Advanced Organic Chemistry Chapter-1 PDF

Advanced Organic Chemistry Chapter-1 MSC Students Dima Sabbah, Ph.D. Fall 2020  Alcohols, Carbonyls and REDOX The Carbonyl Group Oxidation/Reduction Reactions: Review Reduction of Carbonyls to Alcohols Oxidation of Alcohols Organometallic Compounds Organolithium and Ma...

Advanced Organic Chemistry Chapter-1 MSC Students Dima Sabbah, Ph.D. Fall 2020  Alcohols, Carbonyls and REDOX The Carbonyl Group Oxidation/Reduction Reactions: Review Reduction of Carbonyls to Alcohols Oxidation of Alcohols Organometallic Compounds Organolithium and Magnesium Compounds Reactions of Organolithium/Magnesium Species Alcohols from Grignard Reactions Lithium Dialkylcuprates  The Carbonyl Functional Group O O O O O R H R R' R OH R OR' Carbonyl Aldehyde Ketone Carboxylic Carboxylate Acid Ester O 120o R R Planar, sp2 Hybridized Carbon Carbonyl Features 1  and 1  Bond Carbonyl Group Quite Polarized (C+, O-) Resonance Structure for Carbonyl Reflecting Bond Polarization??  General Reactions of Carbonyls Nucleophilic Addition to Carbonyl Groups: Nu Nu   O O Nucleophile Carbonyl Addition Product: TETRAHEDRAL Oxidation of Alcohols/Reduction of Carbonyls: O More Oxidation Less Hydrogen R OH Hydrogen Reduction R H Content Content Primary Aldehyde Alcohol  Oxidation/Reduction Reactions Commonly Termed ‘REDOX’ Reactions From General Chemistry, we Will Recall  Oxidation: Loss of Electrons  Reduction: Gain of Electrons Organic Chemists will Typically use Different Definitions  Reduction: Increase Hydrogen Content (Decrease Oxygen)  Oxidation: Decrease Hydrogen Content (Increase Oxygen) Oxidizing/Reducing Agents: Usually Inorganic Compounds (M+) We will also Recall that in REDOX Reactions:  Oxidizing Agents get Reduced  Reducing Agents get Oxidized  Oxidation States of Carbon: Organics H CH3 CH3 CH3 H H H H3C C C C C H H CH3 CH3 H H H H -4 -3 -2 -1 CH3 H3C C CH3 H3 C 0 O Br O O H3C C C C C CH3 H3C CH3 H3C OH O H3 C 1 2 3 4 +1 For More Electronegative, -1 For Less, 0 For Bonded Carbon  Alcohol Synthesis: Carbonyl Reduction O [H] Reduction ROH Carboxylic Acids, Esters, R OMe 1o Alcohol Aldehydes Reduced to O 1° Alcohols [H] ROH Reduction 1o Alcohol R OH Ketones Reduced to O 2° Alcohols [H] ROH Reduction 1o Alcohol R H Several Hydrogen Sources OH O Are Used In Organic [H] Reduction Reactions: We’ve Already R Me R Me Seen NaBH4 2o Alcohol  Reducing Agents: 1° and 2° Alcohols Sodium Borohydride: NaBH4 Lithium Aluminum Hydride: LiAlH4 (LAH) H2/Transition Metal Catalyst (CuO CuCr2O4) NaBH4 and LiAlH4 are Hydride Transfer Agents Hydride (H¯) Acts as a Nucleophile Carbonyls Have Varying Degrees of Ease of Reduction: O O O O > > > R O R OR' R R' R H Hardest Easiest  Selection of a Reducing Agent Choice of Reducing Agent Impacts Reaction Products For Ketones/Aldehydes Either Reductant Suffices Carboxylate Ester Ketone Aldehyde LiAlH4 1° Alcohol 1° Alcohol 2° Alcohol 1° Alcohol NaBH4 No Reaction No Reaction 2° Alcohol 1° Alcohol Carboxylates/Esters Only Reduced by LiAlH4 For Compounds w/ Multiple Carbonyl F.G.s; Select Based on Which Group(s) Need to be Reduced  NaBH4/LiAlH4 Reduction Examples OH O OH NaBH4 1. LAH/Et2O H 2O 2. H2O/H2SO4 OH NaBH4 1. LAH/Et2O OH NO REACTION H 2O 2. H2O/H2SO4 O OH O OH NaBH4 1. LAH/Et2O H 2O 2. H2O/H2SO4 O OH O OH OH  Oxidizing Agents in Organic Chemistry CrO3/H2SO4 N H CrO3Cl H2CrO4 Pyridinium chlorochromate Chromic Acid (PCC) (Jones Reagent) PCC Generally a Mild Oxidant (1° Alcohol  Aldehyde) Jones Reagent Harsher Oxidant (1° Alcohol  Carboxylic Acid) Alcohol Often Dissolved in Acetone While Jones Reagent Added Choose Oxidant Based on Desired Carbonyl Functional Group  General Oxidizing Agent Selection Just as in Reductions, Oxidation Products Depend on Reagent Generally Don’t Oxidize 3° Alcohols (No Texas Carbons) MeOH 1° Alcohol 2° Alcohol 3° Alcohol No PCC H2C=O Aldehyde Ketone Reaction Cr6+ Carboxylic No HCO2H Ketone H2SO4 Acid Reaction PCC Good For Aldehydes From Primary Alchols Cr6+/H2SO4 Reagents, KMNO4 Primary  Carboxylic Acids Use What You Like For Most Ketones Oxidation of 1°, 2° Alcohols O OH PCC H CH2Cl2, 25 oC OH O H2CrO4 acetone, 35 oC OH OH KMnO4, H2O NaOH, Heat O Oxidation Mechanisms: Chromate Esters H Protonation, Followed by Loss H of Water (Combined Here) O H O O O Cr O HO Cr O O O O H H H H H2O O H O O + Cr O + H 3O O Cr O OH OH Chromate Ester  Organometallic Compounds Organic Compounds Containing Carbon—Metal Bonds Bonds Range From Ionic to Primarily Covalent Ionic C—M Bonds:  C—Na  C—K Primarily Covalent C—M Bonds:  C—Pb  C—Sn  C—Hg Inetermediate C—M Bonds Include C—Mg and C—Li Reactivity Increases with Ionic Character of C—M Bond  Organolithium Reagents Common Solvents for Organolithium Reagents: O O Diethyl Ether Tetrahydrofuran Preparation of Organolithium Reagents: Br 2Li, -10 oC Li + LiBr Et2O Butyllithium (Alkyl Lithium Reagent) Reactive, Carbanion-Like Species (React Slowly w/ Ethers) Halide Reactivity: RI > RBr > RCl (F Not Often Used)  Grignard Reagents Preparation of Grignard Reagents: Br Mg MgBr Et2O Butylmagnesium Bromide (Grignard Reagent) Br MgBr Mg Et2O Phenylmagnesium Bromide (Grignard Reagent) Reactivity of Halides Same as for Organolithium Reagents Generally Exist as Complexes, We’ll Use RMgX for Simplicity  Organometallic Reactions: Notes Can Act as Nucleophiles Towards Polarized Carbonyl Groups Very Strong Lewis Bases (React with Acidic Protons) Basicity Necessitates Dry Conditions (Avoid Reaction w/ H2O) Reason For Basicity: Carbanion-Like Behavior (pKa??) Strong Enough Bases to Deprotonate Terminal Alkynes (pKa??) With No Acidic Protons, Can Do Nucleophilic Substitution Let’s Look at Some Representative Grignard Reactions  Grignard Reactions: Epoxides O 1. Et2O MgBr OH + + 2. H3O O 1. Et2O MgBr OH + 2. H3O+ Grignard Reagents Nucleophilically Open Epoxides Generally Attack Less Substituted Carbon (Steric Hindrance) View This as Carbanion Attacking in SN2 Reaction (O L.G.)  Grignard Reactions w/ Carbonyls Grignard Reagents React With a Variety of Carbonyls  Formaldehyde  1° Alcohols  Higher Aldeydes  2° Alcohols  Ketones  3° Alcohols  Ester  3° Alcohols Attack of Grignard Generates Alkoxide; Protonate to get OH Let’s Look at Some Specific Grignard Reactions w/ Carbonyls Grignard Reactions: Carbonyls MgBr O Et2O OH + H H Me MgBr O Et2O OH + H3 C H Me Me MgBr O Et2O OH + H3 C CH3  Grignard Reactions: Esters Me OH MgBr O Et2O + H3 C OCH3 Grignard Reagents React Twice w/ Esters  3° Alcohols Two Alkyl Groups of Alcohol Correspond to Grignard Reagent Grignard Reactions Quite Useful in Wide Range of Alcohol Syntheses (w/ Varying Degrees of Substitution)  Reactions of Organolithium Compounds Organolithium Reagents React Similarly to Grignards Also Strong Bases, Same Limitations Apply More Reactive Species Than Grignard Reagents Routine Syntheses: Prefer to use Grignard Reagents Sodium Alkynides (Triple Bond Anions) React in Same Manner w/ Aldehydes and Ketones - Na+ H H H Now We’ll Look at One More Organometallic: Lithium Dialkylcuprates (A Coupling Reagent)  Lithium Dialkylcuprates I Me (CH3)2CuLi Et2O 2Li, Et2O CuI CH3Br 2 CH3Li (CH3)2CuLi Br Me (CH3)2CuLi Et2O Quite Versatile C—C Bond Forming Reaction  Oxidation and Reduction Oxidizing agents and Reducing agents Catalytic hydrogenation Dissolving metal reduction Hydride reduction Alkene oxidation to diols Oxidative cleavage of alkenes and alkynes Alcohol oxidation to carbonyls Sharpless epoxidation of allylic alcohols 26  Oxidation and Reduction Some common reducing agents Reducing agents Acts on: Catalytic H2 / Pt, Pd or Ni C=C, CC Hydrogenation C=O Hydroboration BH3 / THF C=C, CC Sia2BH Dissolving Metal Nao / NH3 (liq.) CC Lio / NH3 (liq.) Metal Hydride NaBH4 / alcohol C=O LiAlH4 / ether C=O O O O Other Zno / HOAc Malozonide 27 (CH3)2S  Oxidation and Reduction Some common oxidizing agents Oxidizing agents Acts on: Chromic acid Na2Cr2O7 / H2SO4 alcohol CrO3, pyridine, HCl Permanganate conc. KMnO4,¯OH, heat C=C, CC dilute KMnO4 (Baeyer test) Osmium tetraoxide OsO4, H2O2 C=C Cl O Ozone O3 O C=C, CC OH Peroxy acids MCPBA C=C meta-chloroperoxybenzoic acid (meta-chloroperoxybenzoic acid) Peroxide H2O2 various28