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multistep synthesis guide 1 2 3 4 5 > tutorials > home      

Tip 4 continued... Adding carbon-carbon forming reactions into your retrosyntheses

All right. You've learned your reactions and organized them into (at least) two categories: functional group conversions and carbon-carbon bond forming reactions. You've got a fresh synthetic problem in front of you. So now what?

Now you want to think of which carbon-carbon bonds you have to form to take the starting material into the product.

Take an example synthesis:

In this example, you can think, "well, if I'm starting with cyclohexane, the carbon-carbon bond I'm going to have to make connects the cyclohexane ring to the chain containing the carbonyl (C=O) group."

Then you can think "which of the carbon-carbon forming reactions would be useful to make this carbon-carbon bond?" Then check off the list to see which ones might be used and which can be eliminated from consideration.

  • Acetylide chemistry: This reaction won't work to make this bond. Acetylide reactions work well only with primary halides. The acetylide chain would have to attack a ring carbon which would be a secondary carbon. Also, it's not clear how to selectively take the resulting alkyne to the ketone since it would be an internal alkyne.
  • Cyanide addition: This won't work. Cyanides add only one carbon. You need to add three carbons.
  • Wittig reaction: This one might work. Of course, Wittig reactions form a carbon-carbon double bond and you want a carbon-carbon single bond. Probably it's best to see if there's a better route to go before trying this one.
  • Friedel-Crafts: You don't have an aromatic ring in this problem, so this reaction's out of the question.
  • Diels-Alder reaction. This won't work. The Diels-Alder reaction forms rings and bicyclic compounds. You already have the ring in the starting material.
  • Grignard reagents. This reaction should work. Of course, a Grignard reagent reacts with a carbonyl compound to make an alcohol, not a ketone. Fortunately, since you've learned all of your functional group transformations, you know that it's a straightforward task to take a secondary alcohol into a ketone. This reaction looks the most promising so try this carbon-carbon bond forming reaction.

Now that you've chosen the carbon-carbon forming reaction, notice how all the other functional group conversions required to complete the synthesis seem to fall neatly into place. It's usually best to work backwards (using the retrosynthesis approach I discussed in a previous tip), so do that for this problem.

Since you know the carbon-carbon bond-forming reaction forms an alcohol, the last step must convert that alcohol to the ketone in the product. In this case, a number of oxidizing reagents could be used. PCC or Jones' reagent would work just fine here. (You could use other chromium reagents as well)
To make this alcohol you use the Grignard reagent in the carbon-carbon bond-making step that you decided upon earlier. To make a secondary alcohol, you must react the Grignard reagent with an aldehyde. I chose cyclohexyl magnesium chloride here as the starting material, but you could just as easily have gone with cyclohexyl magnesium bromide (either works fine)
To make Grignard reagents you add magnesium turnings to an alkyl halide. Since I chose in the previous reaction to make a chloride Grignard reagent, the starting material I choose in this case is chlorocyclohexane (it would be bromocyclohexane if you went with the bromo Grignard reagent).
The way to add a chlorine to an alkane is to chlorinate using free-radical chemistry in the presence of light.

And that's the retrosynthesis for this molecule. Notice how the steps all seemed to be logical once the carbon-carbon bond forming reaction was chosen.

 Continue Tutorial :: See tips 5-6

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