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.

H C CH3CH2CH2 C

CH3CH2CH2

from
CH3

1-pentyne

and
X alkyl halide R

cis-2-hexene target

starting materials
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, lets 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

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 carboncarbon 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 carboncarbon bonds are typically of tremendous importance! At this stage, you only know about one reaction that leads to formation of a new CC 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 CC 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 carboncarbon 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 CC 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!

H C CH3CH2CH2 C

CH3CH2CH2

from
CH3

and
R X

This methyl group is not present in the alkyne; introduced by forming a new carboncarbon bond???

The triple bond carbon is attached to a propyl group

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 Lindlars 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.

H C CH3CH2CH2 C

H
CH3CH2CH2 C C CH3

CH3

catalytic hydrogenation of this alkyne over Lindlars catalyst will yield the target compound

a retrosynthetic arrow the target is on the left side the precursor is on the right side
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:

alkyl halide H3C I

CH3CH2CH2 C C CH3

CH3CH2CH2

alkylation of this acetylide ion with methyl iodide will yield the internal alkyne

Were 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):

CH3CH2CH2

CH3CH2CH2 C C 1-pentyne

deprotonation of 1-pentyne will yield the acetylide ion

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:

CH3CH2CH2
CH3I

NaNH2

CH3CH2CH2
H2

Na

CH3CH2CH2

CH3

Lindlar cat.

H C CH3CH2CH2 C

H CH3

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!!!