1. 24-1 William H. Brown Beloit College William H. Brown Christopher S. Foote Brent L. Iverson Eric Anslyn http://academic.cengage.com/chemistry/brown Chapter 24 Carbon-Carbon Bond Formation and Synthesis

2. 24-2 Organometallic Compounds  Following are two extremely important reactions of metals and organometallic compounds: Oxidative addition:Oxidative addition: The addition of a reagent to a metal center causing it to add two substituents and its oxidation to increase by two. Reductive elimination:Reductive elimination: The elimination of two substituents at a metal center causing the oxidation state of the metal to decreased by two.

3. 24-3 Heck Reaction  A palladium-catalyzed reaction in which the carbon group of a haloalkene or haloarene is substituted for a vinylic H of an alkene.

4. 24-4 Heck Reaction Substitution is highly regioselective; most commonly at the less substituted carbon of the double bond. Substitution is highly stereoselective; where E,Z isomerism is possible in the product, the E configuration is often formed almost exclusively.

5. 24-5 Heck Reaction Reaction is stereospecific with regard to the haloalkene; the configuration of the double bond in the haloalkene is preserved.

6. 24-6 Heck Reaction  The catalyst: most commonly Pd(II) acetate. reduced in situ to Pd(0). reaction of Pd(0) with good ligands gives PdL 2. The organic halogen compound: aryl, heterocyclic, benzylic, and vinylic iodides, chlorides, bromides, and triflates (CF 3 SO 2 O-). alkyl halides with an easily eliminated  hydrogen are rarely used because they undergo  -elimination to give alkenes. OH groups and the C=O groups of aldehydes, ketones, and esters are unreactive under Heck conditions.

7. 24-7 Heck Reaction  The alkene The less the crowding on the alkene, the more reactive it is.  The base Triethylamine, sodium, and potassium acetate, and sodium hydrogen carbonate are most common  The solvent. Polar aprotic solvents such as DMF, acetonitrile, and DMSO. aqueous methanol may also be used.  The ligand Triphenylphosphine is one of the most common.

8. 24-8 Heck Reaction

9. 24-9 The usual pattern of acyclic compounds is: replacement of a hydrogen of the double bond with an R group. If attack of the organopalladium group on the double bond occurs so that the R group has no syn H for syn elimination, then the double bond may shift.

10. 24-10 Suzuki Coupling  Susuki coupling:  Susuki coupling: A palladium-catalyzed reaction of an organoborane (R’-BY 2 ) with an alkenyl, aryl, or alkynyl halide, or triflate (R-X).

11. 24-11 Suzuki Coupling Boranes are easily prepared from alkenes or alkynes by hydroboration. Borates are prepared from alkyl or aryl lithium compounds and trimethylborate.

12. 24-12 Suzuki Coupling These examples illustrate the versatility of the reaction.

13. 24-13 Suzuki Coupling Step 1 Ligand exchange: a transmetallation in which RX adds L 2 Pd to give RL 2 Pd(II)X complex of Pd(II). Treatment with base RO - Na + to replace X. Step 2 Borane activation: reaction of the borane R 3 ’B (a Lewis acid) with RO - (a Lewis base). Step 3 Coupling:

14. 24-14 Alkene Metathesis  Alkene metathesis:  Alkene metathesis: A reaction in which two alkenes interchange carbons on their double bonds. If the reaction involves 2,2-disubstituted alkenes, ethylene is lost to give a single alkene product.

15. 24-15 Alkene Metathesis A useful variant of this reaction uses a starting material in which both alkenes are in the same molecule, and the product is a cycloalkene. Catalysts for these reactions are a class of compounds called stable nucleophilic carbenes.

16. 24-16 Stable Nucleophilic Carbenes Carbenes and carbenoids (Chapter 15) provide the best route to three membered carbon rings. Most carbenes are highly reactive electrophiles. Carbenes with strongly electron-donating atoms, however, for example nitrogen atoms, are particularly stable. Rather than being electron deficient, these carbenes are nucleophiles because of the strong electron donation by the nitrogens. Because of their nucleophilicity, they are excellent ligands (resembling phosphines) for certain transition metals. The next screen shows one such stable nucleophilic carbene.

17. 24-17 Nucleophilic Carbene Nucleophilic Carbene A stable nucleophilic carbene.

18. 24-18 Alkene Metathesis Catalyst A particularly useful alkene methathesis catalyst consists of ruthenium, Ru, complexed with nucleophilic carbenes and another carbenoid ligand. In this example, the other carbenoid ligand is a benzylidene group.

19. 24-19 Ring-Closing Alkene Metathesis  Like the Heck reaction, alkene metathesis involves a catalytic cycle: Addition of a metallocarbenoid to the alkene gives a four-membered ring. Elimination of an alkene in the opposite direction gives a new alkene.

20. 24-20 Diels-Alder Reaction  Diels-Alder reaction:  Diels-Alder reaction: A cycloaddition reaction of a conjugated diene and certain types of double and triple bonds. dienophile:dienophile: Diene-loving. Diels-Alder adduct:Diels-Alder adduct: The product of a Diels-Alder reaction.

21. 24-21 Diels-Alder Reaction Alkynes also function as dienophiles. Cycloaddition reaction:Cycloaddition reaction: A reaction in which two reactants add together in a single step to form a cyclic product.

22. 24-22 Diels-Alder Reaction We write a Diels-Alder reaction in the following way: The special value of D-A reactions are that they: 1. form six-membered rings. 2. form two new C-C bonds at the same time. 3. are stereospecific and regioselective. Note the reaction of butadiene and ethylene gives only traces of cyclohexene.

23. 24-23 Diels-Alder Reaction The conformation of the diene must be s-cis.

24. 24-24 Diels-Alder Reaction (2Z,4Z)-2,4-Hexadiene is unreactive in Diels-Alder reactions because nonbonded interactions prevent it from assuming the planar s-cis conformation.

25. 24-25 Diels-Alder Reaction Reaction is facilitated by a combination of electron- withdrawing substituents on one reactant and electron-releasing substituents on the other.

26. 24-26 Diels-Alder Reaction

27. 24-27 The Diels-Alder reaction can be used to form bicyclic systems.

28. 24-28 Diels-Alder Reaction Exo and endo are relative to the double bond derived from the diene.

29. 24-29 Diels-Alder Reaction For a Diels-Alder reaction under kinetic control, endo orientation of the dienophile is favored.

30. 24-30 Diels-Alder Reaction The configuration of the dienophile is retained.

31. 24-31 Diels-Alder Reaction The configuration of the diene is retained.

32. 24-32 Diels-Alder Reaction  Mechanism No evidence for the participation of either radical of ionic intermediates. Chemists propose that the Diels-Alder reaction is a concerted pericyclic reaction.  Pericyclic reaction  Pericyclic reaction: A reaction that takes place in a single step, without intermediates, and involves a cyclic redistribution of bonding electrons.  Concerted reaction: All bond making and bond breaking occurs simultaneously.

33. 24-33 Diels-Alder Reaction Mechanism of the Diels-Alder reaction

34. 24-34 Aromatic Transition States  Hückel criteria for aromaticity:  Hückel criteria for aromaticity: The presence of (4n + 2) pi electrons in a ring that is planar and fully conjugated.  Just as aromaticity imparts a special stability to certain types of molecules and ions, the presence of (4n + 2) electrons in a cyclic transition state imparts a special stability to certain types of transition states. Reactions involving 2, 6, 10, 14.... electrons in a cyclic transition state have especially low activation energies and take place particularly readily.

35. 24-35 Aromatic Transition States Decarboxylation of  -keto acids and  -dicarboxylic acids. Cope elimination of amine N-oxides.

36. 24-36 Aromatic Transition States the Diels-Alder reaction pyrolysis of esters (Problem 22.42)  We now look at examples of two more reactions that proceed by aromatic transition states: Claisen rearrangement. Cope rearrangement.

37. 24-37 Claisen Rearrangement  Claisen rearrangement:  Claisen rearrangement: A thermal rearrangement of allyl phenyl ethers to 2-allylphenols.

38. 24-38 Claisen Rearrangement

39. 24-39 Cope Rearrangement  Cope rearrangement:  Cope rearrangement: A thermal isomerization of 1,5-dienes.

40. 24-40 Cope Rearrangement Example 24.8 Example 24.8 Predict the product of these Cope rearrangements.

41. 24-41 Synthesis of Single Enantiomers We have stressed throughout the text that the synthesis of chiral products from achiral starting materials and under achiral reaction conditions of necessity gives enantiomers as a racemic mixture. Nature achieves the synthesis of single enantiomers by using enzymes, which create a chiral environment in which reaction takes place. Enzymes show high enantiomeric and diastereomeric selectivity with the result that enzyme-catalyzed reactions invariably give only one of all possible stereoisomers.

42. 24-42 Synthesis of Single Enantiomers  How do chemists achieve the synthesis of single enantiomers?  The most common method is resolution which depends on: the different physical properties of diastereomeric salts. the use of enzymes as resolving agents. chromatographic on a chiral substrate.

43. 24-43 Synthesis of Single Enantiomers asymmetric induction chiral auxiliaryIn an alternative strategy, namely asymmetric induction, the achiral starting material is placed in a chiral environment by reacting it with a chiral auxiliary. E. J. Corey used this chiral auxiliary to direct an asymmetric Diels-Alder reaction. 8-Phenylmenthol was prepared from naturally occurring enantiomerically pure menthol.

44. 24-44 Synthesis of Single Enantiomers The initial step in Corey’s prostaglandin synthesis was a Diels-Alder reaction. By binding the achiral acrylate with enantiomerically pure 8-phenylmenthol, he thus placed the dienophile in a chiral environment. The result is an enantioselective synthesis.

45. 24-45 Synthesis of Single Enantiomers A third strategy is to begin a synthesis with an enantiomerically pure starting material. Gilbert Stork began his prostaglandin synthesis with the naturally occurring, enantiomerically pure D- erythrose. This four-carbon building block has the R configuration at each stereocenter. With these two stereocenters thus established, he then used well understood reactions to synthesize his target molecule in enantiomerically pure form.

46. 24-46 Carbon-Carbon Bond Formation and Synthesis End Chapter 24