Bài giảng Organic Chemistry - Chapter 22: What does the benzene ring do to its substituents?

Chapter 22: What does the benzene ring do to its substituents?Benzylic resonance for +/./-All stabilized by the overlapping p orbitalsBenzylic radicals are reactive intermediates in the α-halogenation of alkylbenzenesTherefore: Benzylic halogenationNo EAS (Which needs FeBr3)Mechanism of benzylic halogenationSubstitution occurs only at the benzylic position: Attack on the benzene destroys aromaticity!The two propagation stepsBenzylic cation (SN1 reaction)Mechanism:Octet!Needs e-pushers; parent is too slowSN2 is acceleratedTransition state is delocalizedSNsp2Benzylic Acidity: Resonance in Benzylic AnionsCompare CH2=CH-CH3  pKa ~ 40 Benzylic Oxidation-Reductionor Na2Cr2O7, H+ C-C bond broken via:Can be stopped here(Recall electrophilic aromatic substitution: alkylacyl)Neutral, mildProtecting groupDiscardedDeprotectedUntouchedBenzylic hydrogenolysis: Unique!Compare tert-Bu ethers as protecting groups, need acid for deprotection Compare allylic oxidation wth MnO2Benzenol (Phenol)Keq = 1013Nomenclature(Note: Phenol is an enol!) Phenol ethers: AlkoxybenzenesPhenoxy (from “phenyloxy”)e.g.Methoxybenzene (Anisole)Natural productsAcidity(Enolate!) Substituent effects: Inductive + resonancesp2Multiple resonating e-withdrawing substituents increase the acidity to that of mineral acidsPreparation of PhenolsProblem with EAS: However, when a leaving group is on the ring: Nucleophilic aromatic substitution is possible!We learned earlier that SN2 is not possible on haloalkenes. How does aromatic nucleophilic substitution work? Electrophilic aromatic substitution needs “+OH” equivalent: e-sextet. Difficult to generate, problem is unsolved.::When electron withdrawing groups are present, nucleophilic aromatic addition–elimination takes place.Without e-withdrawing groups: harsh conditions enforce an elimination-addition sequence through reactive benzyne intermediate.With super L = N2, phenyl cation intermediates.And then there is the Nobel-winning Pd (2010)!Four mechanistic scenarios exist:Case 1:NuArMechanismDoes not work with meta-nitro groups Case 2: Elimination-Addition via BenzyneAt highly elevated temperatures and pressures(-33 °C)Mechanism: Elucidated by using 14C labelIndicates formation of benzyne (highly strained)“Biradicaloid” (not E2, but stepwise, via anion)BenzynepKa ~ 44Case 3: Super leaving group nitrogen: Arenediazonium saltsPrimary amineRelatively stable (but explosive!), isolable at low-room temperature“Diazotization”Reminder:In general,Phenyl cationCase 4: Pd-Catalyzed Hydroxylations of HaloarenesPd catalyst is homogeneous (soluble), e.g., Pd[P(C6H5)3]4; unlike Pd/CWorks for aminations:Very abbreviated: There are phosphine ligands around the metal.Chemistry of Phenolsa. Basicity: weak Less basic than alkanols, because e-pair is tied up by resonance with the benzene ringb. No phenyl cations:c. But phenol is a leaving group d. Phenols form ethers by Williamson synthesisd. Phenols form esters10,000 Tons per yearBut:More nucleophilice. Electrophilic aromatic substitution Para productpredominatesHalogenation fast, does not need catalyst, needs cooling to control monobrominationEven CO2 reacts: Kolbe-Schmitt reactionAdolph W. H. Kolbe 1818-1884Rudolf Schmitt 1830–1898 Via:“Salicylic acid” (as salt);precursor to aspirin:Oxygen lone pairs assist in directing ortho by electrostaticsBound reactive groups are also directed ortho: Allyloxyarenes undergo the Claisen rearrangementMechanism:An extension of electrocyclic reactions. The carbon analog is called Cope rearrangement. Rainer Ludwig Claisen 1851-19306e aromatic TSEnolizationCope RearrangementRecall:Dihydro analog of hexatriene ring closureArthur C. Cope 1909-1966Breaking three bondsMaking three bondsRelease of ring strainDegenerate Cope rearrangementCope-ImmelCompare to normal (aromatic) Claisen rearrangementImmelThe oxa analog of the Cope is the “aliphatic” (as opposed to aromatic) Claisen rearrangement:Alt-entArenaminesReact like amines (e.g., acidic, basic, make amides, and undergo alkylation)Less basic than RNH2 (pKa ~ 11), because of resonancepKa = 4.63Further utility stems from diazonium saltsArenediazonium SaltsRelatively stable because: a. ResonanceRevisited:b. Extrusion of N2 forms bad phenyl (aryl) cationPhenyl cationN2 elimination leads to useful substitutions. Recall phenol synthesis with water. Other nucleophiles work, too:Cu catalysisReductive removal of nitrogen: Strategic applications of arenediazonium salts: 1. ArH → ArNO2 → ArNH2 → Ar’NH2 → Ar’HUse of the amino substituent as an activator in EAS, followed by removal.2. ArH → ArNO2 → ArNH2 → ArNuH replaced by OH: H3PO3