
some SN2 as the minor product. It is always best to avoid any unnecessary byproducts that will
affect your percent yield.
Finally, use Br2 with a peroxide to add the Br anti-Markovnikov. Mechanistically, a bromine
radical reacts with the alkene to form the most stable (in this case secondary) radical. This
radical will then react with the hydrogen in H-Br this making the product and another Br∙.
Answers OH
OH
h.
NaOH (SN2)
TsCl
1. BH3·THF
2. NaBH2
Hello
OTs DBU, DBN
or t-BuOK Br
HBr, ROOR
Once again, you have many options here, just make sure your first step avoids H2SO4 since you
will get carbocation rearrangements.
Steps 1-2, turn the alcohol into a good leaving group by making either the OTs, OTf, or OMs, then
eliminate using any non-nucleophilic strong base. NaOMe will still work, you will just have a lower
percent yield do to the formation of the SN2 product as a minor product.
Once the alkene is in hand you have two different options. You can either do a hydroboration to
give the product with the alcohol on the least substituted position, or you can first use HBr and a
peroxide to add the bromide anti-Markovnikov. Once you have the primary bromide, you can
displace it with an HO− through an SN2 reaction.
III. Changing the Carbon Skeleton
• For some transformations, it may be necessary to tamper with the
carbon skeleton (add or remove carbons)
• When a synthesis requires the carbon skeleton to be altered, you
Hello
need to be able to recall the reactions that add/remove carbons
• Most reactions learned so far only change a functional group, or
change the location of it.
26
• So far, we have learned only one transformation that increases the
number of carbons in a molecule
Hello
• For the time being, we know this reaction will have to be used
when we need to add carbons to a compound
27
• We have also learned a way to decrease the number of carbons in a
molecule
Hello
• In the future, we will discuss many more reactions that alter the
carbon skeleton.
• You may want to put a new tab in your notebook and separate
or rewrite all the reactions that create C-‐C bonds. These are the
most important reactions in organic chemistry.
28
Propose an efficient synthesis for each of the following
transformations
a.
Hello
Br
b.
O
c.
Answers:
1. NaNH2 (1 equiv.)
2. EtI
a. 3. NaNH2 (excess)
4. MeI
1. NaNH2 (1 equiv.)
Hello
2. EtI
3. NaNH2 (excess)
4. MeI
At this point in your studies, the only way to increase the number of C-C bonds is by reacting
an acetylide ion with a good leaving group. for this reaction, you can swap steps 1 & 2 with
steps 3 & 4 since it doesn't matter which order you perform the reaction in.
First, use sodium amide (NaNH2) to deprotonate the alkyne. This small nucleophile is excellent
for SN2 reactions and will easily react with ethyl iodide. The same process is repeated for the
seconds step, however methyl iodide is used instead as the electrophile.
Answers:
Br Na
b.
Hello
Br
NaNH2
This reaction simply requires the addition of the acetylide ion to benzyl bromide. However, it is
worth noting that in real life we first need to make the acetylide ion. To do this, we treat the alkyne
with NaNH2 then we can add in the benzyl bromide as the second step to make the product.
Answers:
O O
1. O3
c. +
2. DMS H H
Hello
If you count the number of carbons, you will notice the product is missing one carbon. You’ll
further notice that the carbon missing is one of the double bond carbons indicating that an
ozonolysis reaction must have occurred.
• To approach any synthesis problem, first answer these two

questions:
1. Is there a change in the carbon skeleton? Is it gaining or
losing carbons? Hello
2. Is there a change in the identity and/or location of the

functional group?
Solving a synthesis problem requires the recall of all the reactions
learned, and working through many examples.
33
Propose an efficient synthesis for the following transformation
Hello
1. Is there a change in the carbon skeleton? YES. The starting

compound has 5 carbons, the target compound has 7:
Hello
35
2. Is there a change in the identify and/or location of the

functional group? Alkyne changed to trans alkene, but the
location hasn’t changed (remains between 4 and 5)
Hello
So the synthesis needs to accomplish the following:

• triple bond must be converted to trans alkene
• two additional carbon atoms must be installed
What reagents/reactions will accomplish these tasks?
36
• Two carbon atoms can be introduced by alkylating the starting
alkyne, which gives the correct carbon skeleton:
Hello
• Dissolving metal reduction converts alkynes to trans alkenes:
• So it’s a two-‐step (actually 3 reactions) synthesis…

37
• It’s extremely important to number each reaction in the

multi-‐step synthesis. Merely listing all the reagents together
is not sufficient
Hello
38
Propose an efficient synthesis for the following transformations
a. d.
Hello
Br O
b. e.
Br OH
OH O
c. f. H
Answers 1. NaNH2
2. Propyl iodide 4 5
3. H2, Lindlar’s cat. 1 8
a. 5 2 3 6 7
2 4
1 3
1. NaNH2 H2, Lindlar’s cat.

2. Propyl iodide
Hello 6 8
5 7
2 4
1 3
Start off by numbering your carbon atoms so you can figure out what is happening!
After numbering the carbons, it looks like a propyl chain is added to carbon number 5. You can
also see that the triple bond doesn't go anywhere (it stays between carbons 4 & 5), but it does
get reduced to a double bond.
In the first step, the alkyne is first deprotonated by a strong base then added to propyl iodide
through an SN2 reaction. In the second step, the triple bond needs to be reduced to a cis
double bond, but NOT completely reduced to a single bond. This can only be accomplished
with a “poisoned” catalyst and Lindlar’s catalyst is the most commonly used since it works
great. Na, NH3(l) can not be used since it will give the trans double bond.
Answers Br 1. xs NaNH2 O
2. H2O
b. 1 2 1 2
Br 3. O3 OH
3
4. DMS
1. xs NaNH2
2. H2O 3. O3
Hello 4. DMS
1
2 3
Start off by numbering your carbon atoms so you can figure out what is happening! In this case a
carbon atom has been lost so we know that an ozonolysis reaction is required. We also know that
a carboxylic acid is formed if we ozonize an alkyne.
Step one, use sodium amide (NaNH2) to create the alkyne then treat with O3 and dimethylsulfide
to get the product
Answers 3 1. HBr, ROOR,
2 4 2. t-BuOK 6
c. 3 5
2 4
3. HBr,ROOR
1
4. HC≡CNa 1
HBr, ROOR
Br Hello 3
3 4 Br
3 t-BuOK 2 HBr, ROOR 2
2 4 4
1
1 1
Start off by numbering your carbon atoms so you can figure out what is happening! In this
example, the carbon number increased by two so we know that acetylene (HC≡CH) was added
to the molecule (at carbon 4). This means we must somehow get a good leaving group at
carbon 4. If somehow we can install a double bond between carbons 3 and 4, we can add a Br
leaving group by using HBr and ROOR since the Br will be added anti-Markovnikov.
Steps 1 & 2: Use HBr and ROOR to add a Br to the least substituted position of the double
bond then eliminate using a large base to get the double bond between carbons 3 & 4. DBU,
DBN, and t-BuOK will all work.
Steps 3 &4: Once again, use HBr, and ROOR to add the Br to the least substituted position of
the double bond, then add the acetylide ion in an SN2 reaction to give the desired product.
Answers 5
1. H2, Lindlar’s cat.
2. HBr, ROOR
4 3. HC≡CNa
d. 3 3 5 7
1 2 1 2 4 6
H2, Lindlar’s cat.
Hello
4 4
3
HBr, ROOR 3 Br
1 2 5 1 2
5
Start off by numbering your carbon atoms so you can figure out what is happening! In this
example, the carbon number increased by two so we know that acetylene (HC≡CH) was
added to the molecule (at carbon 5). This means we need to reduce the triple bond and install
a good leaving group at carbon 5 so the acetylide ion can be added through an SN2 reaction.
Step 1: Use H2 and Lindlar’s catalyst to partially reduce the triple bond.
Step 2: Once we have a double bond between carbons 4 & 5, adding HBr with ROOR will
install a bromine atom at the anti-Markovnikov position.
Step 3: Add the acetylide ion through an SN2 reaction since bromide is an excellent leaving
group.
Answers 3
1. HBr, ROOR
2. CH3C≡CNa 5
1 2 4 3. Na, NH3(l) 1 2 3 4 7
e. 6
HBr, ROOR Na, NH3(l)

7
6
HelloBr 5
1 2 3 4 CH3C≡CNa 1 2 3 4
Start off by numbering your carbon atoms so you can figure out what is happening! In this case
the carbon number is increasing by 3 which indicates we need to add methyl acetylene
(CH3C≡CH) to carbon 4. Since the product contains a double bond instead of a triple bond, it
must somehow be reduced.
First HBr is added across the double bond, anti-Markovnikov. Methyl acetylide (CH3C≡C−) can
then be added to the bromide through an SN2 reaction. Finally, the alkyne needs to be reduced
to a trans double bond. Lindlar’s catalyst will not work here since that only gives the cis double
bond. In this case sodium metal in liquid ammonia is required for the reaction.
Answers OH
1. TsCl
O
2. DBU
f. H
3. O3
4. DMS
TsCl 1. O3
2. DMS
Hello
OTs
DBU or t-BuOK
I thought I was clever and didn’t number my carbons in this case, and it initially set me down
the wrong path. If you do number your carbons, you will realize that we lost one! The
aldehyde (our product) must arise from an ozonolysis reaction of an alkene (if it were an
alkyne a carboxylic acid would be the product instead of the aldehyde).
Step 1: Convert the alcohol to a good leaving group using TsCl.
Step 2: Eliminate the OTs using a bulky base like DBU or t-BuOK.
Step 3: Cleave the double bond in half by using the ozonolysis reaction.
• Retrosynthetic Analysis – simply put, this approach means we

solve for the reaction sequence in reverse order
• We begin by solving for the last step in the synthesis, first!
Hello
• Still need to ask the same two questions before getting started:
– (1) is the carbon skeleton changing, and…
– (2) is the functional group changing and/or moving?
1. Analyze the structure of the reactant and product. What

functional groups are we dealing with?
46
Perform a retrosynthetic analysis for the following synthesis:
Hello
1. Is there a change Hello

in the carbon skeleton? No, the carbon
skeleton is not changing
2. Is there a change in the identity of the functional group, and/or
its location? Alcohol is converted to alkyne, but the position is
unchanged.
48
• Work backwards: focus on the last step in the synthesis
3. What reactions do we know that can be used to make an
alkyne?
Hello
49
• An alkyne can be installed on this carbon skeleton by elimination
of any of the following three dibromides:
Hello
This vicinal dihalide is

the only one we currently
know how to make
50
• Recall that a retrosynthetic arrow is used to indicate the type of
“backward” thinking we used to solve for the last step:
Hello
• So we have just solved for the last step in the synthesis by
identifying a reactant we can use to produce the final product
51
• Now we can continue to work backwards another step:

• A vicinal dibromides are made by addition reaction to an alkene
This is the alkene

Hello we would need to
make the dibromide
• Recall Br2 is needed as the reagent for this reaction
52
• So far, our retrosynthetic analysis looks like this:
Hello
• REMEMBER: the arrows are pointing in the reverse direction, so the
forward synthetic sequence looks like this:
We still need to

figure out this step
53
• At this point, we should recognize that an alcohol can be converted
to an alkene via a dehydration (elimination) reaction:
Hello
• We need to convert the alcohol to a tosylate, then eliminate with a
non-‐nucleophilic base:
54
• Overall, here is the multistep sequence:
Hello
• To ensure this is correct, we should work out each reaction and
make sure the correct regio-‐ and stereoselectivity
55
Propose an efficient synthesis for the following transformations.
Using a retrosynthetic analysis may help with your strategy!
OH
a. Br e.
OH
Hello
Br Br O
b. Br f.
O OH
Br Br O Br
c. g. + En
OH
O
d. h.
Answers Br
a.
4 1 OH
can be can be can be

made from made from made from
Br LG
+
OH
1 Hello
2 3 4 5
I definitely found using a retrosynthetic analysis was very helpful with this problem since I didn’t
have a clear path in the forward direction.
Working backwards, the halohydrin (1) can be made from alkene 2. Once we draw the alkene, we
can envision alkene 2 being synthesized from an alkyne 3 through a partial reduction with H2. I
then realized alkyne 3, can easily be made from acetylene (4, our given starting material) along
with a 2-carbon chain with an excellent leaving group.
Now with the retrosynthetic analysis complete, lets write out the steps in the forward direction. It is
worth mentioning that if you used ethyl bromide or EtOTs, they would have also would have
worked as well.
1. NaNH2 H2 Br2/H2O Br
2. EtI Lindlar’s catalyst
OH
Answers 2 4 6
2 3 4 1 3 5
b. Br
1
5 1 O
can be can be can be

Br +
O
1 2 3 5 4
Hello
You likely would have been able to work this problem out from the forward or the reverse direction.
The key is recognizing that the carbon chain increased by two, so acetylene must have been
added at some point. Working backwards, I recognized that epoxide 1, could be made from
alkene 2, which could be made from alkyne 3. Alkyne 3 could simply be made from an SN2
coupling reaction between bromide 5 and acetylene (4).
The forward direction is listed below. Any peroxide (RCO3H) should work to make the epoxide, but
organic chemists most commonly use mCPBA (Meta-chloroperoxybenzoic acid)
H2 mCPBA
Br Lindlar’s catalyst O
2
Br Br O Answers
2
c. 1 3 4 5 1 3 4
5
O can be
Br Br
xs. NaNH2 made from
1
Hello 2
3
2
The first thing I did was number all the carbons to make sure we weren’t gaining or losing carbon
atoms. Then I proceeded as described below.
You may have been able to solve this looking in the forward direction or the reverse direction. I
happened to do both for this problem. When I see a gem dibromide (1), I know I can make an
alkyne if I treat it with a base. Similarly, we also know that we can make a ketone (3) if we start
with an alkyne. After piecing these two strategies together, we have the forward synthesis listed
below. Remember, the second step using water it to simply protonate the acetylide anion.
O
Br Br
1. xs. NaNH2 H2SO4, H2O, HgSO4
2. H2O 2 3
1
Answers 1 4 O
d. 2 5
1 2 3
3 6
The key to this reaction is numbering the carbons and realizing that we lost half of them. This
suggests that we are breaking the C-C bond between carbons 2 & 5. This suggests that in a
retrosynthetic analysis carbons 2 and 5 are connected with a double bond.
can be Hello can be can be
made from made from Br made from
O
1 2 3 4
I was able to solve this problem the quickest retrosynthetically, but the forward direction may be
just as easy. It is worth noting that our starting material (alkane 4) is fully saturated and has no
functional groups. Therefore we know that we must use a radical reaction to install a bromide on
the most substituted position. From there all the other steps fall into place. First elimination with
a small base to give the Zaitsev product followed by ozonolysis.
Br O
Br2, hv NaOMe 1. O3
2. DMS
Answers OH
e.
DBU
Br or OH
Br2, hv t-BuOK 1. BH3·THF
2. H2O2/NaOH
Hello
1 2 3 4
I decided to attack this problem from the forward direction instead of using a retrosynthetic
analysis. First, I hope you realized that we did not gain or lose any carbon atoms.
First step: This has to be a radical bromination reaction regardless of our path since we don't
know how to do anything else with an unsubstituted saturated alkane.
Once we have bromide 2 the path becomes a lot more clear.
Step 2 & 3: Eliminate the bromide to form the Hoffman product using a large strong base like
DBU or t-BuOK. Then the alkyne can be treated with BH3 in order to obtain the desired alcohol
through anti-Markovnikov addition.
Answers Br Br O
f.
1 2 3 4 1 3 OH
2
O can be can be
made from made from Br Br
OH Hello 3
1 2
O
Br Br
1. xs. NaNH2 1. O3
2. H2O 2. DMS OH
3 2 1
Both the retrosynthetic analysis and the forward synthesis are listed above. The key is to realize
that we lost a carbon atom at some point so an ozonolysis reaction was used. We also know that
acid 1 can be made from alkyne 2 through ozonolysis. Finally, we also know that we can
synthesize alkyne 2 if we have a dibromocompound such as compound 3.
Answers Br
g. 1 2 3 4 5 6 + En
2
1
OH
Br can be can be can be

+ En +
LG
1
OH Hello 2 3 4 5
For this reaction, I feel like a retrosynthetic analysis is a must, but I am sure many of you still like
the forward direction better and that is okay too. Using a retrosynthetic analysis, product 1, can
easily be obtained from alkene 2, which can be made from alkyne 3. Alkyne 3 is perfectly
symmetrical so it can be synthesized by a two sequential SN2 coupling reactions with two
equivalents of compound 5 (an ethyl unit attached to a good leaving group).
Br + En
1. NaNH2 1. NaNH2 Na, NH3(l) Br2, H2O
2. EtI 2. EtI
OH
You need to make sure you repeat the first two steps twice instead of trying to be clever and
adding excess NaNH2 with two equivalents of EtI. The problem is that you probably will not be
able to deprotonate acetylene twice (forming the dianion) and instead NH2− may act as a
nucleophile and attack ethyl iodide directly.
Answers h.
1
2 4
1
2
4 5
3 5 3
Br
Br
hv Br2 NaOMe HBr
ROOR 4
1 2 3
Hello t-BuOK
Br
Br2
1. xs NaNH2
2. H2O
6 Br 5
7
This synthesis is very long, but also straight forward. We are not gaining or losing any carbons
so we are just moving around our functional groups. I happened to attack this in the forward
direction, but a retrosynthetic analysis may be valuable to some of you. If you haven’t noticed,
you have two options to solve every problem. Work backwards, work forwards, and sometimes
do both and meet in the middle.
Starting with alkane 1, the only reaction we can do is a radical bromination to install a bromide
on the most substituted carbon. We can then move the bromide over one position by first
generating the internal double bond (3) with a small base, followed by another bromination
reaction. It is essential we make bromide 4 (anti-Markovnikov) so HBr is used in the presence of
a peroxide. Next we perform another elimination using a bulky base to generate the Hoffman
product. Dibromination, and elimination with NaNH2 finally affords the product, alkyne 7.
VI. Green Chemistry
• Green Chemistry – refers to reactions that are more environmentally

friendly, and has 4 guiding principles:
1. Prevent waste.
Hello
2. Use less hazardous substances.
3. Use safer solvents – ones that are environmentally benign
4. Maximize atom economy -‐ use reactions where all or most of the
atoms from the reagents are incorporated into the product(s)
65
VI. Green Chemistry
• Consider two reactions to know (convert alkene to alcohol):
The atoms in red

are waste material
Hello
Only the H+ is waste

material, but it is only
needed in a
catalytic amount
66
VI. Green Chemistry
• Green Chemistry – refers to reactions that are more environmentally

friendly, and has 4 guiding principles:
5. Use catalysts rather than stoichiometric reagents

Hello
6. Energy efficiency – reactions performed at room temperature more
more efficient than those requiring heat
7. Renewable feedstocks – using sources such as grains, or corn, as a
source of carbon as opposed to petroleum
67
VII. Increasing Proficiency: Practical Tips
• To build a molecule, you must be able to choose the right tools for
the job
• It is helpful to organize the reactions, as you learn them, into two
sets of reactions: Hello
1. Reactions that alter the carbon skeleton

2. Reactions that alter the functional groups
• As more reactions are learned, add them to the appropriate list
68
VII. Increasing Proficiency: Practical Tips
• There will often be more than one way to solve a synthesis problem
Hello
• In general, a chemist’s goal is to find the most facile synthesis
generally having the fewest steps
69

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Chapter 11: Synthesis Strategies

II. Functional Group Transformations

III. Reactions Hello

IV. How to Approach a Synthesis Problem

VI. Green Chemistry

VII. Practical Tips for Increasing Proficiency

• Solving a synthesis problem (i.e. “providing the reagents”) is

• Here, we would need Br2.

a. Br2 hv h. Br2, H2O

a. HBr h. Br2 (1 equiv.)

b. 1. xs NaNH2 i. Br2 (excess)

• Moving a functional group from one carbon to the next:

• It’s logical to review the two-­‐step synthesis strategies from

• Moving a functional group from one carbon to the next:

• The second step must be Markovnikov addition of HBr

• A similar, modified approach can be used for the analogous

• A similar, modified approach can be used for the analogous

• Moving an alkyne from one position to the next:

TsCl HBr, ROOR

• To approach any synthesis problem, first answer these two

2. Is there a change in the identity and/or location of the

Propose an efficient synthesis for the following transformation

1. Is there a change in the carbon skeleton? YES. The starting

2. Is there a change in the identify and/or location of the

So the synthesis needs to accomplish the following:

What reagents/reactions will accomplish these tasks?

• Dissolving metal reduction converts alkynes to trans alkenes:

• So it’s a two-­‐step (actually 3 reactions) synthesis…

• It’s extremely important to number each reaction in the

1. NaNH2 H2, Lindlar’s cat.

H2, Lindlar’s cat.

HBr, ROOR Na, NH3(l)

• Retrosynthetic Analysis – simply put, this approach means we

1. Analyze the structure of the reactant and product. What

Perform a retrosynthetic analysis for the following synthesis:

1. Is there a change Hello

This vicinal dihalide is

• Now we can continue to work backwards another step:

This is the alkene

• So far, our retrosynthetic analysis looks like this:

We still need to

• Overall, here is the multistep sequence:

can be can be can be

can be can be can be

Br can be can be can be

1. NaNH2 1. NaNH2 Na, NH3(l) Br2, H2O

• Green Chemistry – refers to reactions that are more environmentally

3. Use safer solvents – ones that are environmentally benign

• Consider two reactions to know (convert alkene to alcohol):

The atoms in red

Only the H+ is waste

• Green Chemistry – refers to reactions that are more environmentally

5. Use catalysts rather than stoichiometric reagents

1. Reactions that alter the carbon skeleton

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• It’s logical to review the two-‐step synthesis strategies from

• So it’s a two-‐step (actually 3 reactions) synthesis…