CH 310M/318M

Dr. Brian M. Bocknack

Synthesis Problems in Organic Chemistry

In a synthesis problem, you need to propose a sequence of reactions to prepare some target compound

from a particular starting material (or starting materials). Consider the following synthesis problem as

a representative example.

Problem: Propose a sequence of reactions to prepare cis-2-hexene from 1-pentyne and any alkyl halide

necessary. You may also use any other organic and/or inorganic reagents necessary during the course of

your synthesis.

The most effective strategy to take when confronted with a synthesis problem is to...

“THINK BACKWARDS”

As you progress in your study of organic chemistry, you will learn a large number of reactions. Any one

of these reactions could end up being the key step in the synthesis you propose! To narrow down the

number of reactions that you have to consider, you want to begin by thinking about how the target could

be formed from a suitable precurser, in a single reaction. There may be several possible precursors!

Next, consider how these immediate precursors to the target could be formed in a single step. Keep

working “backwards” in this way, until the precursors are the “allowed” starting materials defined in the

problem. This approach to working synthesis problems is called retrosynthetic analysis.

Before we consider the retrosynthetic analysis for our sample problem, let’s consider the three types of

chemical operations that are typically involved in an organic synthesis.

� Functional group transformations

Most of the reactions you have learned at this (early) stage in your study of organic chemistry

involve a functional group transformation – one functional group is converted into another

C CCH3CH2CH2 H

R X

C C

H

CH3CH2CH2 CH3

H1-pentyne

alkyl halide cis-2-hexene

“target”

starting materials

from and

during the course of the reaction. For example, in the hydrohalogenation of an alkene

(Markovnikov addition of HX), the alkene functional group is converted into the alkyl halide

functional group.

� Control of stereochemistry

If a particular stereoisomer of the target is desired, use of stereoselective reactions will be

necessary during the course of the synthesis. Several of the reactions you have learned thus far

allow for control of stereochemistry. For instance, the halogenation of an alkene (addition of X2)

is an anti addition – the halogen atoms add to opposite faces of the pi bond, and end up having a

trans relationship in the product. The catalytic reduction of an alkene (addition of H2 over a Pd

or Pt catalyst), on the other hand, is a syn addition – the hydrogen atoms add to the same face of

the double bond, and end up having a cis relationship in the product.

� Formation of carbon–carbon bonds

Since a primary goal of organic synthesis (in the real world, at least) is to build up complex

target compounds from simple (and hopefully inexpensive) starting materials, reactions that form

new carbon–carbon bonds are typically of tremendous importance! At this stage, you only know

about one reaction that leads to formation of a new C–C bond, the alkylation of an acetylide

anion via treatment with a methyl or 1° alkyl halide. You will learn about many other reactions

that lead to formation of C–C bonds, particularly if you take second semester organic chemistry!

The sample synthesis problem given above involves all three of these operations:

� Functional group transformation – an alkyne is converted into an alkene.

� Control of stereochemistry – the target alkene must have the cis configuration about the double

bond.

� Formation of a carbon–carbon bond – the alkyne starting material contains 5 carbon atoms.

The target alkene contains 6 carbon atoms. Whenever the target contains more carbon atoms

than the starting material, it is necessary to form at least one new C–C bond during the course of

the synthesis.

Before tackling the retrosynthetic analysis, it is usually a good idea to make note of the differences that

you observe when comparing the target to the the starting material(s). All of the changes that occur in

going from the starting material(s) to the target must be accounted for during the course of the synthesis!

C C

H

CH3CH2CH2 CH3

H C CCH3CH2CH2 H

R X

from and

The triple bond carbon is attached to a propyl group

This methyl group is not present in the alkyne; introduced by forming a

new carbon–carbon bond???

Retrosynthetic Analysis:

Remember, “thinking backwards” is the best way to approach a synthesis problem. Do you know of any

reactions that will produce a cis alkene (like our target, cis-2-hexene) in a single step? Of course you

do! If an alkyne is subjected to catalytic hydrogenation over Lindlar’s catalyst, one equivalent of H2

will add across the triple bond with syn stereoselectivity to yield a cis alkene. Since we are “thinking

backwards” in a retrosynthetic analysis, a different kind of arrow is used, as shown below.

Given the reactions you have learned thus far, 2-hexyne is really the only reasonable direct precursor to

the target. At this stage, you do not know about any other reactions that could yield cis-2-hexene as the

major product, in a single step (this will change once we discuss elimination chemistry in Chapter 9,

however).

Continue the retrosynthetic analysis by considering how 2-hexyne might be produced as the direct

product of some reaction. 2-Hexyne is an internal alkyne. Recall that internal alkynes can be produced

via alkylation of a suitable acetylide anion:

C C

H

CH3CH2CH2 CH3

H

a retrosynthetic arrow

the precursor is on the right side

C CCH3CH2CH2 CH3

catalytic hydrogenation of this alkyne over Lindlar’s catalyst will

yield the target compound

the target is on the left side

C CCH3CH2CH2 CH3

H3C I

+

C CCH3CH2CH2

alkyl halide

alkylation of this acetylide ion with methyl iodide will yield the

internal alkyne

We’re almost there! Methyl iodide is an alkyl halide, and is therefore an “allowed” starting material as

defined by the problem. The other “allowed” starting material is 1-pentyne. Is there a way to produce

the acetylide anion needed for the alkylation reaction directly from 1-pentyne? Sure!!! Treat 1-pentyne,

a terminal alkyne, with a strong base (like NaNH2):

Once we have worked back to the “allowed” starting materials, the retrosynthetic analysis is complete.

We are not finished answering the question, however! The questions asked us to propose a sequence of

reactions, in the forward direction, to prepare the target compound from the allowed starting materials.

The synthesis provides this sequence of reactions.

Synthesis:

As usual, the best way to get good at working synthesis problems is to practice, practice, practice! The

strategy outlined above is a good general approach to take, but the details will obviously depend on the

specifics of the problem you are trying to solve. Finally, there is often more than one “correct” answer

for a synthesis problem. Your answer may not exactly agree with an answer key, but may still be

perfectly correct. When in doubt, be sure to visit office hours to ask questions!!!

C CCH3CH2CH2 C CCH3CH2CH2 H

deprotonation of 1-pentyne will yield the acetylide ion

1-pentyne

C CCH3CH2CH2 HNaNH2

C CCH3CH2CH2 Na

CH3IC CCH3CH2CH2 CH3

H2

Lindlar cat.

C C

H

CH3CH2CH2 CH3

H