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3150 Ch 19 Handout Klein Ald Ketone.Cdx California State Polytechnic University, Pomona 19-1 Organic Chemistry II, CHM 3150, Dr. Laurie S. Starkey Chapter 19 (Klein): Aldehydes & Ketones I) Nomenclature (19.1, 19.2) Try SkillBuilder 19.1 O Aldehydes (RCHO) C parent: alkanal (C=O is always C#1) R H O O O O O H H H CH3 H H H methanal ethanal 3-methylpentanal (E)-2-butenal benzaldehyde (common) (formaldehyde) (acetaldehyde) IUPAC: O Ketones (RCOR) parent: #-alkanone C (C=O gets lowest possible #) R R OH O O CH CH 3 3 O O 2-propanone (S)-3-hydroxy-2-butanone benzophenone (common) 2-cyclohexen-1-one (acetone) (ketone is higher priority FG) IUPAC: II) Preparation/Synthesis of Aldehydes & Ketones (19.3) O a) Oxidation of alcohols (12.10) OH O [ox] R C R' R C R' H , , indicates relative position aldehyde (R' = H) ( means "next to" carbonyl) or ketone b) Ozonolysis of alkenes (8.12) c) Hydration of alkynes (9.7) R H O O O 1) O "H2O" 3 R C C H R C CH R C R R' C H 2 methods 3 R R' 2) (CH3)2S 1) Sia2BH OH H III) Reactions with Nucleophiles (Nu:) (19.4) 2) H O A) Hydride (12.4, 19.9) 2 2 R C CH NaOH B) Carbon Nu: (19.10) H OH enol O 1) NaCN and NaC CR 2) Organometallic reagents (RMgBr, RLi) R C CH R CH2 CH 3) Wittig reaction (& HWE) C) Oxygen Nu: (19.5) & hydrolysis (19.7) Read on your own: 19.13 (IR/NMR Spectroscopy) D) Nitrogen Nu: (19.6) Skip section 19.11 (Baeyer-Villiger Oxidation): IV) Oxidation and Reductions (19.8, 19.9) V) Applications of Acetals O O A) carbohydrates (24.5) RCO3H B) protective groups (19.5, 12.7) O VI) Synthesis strategies (19.12) ketone ester The carbonyl (19.4) 19-2 O O resonance inductive effects Reactivity O ** C=O is very strong and stable functional group H2C CH3 BDE(kcal/mol) C-O 79 C=O 173 H ** formation of C=O can be a driving force for a reaction Carbonyl-containing functional groups: O O O O O O R R R H R OH R Cl R OR' R NH2 III) Reactions with Nucleophiles (Nu:) (19.4) A) Hydride (12.4) LiAlH - lithium aluminum hydride (LAH) 4 both are sources of hydride NaBH4 - sodium borohydride + O 1) LiAlH4 2) H3O CH3 CH3 (workup) this reaction is described as a(n) reduction / oxidation B) Carbon Nu: 1) Carbanions: NaCN and NaC CR Acetylide anion O 1) NaNH2 2) HC CH 3) H3O+ Cyanide anion 19-3 O 1) NaCN a "cyanohydrin" -- reaction is reversible (NC- ok LG) Ph + + 2) H3O H3O --RCN(nitrile) RCO2H (Ch. 20) 2) Organometallic reagents (RMgX, RLi) (12.6) O 1) PhMgBr H C CH CH 2 3 + 2) H3O Retrosynthesis of alcohols Ketone + Grignard Alcohol OH R R" R' Example: Transform HO Cl Example: Transform (clicker) OH HO CH2CH3 CH3 CH3 CH3 CH3 Example: Transform OH OH SkillBuilders 12.5 & 13.7 III) Reactions with Nucleophiles (Nu:) 19-4 Wittig Reagent - B) Carbon Nu: (19.10) a resonance-stabilized carbanion (Nu:) 3) Wittig Reaction (pronounced "Vittig") Example: Use of Wittig reagent: Ph3P CH2 reacts with aldehydes & ketones a phosphonium ylide (+/- charges) Example: O Ph3P CH2 Mechanism (FYI): Ph Ph Ph Ph3P O P H2C O H2C oxaphosphetane intermediate (falls apart) Preparation of Wittig reagent: two steps from an alkyl halide (RX) H H PPh3 BuLi H Br BuLi = CH CH CH CH Li Alkyl halide 3 2 2 2 Butyllithium is a strong base Predict the major product: O Ph3P H Wittig Retrosynthesis TM Synthesis: Try SkillBuilder 19.6 Try Summary: Synthesis of Alkenes Target 19-5 Molecule: StartingMaterial Reagents Mechanism OH E1 conc. H SO , heat alcohol 2 4 -- Carbocation can rearrange (dehydration) (ROH) -- Gives most stable alkene (Zaistev) Br E2 alkyl halide NaOH, heat -- Anti elimination (RX) (t-BuOK gives -- Gives most stable alkene (Zaistev) Hofmann regio.) (bulky base = less hindered H= less subt'd alkene, Hofmann) O Wittig ketone or -- Alkene replaces C=O aldehyde -- Great regiocontrol -- Ideal for synthesis Also: R trans R' alkene Mechanism: N/A R R' (reduction rxn) cis alkyne R R' alkene O III) Reactions with Nucleophiles (Nu:) HO OH C) Oxygen Nu: (19.5) H2O R R' R R' 1) addition ofwater hydrate a ket/ald a hydrate exceptions: a) Formaldehyde is 99% hydrate in aqueous solution O H O H H 2 b) Hydrate is favored if there is a + center near carbonyl O chloral hydrate HO OH Cl - more stable (less +) C H H2O - can be isolated Cl Cl C H 3 - “Mickey Finn” knockout drops Cl chloral III) Reactions with Nucleophiles (Nu:) TsOH = tosic acid (catalyst) O 19-6 C) Oxygen Nu: (19.5) S OH 2)additionofROH acetal O O TsOH RO OH ROH RO OR + ROH + H2O R' R" R' R" R' R" ald/ketone alcohol acetal + H3O causes reverse reaction (19.7) Predict: O CH3OH CH3CH2 H TsOH Mechanism: - acid catalyzed so first step: Try SkillBuilder 19.2 - only neutral or negative / positive charges What is a CTI? Charged Tetrahedral Intermediate Tetrahedral Intermediate Charged Tetrahedral Intermediate - sp3 carbon - sp3 carbon, two groups have lone pair(s) - at least two groups have lone pair(s) - one group has a charge (+ or ) - can collapse! (push-pull) X Y acid- X base- X catalyzed Y catalyzed Y H Acetal Summary 19-7 O RO OR formation of acetal adds ___ equivalents of alcohol acetal hydrolysis regenerates C=O is this an oxidation reaction? Cyclic Acetals O TsOH O O use a diol (both equiv. of HO OH ROH in same molecule) to make a cyclic acetal what makes this an acetal? Hydrolysis of an Acetal (19.7) + O CH3O OCH3 H3O + 2 CH3OH CH CH H CH CH H 3 2 (H2O+ HA) 3 2 Mechanism: exact reverse of acetal formation (theory of microscopic reversibility) CH3O OCH3 CH3CH2 H III) Reactions with Nucleophiles (Nu:) 19-8 D) Nitrogen Nu: (19.6) R O N TsOH 1) Reaction with NH3 or RNH2 R-NH2 + H2O (ammonia or a primary/1º amine) imine R R 2) Reaction with R2NH O R R N (a secondary/2º amine) N TsOH + H2O H enamine Predict: O CH3NH2 TsOH Mechanism (SkillBuilder 19.3) O Predict: O N TsOH H Mechanism (SkillBuilder 19.4) O + Like acetals, imines and enamines undergo hydrolysis with H3O (19.7). Try SkillBuilder 19.5 3 IV) Oxidation and Reductions 19-9 + Aldehydes can be oxidized to carboxylic acids Tollens’ silver mirror test (Ag Ag°) O [ox] O Carbohydrates with an aldehyde group are referred to as “reducing sugars” because R H R OH they can be oxidized - Benedict’s Test (red/brown precipitate) - Fehling’s Solution (Cu2+ Cu+) Reduction of aldehydes and ketones (19.8, 19.9) + 1) LiAlH4; 2) H3O O [red] OH or NaBH4, MeOH R R' R R' or ketone/ald alcohol Raney nickel (Ni-H2) - catalytic hydrogenation of C=O - reduces alkenes/alkynes also O [red] Clemmenson Reduction R R' R R' Zn(Hg), HCl, H2O ketone/ald alkane or Wolff-Kishner Reduction 1) NH NH ; 2) KOH, heat TsOH 2 2 Raney Ni or HS SH Raney Ni (Ni-H2) reduction of thioacetal (19.8) V) Application of Acetals 19-10 A) Carbohydrates (24.5) O H O H OH HO H predominantly in cyclic form H OH in solution D-glucopyranose H OH link two sugars to make CH2OH a disaccharide, and sugar OH D-glucose continue links to make (an aldose) polysaccharides HOCH2 H OH H H OH H OH O H OH D-glucose Formation of a 5-membered ring (furanose form) O HOCH2 CH H O OH H OH H OH H H OH OH H H OH H OH CH2OH -D-glucopyranose (Haworth projection) D-ribose cyclic form (5 memb. ring) HOCH2 Eample (clicker): draw the pyranose form of fructose H O H H O OH OH H O HO OH OH OH H OH OH OH -D-glucopyranose Try this mechanism: OH OH 19-11 HO OH O HO OH O HO HO OH OH Formation of Disaccharides (24-7) Polysaccharides (24-8) H OH OH H O O HO OH O HO H H HO H OH H O OH OH OH H HO H O HO H O O D-glucose OH HO H HO O OH O HO H O OH O OH HO OH H O OH OH H O OH H OH Starch O H OH H OH sucrose amylose (unbranched) OH D-fructose (a disaccharide) amylopectin (highly branched) O -1,4-glycosidic bonds water-soluble, digestible by animals OH OH OH OH O O HO O O HO O O HO O O HO O OH OH OH OH Cellulose -1,4-glycosidic bonds rigid, insoluble, not digestible Other Sugar-Containing Biomolecules (24.10) NH2 NH2 N N N N N N HO N HO N O O H H H H H H H H OH OH OH H ribonucleoside deoxyribonucleoside (RNA) (DNA) (RNA) (DNA) V) Application of Acetals B) Protective Groups (19.5, 12.7) 19-12 ** Protective group strategy: hide carbonyl, do reaction elsewhere on molecule, regenerate C=O O ROH, HA RO OR Nu: or base + + H O * C=O is an Electrophile * not an E 3 (due to C=O resonance) (no LG or C=O) * no acidic protons * has acidic protons hydrolysis is only acetal reaction (acetal is unstable to acidic conditions) What happens when the following synthesis is attempted? O O O 1) O Mg H H OH Cl MgCl + 2) H3O ** Can also protect alcohols (hide the acidic OH proton) (12.7) TMS = trimethylsilyl CH 3 TES = triethylsilyl (CH3)3SiCl OH O Si CH3 (TMSCl) TBS = t-butyldimethylsilyl CH3 base TiPS = silyl ether + - O SiR3 Bu4N F Fluoride removes silyl F (TBAF) ether protective groups O OH OH Br OLC/Group activity: provide reagents for an alternate synthetic route (Grignard reaction first) VI) Synthesis Strategies (19.12) Try SkillBuilder 19.7 19-13 OH O R OH Acetal Mechanism Practice Problems See also Klein (3rd ed.) problems 8, 12, 14, 19, 55, 63 1.
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