GLOSSARY

3. GLOSSARY TARGET MOLECULE the molecule that we want to sintetize STARTING MATERIAL the molecule from which we start FUNCTIONAL GROUP INTERCONVERSION reaction that allows the passage from a functional group to another by substitution, addition, elimination, oxidation or reduction, or the opposite operation used in synthesis DISCONNECTION formal breaking of a bond of a molecule to split it into its possible precursors. It is the formal reverse of the reaction. SYNTHON formal fragment (usually positively or negatively charged) obtained by disconnection. It is not necessarily involved in the synthesis. When the retrosynthetic analysis is complete it is replaced by the reagent REAGENT real molecule, used in practice for the sinton

4. HOW OPERATE TO PROGRAM A SYNTHESIS: RETROSYNTHETIC ANALYSIS a) recognize the functional groups present in the target molecule b) disconnect with methods corresponding to known and reliable reactions c) repeat, if necessary, to reach easily available starting materials SYNTHETIC PLAN a) write out the plan according to the rethrosynthetic analysis, adding reagents and conditions b) modify the synthetic plane according to unexpecyted successes or failures taken in the lab OF COURSE, IN ORDER TO SUCCESS, THE ORGANIC CHEMIST MUST: 1) possess a deep understanding of the reaction mechanisms 2) possess a working knowledge of the reliable reactions 3) know that some compounds are easily available 4) know stereochemistry

5. GUIDELINES FOR A GOOD DISCONNECTION 1) Make the synthesis as short as possible 2) Use disconnections that correspond to known and reliable reactions 3) Disconnect C-X and R-(C=O)X bonds 4) Disconect C-C bonds according to the functional groups present on the target . If it is possible a) greatest simplification, disconnecting - in the middle of the molecule, - at branchpoints - separing rings from side chains b) using symmetry, when present 5) Choose disconnections corresponding to high yielding reactions, if they are known 6) Disconnect until a recognisable starting material is reached or alternatively an easily obtainable molecule.

6. GUIDELINES FOR A GOOD DISCONNECTION • The more important among these guidelines is the number one, because every step more means a decreasing of the overall yield of the synthesis. • Once designed, the synthesis will follow only some of these guidelines. • At the same time it may be that some of then are in contradiction. • A good evaluation can be made only on the basis of experience.

7. a) towards the middle of the molecule, as to break it in two similar moyeties, rather than detach one or two carbon atoms from the ends b) in the branching points, because it is easier to obtain linear chain fragments and they are more easily available SOME EXAMPLES Greatest simplification It will be possible to attain simple starting materials more easily, if the disconnection will be done ANALYSIS SYNTHESIS

8. SOME EXAMPLES Symmetry ANALYSIS SYNTHESIS

9. SOME EXAMPLES Symmetry ANALYSIS ? SYNTHESIS

10. SOME EXAMPLES High yielding steps ANALYSIS SYNTHESIS

11. straight chain compounds C1 to C8 alcohols, alkyl halides, aldehydes, amines, acids the same classes of compound of the straight chain molecules branched chain compounds cyclic alcohols and ketones C4 to C8 ketones butadiene isoprene styrene vinyl chloride monomers used to make plastics acrylates R = H methacrylates R = Me Recognisable starting materials

12. SOME EXAMPLES Nuciferal ANALYSIS SYNTHESIS

13. REGIOSELECTIVITY STEREOSELECTIVITY CHEMOSELECTIVITY Three aspects of control

14. CHEMOSELECTIVITY Selectivity between different functional groups REGIOSELECTIVITY Control between different aspects of the same functional group STEREOSELECTIVITY Control over stereochemistry CONTROL = The confidence that molecules can be compelled to combine in the ways that we require

15. discrimination displayed by a reagent A when it reacts with two different reactants B and C SELECTIVITY discrimination between two different reaction pathways when A is made to react with a single reactant B

16. REGIOSELECTIVITY the directional preference of the breaking or making of a chemical bond + CHEMOSELECTIVITY the preferential reaction of a given reagent with one of two or more functional groups that are present in a reactant or a group of reactants. + STEREOSELECTIVITY controlling the stereochemical outcome of a reaction

17. CHEMOSELECTIVITY: when we want that one and not another functional group in a molecule reacts • relative reactivity of two different functional groups • reaction of one of two identical functional groups • reaction of a group once when it may react again

18. GUIDELINE 1: with two functional groups of unequal reactivity, the more reactive can always be made to react alone ANALYSIS • Paracetamol is a simple amide and should be available by acetylation of p-aminophenol. SYNTHESIS • Here it is necessary to keep phenol not ionised, so that NH2 will be more reactive than OH. (NH3 is more nucleophilic than water, but less than OH-).

19. GUIDELINE 2: when one functional group can react twice, starting material and first product will compete for the reagent. The reaction will be successful only if the first product is less reactive than the starting material ANALYSIS • Disconnection of the ester bond gives simple starting materials, but the synthesis will require COCl2 (phosgene) to react once only with benzylic alcohol. • This succeeds since the half ester is less reactive than the double acid chloride because of conjugation. SYNTHESIS

20. GUIDELINE 3: If we wish to react the less reactive of two different functional groups or if the product of a reaction is as reactive or more reactive than the starting material, the unwanted reaction must be blocked with a protecting group. FOR EXAMPLE • In most reactions of the COOH group in aminoacids, the more reactive NH2 group must be protected, for example by benzyl chloroformate. • It can react twice with amine, but the first product is even more conjugated than benzyl chloroformate itself, and so less reactive. • The COOH group is less reactive than NH2 and does not react.

21. ANOTHER EXAMPLE The synthesis of thiol RSH by direct alkylation of H2S is not a good reaction, as the product is at least as reactive as the starting material Thiourea is used as masked H2S equivalent, the thiouronium salt being unable to react further and easily hydrolised to the thiol

22. GUIDELINE 4: one of two identical groups may react if the product is less reactive than the starting material FOR EXAMPLE • Reduction involves acceptance of electrons from the reducing agent. • The product has only one electron-withdrawing nitro group and so is reduced more slowly than the starting material.

23. GUIDELINE 5: one of two identical groups may react with one equivalent of reagent using the statistical effect FOR EXAMPLE This is an unreliable method, but if successful it avoids protecting groups or roundabout strategy. The two groups must be identical and must be separated from one another • This diol can be monoalkylated in reasonable yield by using one equivalent of sodium in xylene to generate mostly the monoanion. • Although this will be in equilibrium with the dianion, adding the alkyl halide gave an aceptable yield of hydroxy ether, used in the synthesis of vitamin E.

24. GUIDELINE 6: a more reliable method with two identical functional groups is to use a derivative which can react once only FOR EXAMPLE A cyclic anhydride is the most important example. When the anhydride has combined once with a nucleophile the product is no longer reactive. Further reactions can maintain the distinction to give e.g. the half ester, the half acid chloride and so on.

25. GUIDELINE 7: when two groups are nearly but not quite identical, avoid attempts to make only one of them react FOR EXAMPLE IT DOES NOT WORK!