Retrosynthetic Disconnections

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Bertram Gray
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1 1 Retrosynthetic Disconnections These notes should help somewhat when planning a synthesis. Recall that retrosynthetic analysis is the method used to work backwards from the target molecule to the starting materials. Retrosynthetic analysis can involve a number of steps, each of which should simplify the molecule. In retrosynthetic analysis, there are functional group interconversions (FGI) and disconnections (DIS). The abbreviation is often written over the retrosynthetic arrow (=>). Functional group interconversions make up most of the reactions that we studied in Chem 231 and Chem 232 these are the oxidations, eliminations, substitutions, etc. The disconnections correspond to the carbon-carbon bond forming reactions, and were seen as alkylations, cycloadditions and Grignard reactions. This isn t a summary of the FGI s; you can see the reaction summaries in the last pages of every chapter. You will need to know these reactions in order to plan a synthesis. Each FGI must correspond to a valid reaction in the synthetic sense for example the FGI shown corresponds to the reaction below it. You also need to remember is that each reaction equation shows four pieces of information: 1: This is a reaction of a ketone, it is being reduced. 2: This is the synthesis of an alcohol, it is being made from a ketone. 3: This is a reaction of the reagent sodium borohydride, it is effecting the reaction shown. 4: There are other details, i.e. the appropriate solvent, time, temperature, workup The disconnections in a retrosynthetic analysis must correspond to a valid synthetic reaction. All of the reactions are described in the chapter summaries, but since we don t study them in the same way, seeing the disconnection possibility is not always straightforward. In the examples below, I ve tried to cover the major carbon-carbon bond forming reactions from each chapter. One last note before summarizing the disconnections. In the details of retrosynthetic analysis the parts after the disconnection (termed synthons ) are correctly drawn showing the polarity of the atoms involved (which can lead to different problems). I ve taken the liberty of showing specific reagents that correspond to known reactions. It s less rigorous, but more to the point. Chapters 11 and 12 Alcohols Alcohols are the product of the reaction between carbonyl compounds and Grignard reagents (chapter 12). Disconnect the carbon-carbon bond next to the alcohol to get the possible starting reagents. The alcohol group must have come from the carbonyl group. If you have a secondary alcohol, you can disconnect on either side of the alcohol. For a tertiary alcohol, any of the three groups can be disconnected.

2 2 Remember that the Grignard reagent can t contain any group that can easily lose a proton (OH, NH 2, CO 2 H ) nor can it contain any carbonyl group (it would react with itself). Chapter 13 Diels-Alder Reaction This one is fairly easy find a six-member ring containing an alkene. Draw the mechanism in reverse, and note the new products. The caveat here is recalling that the Diels-Alder reaction is stereospecific, and to track the stereochemistry correctly through the disconnection. In the above example, having R as an electron withdrawing group is always a good idea as the reaction is easier. Chapter 15 Aromatic Compounds There are a lot of functional group interconversions here too, but the one disconnection that we can do is to recognize a Friedel-Crafts reaction. X can be a halide (R is Me, Et, i-pr or t-bu, or won t rearrange) for the Friedel-Crafts alkylation, or it can represent an acid chloride group for the Friedel-Crafts acylation. It s also useful here to remember the directional ability of a group, and how directional ability can be modified by FGI. Chapter 16 Ketones and Alkenes This is the carbonyl group chapter, and since a carbonyl group is an oxidized alcohol group, we can use the Grignard disconnection to get an alcohol, and then oxidize it (a FGI) to get the carbonyl. This chapter s really big idea in synthesis is the Wittig reaction, which is very useful at transforming aldehydes and ketones to carbon-carbon double bonds. Two disconnections are presented at the top of the following page. The first shows disconnection of a methylene (CH 2 ) group, the Wittig reaction is the method of choice here as the CH 2 ends up exactly where the carbonyl group was located. In the second example, two different disconnections are given for the same target molecule. The better choice usually has the simpler Wittig

3 3 reagent and the more complex carbonyl group. You can make up to a trisubstituted alkene with this reaction. Chapter 17 Carboxylic Acids and Nitriles It s possible to make an carboxylic acid in a carbon-carbon bond forming reaction. Use Grignard chemistry, and carbon dioxide as the electrophile. The usual caveats for the Grignard reaction apply here too. Nitrile synthesis wasn t discussed as much in Chem 232, the big disconnection here comes from a Chem 231 topic. Since cyanide ( - CN) is nucleophilic, it can displace a leaving group to give a new carbon-carbon bond. Since this is an S N 2 reaction, and the conditions for an S N 2 process apply. As the CN group can undergo FGI to an acid, an amine, or even a ketone, this is a remarkably powerful way to add one carbon atom to the molecule. Chapter 18 Carbonyl α-substitutions This disconnection involves removing an alkyl group from the α-position of a carbonyl (aldehyde, ketone, ester or nitrile), the forward reaction is an alkylation reaction, so the R group is shown with a leaving group attached. The concept of alkylation extended into two general syntheses. The malonic ester synthesis used diethyl malonate as an acetic acid equivalent, thus adding two carbons to an alkyl chain.

4 4 Since the starting diester can be alkylated twice, I ve shown that in the first equation. Any malonic ester can be used, but the diethyl is the cheapest. The acetoacetic acid synthesis is even more general than the malonic ester synthesis. The acetoacetic ester synthesis is most typically used with ethyl acetoacetate as an acetone equivalent, thus adding three carbon atoms to an alkyl chain. Again, the starting β-ketoester can be alkylated twice. Since there can be a number of different β-ketoesters (with groups other than methyl next to the ketone), the acetoacetic ester synthesis is much more versatile. Consider the compounds form in the Claisen reaction. One the malonic or acetoacetic ester syntheses are done, the carboxylic acid and the ketone are available as new functional groups and can be used in further reactions. Chapter 19 Aldol and Claisen Condensations The aldol condensation produces an α,β-unsaturated carbonyl compound. Disconnect the target molecule between the α and β carbon atoms. What is shown is an aldol condensation of a carbonyl compound with itself. It s possible to do a mixed aldol condensation (R R, R R ) but make sure that it s not a mixed aldol condensation between two partners of equal reactivity. Claisen condensations produce β-ketoesters. Disconnect the target between the ketone (on the β-carbon) and the α-carbon.

5 5 As with the aldol condensation, what is shown is a Claisen condensation of an ester with itself. It s possible to do a mixed Claisen condensation (R R) but make sure that it s not a reaction between two partners of equal reactivity. Don t forget that both the aldol and the Claisen condensations can be intramolecular both carbonyl groups are attached and a ring is formed. Conclusion (for now) Remember that retrosynthetic analysis is a planning tool for determining a possible synthesis. Since most of the syntheses in Chem 232 are short (five or fewer steps), you may be able to see the synthetic pathway without doing a retrosynthesis, and that s just fine. If you are stuck, however, even one or two retrosynthetic steps can make the problem less complex, and the solution may become fairly obvious. Peter Marrs, Chemistry 232 Notes, University of Victoria, July 2013

Chapter 22 Carbonyl Alpha-Substitution Reactions

John E. McMurry www.cengage.com/chemistry/mcmurry Chapter 22 Carbonyl Alpha-Substitution Reactions The α Position The carbon next to the carbonyl group is designated as being in the α position Electrophilic