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1、24-24-1 1Carbon-Carbon Bond Formation and Synthesis24-24-2 2Organometallic CompoundsuRecall: two extremely important reactions of metals and organometallic compounds: Oxidative additionOxidative addition: : The addition of a reagent to a metal center causing it to add two substituents which extract
2、two electrons from the metal and increasing its oxidation state by two. Reductive eliminationReductive 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. 24-24-3 3Heck ReactionOverall: A palla
3、dium-catalyzed reaction in which the R group of RX, a haloalkene or haloarene, is substituted for a vinylic H of an alkene.24-24-4 4Heck Reaction (consider the alkene)Substitution (H R) is highly regioselective; most commonly at the less substituted carbon of the double bond.Substitution is highly s
4、tereoselective; the E configuration is often formed almost exclusively.ENeither E nor ZLess substituted, H Phsubstitution occurs here.24-24-5 5Heck Reaction (RX = Haloalkene)For RX = haloalkene: Reaction is stereospecific; the configuration of the double bond in the haloalkene is preserved.EE24-24-6
5、 6Heck Reaction. Some considerations.uThe 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
6、 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.24-24-7 7Heck Reaction. MoreuThe alkeneThe less the crowding on the alkene, the more reactive it is.uThe b
7、aseTriethylamine, sodium, and potassium acetate, and sodium hydrogen carbonate are most commonuThe solvent.Polar aprotic solvents such as DMF, acetonitrile, and DMSO.aqueous methanol may also be used.uThe ligandTriphenylphosphine, PPh3, is one of the most common.24-24-8 8Heck ReactionRotation about
8、the C-C bond. This is where the R is swapped in, replacing the H.L = PPh3RStart here0IIIIIIII24-24-9 9Heck ReactionThe 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 H may be abstracted elsewhere.T
9、his H should be brought into position for syn elimination with the Pd. Cant happen due to cyclohexane ring.24-24-1010Suzuki CouplingSuzuki coupling:Suzuki coupling: A palladium-catalyzed reaction of an organoborane (R-BY2) or organoborate (RB(OMe)2) with an alkenyl, aryl, or alkynyl halide, or trifl
10、ate (R-X) to yield R-R.Overall:24-24-1111Suzuki CouplingRecall boranes are easily prepared from alkenes or alkynes by hydroboration.Borates are prepared from alkyl or aryl lithium compounds and trimethylborate.PhCl + Li24-24-1212Suzuki CouplingThese examples illustrate the versatility of the reactio
11、n.24-24-1313Suzuki CouplingOxid. AddnSubstitutionTransmetalation R1 and OtBu swapReductive elimination24-24-1414Alkene MetathesisuuAlkene metathesis:Alkene metathesis: A reaction in which two alkenes interchange carbons on their double bonds.If the reaction involves 2,2-disubstituted alkenes, ethyle
12、ne is lost to give a single alkene product.24-24-1515Alkene MetathesisA 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
13、.24-24-1616Stable Nucleophilic CarbenesCarbenes 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
14、 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.24-24-1717 Nucleophilic Carben
15、eA stable nucleophilic carbene.24-24-1818Alkene Metathesis CatalystA 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.24-24-1919Ring-Closing Alkene Metath
16、esisuLike 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.24-24-2020Ring-Closing Alkene Metathesis24-24-2121Ring-Closing Alkene MetathesisInit
17、iation StepCyclestart24-24-2222Diels-Alder ReactionuuDiels-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 reacti
18、on.24-24-2323Diels-Alder ReactionAlkynes 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.24-24-2424Diels-Alder ReactionWe write a Diels-Alder reaction in the following way:The specia
19、l 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. 24-24-2525Diels-Alder ReactionThe conformation of the diene must be s
20、-cis.24-24-2626Diels-Alder Reaction Steric RestrictionsDiels-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.24-24-2727Diels-Alder ReactionReaction is facilitated by a
21、 combination of electron-withdrawing substituents on one reactant and electron-releasing substituents on the other.24-24-2828Diels-Alder Reaction24-24-2929Diels-Alder ReactionThe Diels-Alder reaction can be used to form bicyclic systems.24-24-3030Diels-Alder ReactionExo and endo are relative to the
22、double bond derived from the diene.24-24-3131Diels-Alder ReactionFor a Diels-Alder reaction under kinetic control, endo orientation of the dienophile is favored.24-24-3232Diels-Alder ReactionThe configuration of the dienophile is retained.24-24-3333Diels-Alder ReactionThe configuration of the diene
23、is retained.24-24-3434Diels-Alder ReactionuMechanismNo evidence for the participation of either radical of ionic intermediates.Chemists propose that the Diels-Alder reaction is a concerted pericyclic reaction.uuPericyclic reactionPericyclic reaction: A reaction that takes place in a single step, wit
24、hout intermediates, and involves a cyclic redistribution of bonding electrons.uConcerted reaction: All bond making and bond breaking occurs simultaneously.24-24-3535Diels-Alder ReactionMechanism of the Diels-Alder reaction24-24-3636Aromatic Transition StatesuuHckel criteria for aromaticity:Hckel cri
25、teria for aromaticity: The presence of (4n + 2) pi electrons in a ring that is planar and fully conjugated.uJust 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 t
26、ypes 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.24-24-3737Aromatic Transition StatesDecarboxylation of -keto acids and -dicarboxylic acids.Cope elimination of amine N-oxides
27、.24-24-3838Aromatic Transition Statesthe Diels-Alder reactionpyrolysis of esters (Problem 22.42)uWe now look at examples of two more reactions that proceed by aromatic transition states:Claisen rearrangement.Cope rearrangement.24-24-3939Claisen RearrangementuuClaisen rearrangement:Claisen rearrangem
28、ent: A thermal rearrangement of allyl phenyl ethers to 2-allylphenols.24-24-4040Claisen Rearrangement24-24-4141Cope RearrangementuuCope rearrangement:Cope rearrangement: A thermal isomerization of 1,5-dienes.24-24-4242Cope RearrangementExample 24.8Example 24.8 Predict the product of these Cope rearr
29、angements.24-24-4343Synthesis of Single EnantiomersWe 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
30、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.24-24-4444Synthesis of Single EnantiomersuHow do chem
31、ists achieve the synthesis of single enantiomers?uThe 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.24-24-4545Synthesis of Single Enant
32、iomersIn a second strategy, asymmetric inductionasymmetric induction, the achiral starting material is placed in a chiral environment by reacting it with a chiral auxiliarychiral auxiliary. Later it will be removed.E. J. Corey used this chiral auxiliary to direct an asymmetric Diels-Alder reaction.8
33、-Phenylmenthol was prepared from naturally occurring enantiomerically pure menthol.24-24-4646Synthesis of Single EnantiomersThe initial step in Coreys prostaglandin synthesis was a Diels-Alder reaction.By binding the achiral acrylate with enantiomerically pure 8-phenylmenthol, he thus placed the die
34、nophile in a chiral environment.The result is an enantioselective synthesis.24-24-4747Synthesis of Single EnantiomersA 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.
