Bài giảng Organic Chemistry - Chapter 17: Aldehydes and Ketones

Chapter 17: Aldehydes and KetonesFunctional Group: CarbonylAldehyde: RCHO,Ketone: RCOR’, NomenclatureThe carbonyl group of aldehydes and ketones has priority over all other polar or functions used so far, namely RX, ROH, , ,(But not COOH—to be covered later)>In addition:Systematic Naming (IUPAC)AldehydesAlkane  Alkanal. Longest chain starts at -CH=O, which contains C1.Examples:Formaldehyde AcetaldehydeIUPAC-accepted common namesCyclic aldehydes have the ending-carbaldehyde after cycloalkane name. The carbon attached to -CH=O is C1.Examples:Theunit as a substituent is calledformyl.Cis-2-ethenylcyclo-hexanecarbaldehyde●●●KetonesAlkane  Alkanone. Longest chain incorporates carbonyl carbon and is numbered from terminus close to C=O.Cyclic ketones are cycloalkanones; C=O is C1.Examples:2-PentanoneAn aldehyde containing a ketone C=O is called an oxoalkanal.Example:Substituent name: acyl OROCH3acetyl, but propanoyl(IUPAC accepted common name)OCH3CH2Structure OrbitalsThe carbonyl group contains a short, strong, and very polar bond.ResonancePolarizationMolecular structureElectrostatic Potential Map175 kcal mol-1Synthesis (A review of Chapter 8)Old: Oxidation of Alcohols Primary  aldehydes Secondary  ketones Use chromium(VI) reagents (CrO3, Na2Cr2O7) Selective: Will not oxidize alkene or alkyne units. Especially mild is PCC:PyridinePyridinium chlorochromate : “PCC” NH +NCrO3Cl-PCC avoids water, which causes overoxidation of primary alcoholsExamples:New: Allylic Oxidation with MnO2Selective: Will not attack ordinary alcoholsAllylic H is reactiveNot allylic3. Old: Ozonolysis of Alkenes: O3, then reducing agent [(CH3)2S or Zn, CH3COOH]Oxidative cleavage of carbon-carbon double bonds4. Old: Hydration of AlkynesHydration of the carbon–carbon triple bond yields enols that tautomerize to carbonyl compoundsMarkovnikov: Use Hg2+, H2O, H+:Anti-Markovnikov: Use hydroboration-oxidation5. Old: Friedel-Crafts acylation (Electrophilic Aromatic Substitution)(work-up)(work-up)ReactionsE.g., NaBH4, RLi, RMgX(H+)There are three regions of reactivity in aldehydes and ketonesReviewAllylicNucleophilic additions to carbonyls to give alcoholsNew: Addition reactions also occur with milder nucleophiles, such as water, alcohols, and amines. To speed them up, acid or base catalysis is required. Moreover: They are reversible!Old:1. Hydration: Geminal Diols (Carbonyl Hydrates)K ~ 1K depends on “unhappiness” of C=O polarization: Electron-withdrawing substituents activate, donors deactivate.Mechanisms:2. Addition of AlcoholsSame as water, initially, to form hemiacetalsKKK varies from 1, as with water. Depends on R.H+ or HO-H+ or HO-Note: Two molecules turn into one.Intramolecular variant (important for sugars, Chapter 24): Best for 5- and 6-membered rings.Favored by entropy relative to intermolecular addition: ΔG ° = ΔH ° − TΔS °ΔS ° is less negative for intramolecular reaction.K >1!We can drive the hemiacetal step further with more alcohol and with H+ (not HO-) catalysis: Acetals Acetals are stable to: Base Oxidizing agents Nucleophiles (Grignards, alkyllithiums, hydrides)Acetals are NOT stable to: Acid (you can reverse the above with excess H2O)(A geminal diether)K >1!(isolated)Three molecules turn into two Mean 152 61% Stddev 44 Mechanism:AcetalAddition of R’OH to carbonyl functionReplacement of HO- with R’O-Cyclic Acetals: mutual protection of carbonyl and diol functions: H+Intramolecular variant (important for sugars, Chapter 24). Best for 5- and 6-membered rings.H+, H2OHydrolysis = DeprotectionLocks the ringTwo molecules turn into two1.2. Mg3.4. H+, H2O Examples:Diol protection:Carbonyl protection:Thiols Form Thioacetals. Even better protectors: stable to acid! Another application of thioacetals: DesulfurizationDeprotectionNeeds Hg2+ catalysis:Thioacetalization uses Lewis acid catalysis, e.g., ZnCl2. Again, cyclic version particularly favorable.More applications: Chapter 23.Acetal Prodrugs: ResveratrolSame effect as dietary restriction and exercise. Benefits: lifespan extension in model systems, improvements of functionality in aging, protection of the cardiovascular system, anti-inflammatory activity (arthritis), cancer chemoprevention.AgingThe French paradoxProblem for drug applications: rapid metabolism. Solution: administer an acetal for time controlled delivery:Mol. Pharmaceutics 2013, 10, 2781−27923. Amine AdditionsExample:NH3 and RNH2 add to the carbonyl function, followed by dehydration: A “condensation” reaction. Water is lost with simultaneous C=N bond formation (opposite of hydrolysis). An imineMechanism:Hemiaminal DehydrationImine Formation via hemiaminalA condensation product (-H2O)Exact sequence of nucleophilic addition and H+ shuttle is pH dependent.Intramolecular reaction: Best for 5- and 6-membered rings.Cat. H+Cat. H+Reaction of the carbonyl function with RR’NH gives hemiaminals from which normal dehydration to imines is not possible: No H left on N. Therefore, water loss occurs to the “carbon side” to form an enamine (does not occur for hemiacetals).Enamine FormationNo H leftGoes for this HMechanism:Enamines are useful, can be alkylated (Chapter 18-4).e-rich●Wolff-Kishner Reduction An Application of Hydrazones Synthesis of a Hydrazone by Imine FormationMechanism: Nitrogen eliminationIn practice, the reaction is carried out without isolating the intermediate hydrazone.A diazaallyl anion4. Addition of Non-organometallic Carbon Nucleophilesa. Cyanide makes cyanohydrinsTo make HCNMechanism:NaOHUsefulness: C-C bond formation with -CN as a versatile functional group.Burnet mothb. The Wittig ReactionPhosphonium salt synthesisGeorg Wittig (1897–1987) NP 1979Discovered during an investigation of SN2 reactions of phosphines with haloalkanes.The charge on P acidifies the adjacent C-H: Deprotonation gives a so-called ylideOther (weaker) bases OK, such as CH3O-, CH3OH, generate the ylide in equilibrium concentrations sufficient for the next step: Attack on carbonyl carbon and formation of alkenes.NucleophilicValence shell expandedWittigCompare:E and Z-Examples:Reactive ylides are cis-selectiveResonance-stabilized ylides are trans-selectiveNo additional resonating double bondsBASF Vitamin A1 SynthesisReact with aldehydes, but not ketones5. Addition of Hydroxy Groups Revisited: Baeyer-Villiger OxidationOxidation of ketones by peroxycarboxylic acids gives esters:Mechanism:Adolf von Baeyer (1835-1917) NP 1905. Victor Villiger1868 - 1934 Two stepsFamiliar? Recall: Chapter 9-3And Chapter 12-8The transition state of the Baeyer-Villiger oxidation involves migration of R’ through a push-pull electronic relay:PushPullPushPushPullPullExamples:Regioselective!H3CCOOHORegioselective!