1 / 47

Carbon-Carbon Bond Formation and Synthesis

Carbon-Carbon Bond Formation and Synthesis. Organometallic Compounds. Recall: two extremely important reactions of metals and organometallic compounds:

paul2
Download Presentation

Carbon-Carbon Bond Formation and Synthesis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Carbon-Carbon Bond Formation and Synthesis

  2. Organometallic Compounds • Recall: two extremely important reactions of metals and organometallic compounds: • Oxidative addition: The addition of a reagent to a metal center causing it to add two substituents which extract two electrons from the metal and increasing its oxidation state by two. • Reductive elimination: The elimination of two substituents which donate two electrons to the metal center causing the oxidation state of the metal to decrease by two.

  3. Heck Reaction Overall: A palladium-catalyzed reaction in which the R group of RX, a haloalkene or haloarene, is substituted for a vinylic H of an alkene.

  4. Heck Reaction (consider the alkene) • Substitution (H  R) is highly regioselective; most commonly at the less substituted carbon of the double bond. • Substitution is highly stereoselective; the E configuration is often formed almost exclusively. E Less substituted, H  Ph substitution occurs here. Neither E nor Z

  5. Heck Reaction (RX = Haloalkene) • For RX = haloalkene: Reaction is stereospecific; the configuration of the double bond in the haloalkene is preserved. E E

  6. Heck Reaction. Some considerations. • The catalyst: • most commonly Pd(II) acetate. • reduced in situ to Pd(0). • reaction of Pd(0) with good ligands gives PdL2. • The organic halogen compound: aryl, heterocyclic, benzylic, and vinylic iodides, chlorides, bromides, and triflates (CF3SO2O-). • alkyl halides with an easily eliminated b hydrogen are rarely used because they undergo b-elimination to give alkenes. • OH groups and the C=O groups of aldehydes, ketones, and esters are unreactive under Heck conditions.

  7. Heck Reaction. More… • 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, PPh3, is one of the most common.

  8. Heck Reaction Start here L = PPh3 R 0 II II II II Rotation about the C-C bond. This is where the R is swapped in, replacing the H.

  9. Heck Reaction • The usual pattern of acyclic compounds: replacement of a hydrogen of the double bond with the R group. • If the R group has no H for syn elimination, then a b H may be abstracted elsewhere. This b H should be brought into position for syn elimination with the Pd. Can’t happen due to cyclohexane ring.

  10. Suzuki Coupling Suzuki coupling: A palladium-catalyzed reaction of an organoborane (R’-BY2) or organoborate (RB(OMe)2) with an alkenyl, aryl, or alkynylhalide, or triflate (R-X) to yield R-R’. Overall:

  11. Suzuki Coupling • Recallboranes are easily prepared from alkenes or alkynes by hydroboration. • Borates are prepared from alkyl or aryl lithium compounds and trimethylborate. PhCl + Li

  12. Suzuki Coupling • These examples illustrate the versatility of the reaction.

  13. Suzuki Coupling Reductive elimination Oxid. Addn Transmetalation R1 and OtBu swap Substitution

  14. 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. 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. Stable Nucleophilic Carbenes • Carbenes and carbenoids 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 they donate electrons well, they are excellent ligands (resembling phosphines) for certain transition metals. • The next screen shows a stable nucleophilic carbene.

  17. Nucleophilic Carbene • A stable nucleophilic carbene.

  18. Alkene Metathesis Catalyst • A 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. 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. Ring-Closing Alkene Metathesis

  21. Ring-Closing Alkene Metathesis Initiation Step Cycle start

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

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

  24. 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.

  25. Diels-Alder Reaction • The conformation of the diene must be s-cis.

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

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

  28. Diels-Alder Reaction

  29. Diels-Alder Reaction • The Diels-Alder reaction can be used to form bicyclic systems.

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

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

  32. Diels-Alder Reaction • The configuration of the dienophile is retained.

  33. Diels-Alder Reaction • The configuration of the diene is retained.

  34. 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: 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.

  35. Diels-Alder Reaction • Mechanism of the Diels-Alder reaction

  36. Aromatic Transition States • 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.

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

  38. 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.

  39. Claisen Rearrangement • Claisen rearrangement: A thermal rearrangement of allyl phenyl ethers to 2-allylphenols.

  40. Claisen Rearrangement

  41. Cope Rearrangement • Cope rearrangement: A thermal isomerization of 1,5-dienes.

  42. Cope Rearrangement Example 24.8 Predict the product of these Cope rearrangements.

  43. 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.

  44. Synthesis of Single Enantiomers • How do chemists achieve the synthesis of single enantiomers? • The most common method is to produce a racemic mixture and then resolve it. How? • the different physical properties of diastereomeric salts. • the use of enzymes as resolving agents. • chromatographic on a chiral substrate.

  45. Synthesis of Single Enantiomers • In a second strategy, asymmetric induction, the achiral starting material is placed in a chiral environment by reacting it with a chiral auxiliary. Later it will be removed. • E. J. Corey used this chiral auxiliary to direct an asymmetric Diels-Alder reaction. • 8-Phenylmenthol was prepared from naturally occurring enantiomerically pure menthol.

  46. 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.

  47. 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.

More Related