Diazo Retrosynthesis: Study with Video Lessons, Practice Problems & Examples

In aromatic synthesis, diazoreplacement reactions are crucial for transforming smaller benzene compounds into larger ones. Understanding the roles of activating and deactivating groups, as well as the use of blocking groups, is essential for planning effective synthesis sequences. Mastery of these concepts enables students to navigate complex reactions, such as electrophilic aromatic substitution, and apply retrosynthetic analysis to design pathways for desired products. Familiarity with key terms like acylation, nucleophilic substitution, and regioselectivity enhances comprehension of the mechanisms involved in these transformations.

Proposing Aromatic Synthesis

Now we're going to get some practice proposing aromatic synthesis, specifically using diazoreplacement reactions. As you guys know, a big part of this topic is being able to turn a smaller benzene into a bigger one. We must use our knowledge of sequence groups and blocking groups to plan out our synthesis in the correct order. You should have already had some practice with this at this point, so I'm going to leave these up to you completely. Go ahead and try to do this one from scratch with everything you know about diazo, and then I'll step in and show you guys the answer. Go for it.

Synthesize the target molecule

I think this one might have been a little too hard for you considering that you just learned how to use diazole replacement reactions. But I just want to show you an example of a more advanced synthesis that requires pretty much all the different directing effects we've talked about. Before we begin, let's look at a few interesting things here. First of all, notice that I need to add a chlorine in this position here which is tricky because my end product has a meta director here. This is a meta director. I'm probably going to want to add the chlorine before I turn this into a meta director. Right now, this is currently an ortho/para director. I'm probably going to want to add the chlorine before I turn it into a carboxylic acid. Cool. Awesome. What else? Notice that I also have to add an OH here. I have to add an OH here but this chlorine is meta to it. I probably want to have some kind of meta director here before I add that chlorine because once that alcohol is there, it's going t

Here’s what students ask on this topic:

What is diazo retrosynthesis in organic chemistry?

Diazo retrosynthesis is a strategy used in organic chemistry to design synthetic pathways for aromatic compounds. It involves the use of diazonium salts, which are intermediates that can be transformed into various functional groups through substitution reactions. This method is particularly useful for expanding smaller benzene rings into larger, more complex aromatic systems. By understanding the roles of activating and deactivating groups, as well as blocking groups, chemists can plan the sequence of reactions needed to achieve the desired product.

How do activating and deactivating groups affect diazo retrosynthesis?

Activating and deactivating groups significantly influence the reactivity and orientation of electrophilic aromatic substitution reactions in diazo retrosynthesis. Activating groups, such as -OH and -NH₂, increase the electron density on the benzene ring, making it more reactive towards electrophiles and directing new substituents to the ortho and para positions. Deactivating groups, like -NO₂ and -CF₃, decrease the electron density, making the ring less reactive and directing new substituents to the meta position. Understanding these effects is crucial for planning the correct sequence of reactions in synthesis.

What are blocking groups and how are they used in diazo retrosynthesis?

Blocking groups are temporary substituents introduced into a molecule to control the position of subsequent reactions. In diazo retrosynthesis, they are used to prevent unwanted reactions at specific sites on the benzene ring. For example, a methyl group can be used as a blocking group to direct electrophilic substitution to the desired position. After the desired transformation is achieved, the blocking group can be removed or transformed into another functional group. This strategy helps in achieving regioselectivity in complex aromatic syntheses.

What is the role of diazonium salts in aromatic synthesis?

Diazonium salts play a crucial role in aromatic synthesis as versatile intermediates. They are formed by the reaction of aromatic amines with nitrous acid. Once formed, diazonium salts can undergo various substitution reactions, such as Sandmeyer reactions, to introduce different functional groups like -Cl, -Br, -CN, and -OH into the aromatic ring. This versatility makes diazonium salts invaluable for constructing complex aromatic compounds from simpler benzene derivatives.

Can you explain the Sandmeyer reaction in the context of diazo retrosynthesis?

The Sandmeyer reaction is a key transformation in diazo retrosynthesis, allowing the conversion of diazonium salts into aryl halides, cyanides, or other functional groups. In this reaction, a diazonium salt reacts with a copper(I) halide (CuCl, CuBr) or copper(I) cyanide (CuCN) to replace the diazo group with a halide or cyanide group. This reaction is highly useful for introducing functional groups into aromatic rings, facilitating the synthesis of complex aromatic compounds from simpler precursors.