SYNTHESIS

Organic Chemistry

DITA FLORESYONA
Nucleophilicy vs basicity
Substitution vs. Elimination:
Identifying the Mechanism(s)
OUTLINE

1. One – step syntheses

2. Functional group transformation

3. Reactions that change the carbon skeleton

4. How to approach a synthesis problem?

5. Retrosynthetic analysis

6. Practical tips for increasing proficiency

1. ONE – STEP SYNTHESES
The most straightforward synthesis problems are the ones that can be solved in just one step. For example,
consider the following:

This transformation can be accomplished by treating the alkene with Br2 in an inert solvent, such as CCl4.
Identify the reagents necessary to accomplish each of the transformations shown below.
Identify the reagents necessary to accomplish each of the following transformations.
2. FUNCTIONAL GROUP TRANSFORMATION
❑ Changing the position of a halogen by performing an elimination reaction followed by an addition
reaction.

❑ The choice of base in the elimination step determines whether the more substituted or the less substituted
alkene is formed.

❑ In the addition step, the decision whether or not to use peroxides will determine whether a Markovnikov
addition or an anti-Markovnikov addition occurs.
2. Functional Group Transformation
Those technique must be slightly modified when the functional group is a hydroxyl group (OH). In such a case, the
hydroxyl group must first be converted into a tosylate (a better leaving group), and only then can the technique be
employed (elimination followed by addition):
After converting the hydroxyl group into a tosylate, the regiochemical outcome for elimination and addition can be
carefully controlled, as summarized below:
2. Functional Group Transformation
A two-step technique for moving the position of a double bond.
Once again, the regiochemical outcome of each step can be controlled by choice of reagents, as summarized below:
2. Functional Group Transformation
Installing functionality in a compound with no functional groups:

This procedure, together with the other reactions covered in the previous chapters, enables the interconversion
between single, double, and triple bonds:
3. REACTION THAT CHANGE THE CARBON SKELETON

In some cases, the number of carbon atoms in the skeleton increases, and in other cases, the number of carbon
atoms decreases.
If the size of the carbon skeleton increases, then a C—C bond-forming reaction is required. Alkylation of a terminal
alkyne will increase the size of a carbon skeleton:
 ALKYLATION OF TERMINAL ALKYNES
A terminal alkyne can be deprotonated in the presence of a sufficiently strong base, such as sodium amide
(NaNH2):

This reaction has powerful synthetic utility, because the resulting alkynide ion can function as a nucleophile when
treated with an alkyl halide:

This transformation proceeds via an SN2 reaction and provides a method to install an alkyl group on a terminal alkyne.
This process is called alkylation, and it is achieved in just two steps; for example:
Alkylation of Terminal Alkynes
Acetylene possesses two terminal protons (one on either side) and can therefore undergo alkylation twice:

Notice that two separate alkylations are required. One side of acetylene is first alkylated, and then, in a separate
process, the other side is alkylated. This repetition is required because NaNH2 and RX cannot be placed into the
reaction flask at the same time. Doing so would produce unwanted substitution and elimination products resulting
from the reactions between NaNH2 and RX. It might seem burdensome to require two separate alkylation processes,
but this requirement does provide additional synthetic utility. Specifically, it enables the installation of two different
alkyl groups; for example:
Reactions That Change the Carbon Skeleton
If the size of the carbon skeleton decreases, then a C—C bond-breaking reaction, called bond cleavage, is required.
Ozonolysis of an alkene (or alkyne) achieves bond cleavage at the location of the π bond:
 OZONOLYSIS OF ALKYNES
When treated with ozone followed by water, alkynes undergo oxidative cleavage to produce carboxylic acids:

When a terminal alkyne undergoes oxidative cleavage, the terminal side is converted into carbon dioxide:
4. HOW TO APPROACH A SYNTHESIS PROBLEM

Every synthesis problem should be approached by asking the following two questions:

1. Is there a change in the carbon skeleton? Compare the starting material with the product to determine if the
carbon skeleton is gaining or losing carbon atoms.

2. Is there a change in the identity or location of the functional group? Is one functional group converted into
another, and does the position of functionality change?
5. RETROSYNTHETIC ANALYSIS
Analysis of the following synthesis problem will illustrate this process:

Rather than focusing on what can be done with an alcohol that will ultimately lead to an alkyne, we instead focus on
reactions that can generate an alkyne:

Retrosynthetic analysis by E. J. Corey (Harvard University)

5. Retrosynthetic Analysis

We must always begin by determining

whether there is a change in the
carbon skeleton or in the identity or
location of the functional group. In this
case, both the starting material and the
product contain six carbon atoms, and
the carbon skeleton is not changing in
this instance. However, there is a
change in the functional group.
5. Retrosynthetic Analysis
The geminal dibromides can be ruled out, because we only saw one way to make a geminal dihalide—and that was
starting from an alkyne.We certainly do not want to start with an alkyne in order to produce the very same alkyne:
5. Retrosynthetic Analysis
Therefore, the last step of our synthesis must be formation of the alkyne from a vicinal dihalide:
5. Retrosynthetic Analysis
A special retrosynthetic arrow is used by chemists to indicate this type of “backward” thinking:

We have learned only one way to make a vicinal dihalide, starting with an alkene:

The figure indicates that the vicinal dibromide can be made from an alkene. In other words, the alkene can be used as
a precursor to prepare the desired dibromide.
5. Retrosynthetic Analysis
Therefore, our retrosynthetic analysis, so far, looks like this:

This scheme indicates that the product (alkyne) can be prepared from the alkene. This sequence of events represents
one of the strategies discussed earlier in this chapter—converting a double bond into a triple bond:
5. Retrosynthetic Analysis
In order to complete the synthesis, the starting material must be converted into the alkene. At this point, we can
think forward, in an attempt to converge with the pathway revealed by the retrosynthetic analysis:
5. Retrosynthetic Analysis
This step can be accomplished with an E2 elimination. Just remember that the hydroxyl group must first be converted
into a tosylate (a better leaving group). Then, an E2 elimination will create an alkene, which bridges the gap between
the starting material and the product:
5. Retrosynthetic Analysis
The synthesis seems complete. However, before recording the answer, it is always helpful to review all of the
proposed steps and make sure that the regiochemistry and stereochemistry of each step will lead to the desired
product as a major product. It would be inefficient to involve any steps that would rely on the formation of a minor
product. We should only use steps that produce the desired product as the major product. After reviewing every step
of the proposed synthesis, the answer is recorded like this:
6. PRACTICAL TIPS FOR INCREASING PROFICIENCY
Creating your own synthetic problems
Begin by choosing a starting compound. To illustrate this, let’s begin by choosing a simple starting compound, such as acetylene.
Then choose a reaction expected for a triple bond, perhaps an alkylation:

Next, choose another reaction, perhaps another alkylation:

Then, treat the alkyne with another reagent. Look at the list of reactions of alkynes and choose one; perhaps hydrogenation with a
poisoned catalyst:
Creating your own synthetic problems
Finally, simply erase everything except for the starting compound and the final product. The result is a synthesis
problem:
Multiple correct answers
Most synthesis problems will have numerous correct answers. As an example, anti-Markovnikov hydration of an
alkene can be achieved through either of the two possible routes: