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Acid Catalyzed Reactions You Should Be Able to Write Arrow-Pushing Mechanisms For

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Acid Catalyzed Reactions You Should Be Able to Write Arrow-Pushing Mechanisms For 1 Acid catalyzed reactions you should be able to write arrow-pushing mechanisms for. O H O H2SO4 HO OH O H O S OH H2O O R R (both ways) R R ∆ (-H2O) H OTs O O OH H3C HO H O S OH O (-H2O) O O O R R R R ∆ (-H2O) H2SO4 / H2O H OTs H O OH O O O H O S OH O OH (-H2O) O ∆ (-H2O) H OTs H (THP) O O O H2SO4 OH H2O O H3C H2SO4 / H2O O H SO OH 2 4 H2SO4 CH OH 3 O H2O H2SO4 OH OH H2O OH O O H CH3 H OTs O H C H2SO4 OH 3 H2O H O OH H CH3 O CH3 O H OTs O H2SO4 H2O H OTs O O O (-H O) H 2 O H2SO4 O H2O OH H2SO4 / H2O C N NH2 O pH≈ 5 N H2N H OTs H2SO4 (-H O) imines O OH 2 H2O R R R R O OH (both ways) H2SO4 / H2O O pH≈ 5 H OTs N N (-H2O) R H ketones & R aldehydes H2SO4 / H2O pyrrolidine enamines R = C or H Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 2 Examples of acyl substitution reactions, you should be able to write arrow-pushing mechanisms for. O O O O O O O N H OH N Cl O O O O O SH O O Cl S O O O AlCl3 Rriedel-Crafts OH reactions Cl O H O O O H Al H Li R N R H OH HO H N O Cl H O H B H O Na Li O R H very slow reaction Cu O Cl (cuprates) O Al O O O R 1. H (DIBAH) Al O 2. WK H 1. H (DIBAH) Cl H 2. WK O O O O N O R H N H H H O Cl undesired O side rxn. O 2 eqs. OH O 1. Li R R O 2. WK O R (Grignard reagents too) R Cl AlCl3 O H O Rriedel-Crafts 1. Na O reactions R 2. WK R O O O O OH HO OH O H O O O 1. Na O N 2. WK HN OH Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 3 Reaction Mechanism Worksheet Guidelines 1. Factors to consider when looking at reactants, reaction intermediates and product(s). a. Are there any resonance effects? b. Are there any inductive effects? c. Are there any steric effects? d. Are there any stereochemical considerations? 2. Where are the pairs of electrons that can be donated? (nucleophilic sites) 3. Which site(s) can accept a pair of electrons? (electrophilic sites) 4. Is the reaction in acid? (A Lewis or Bronsted acid = E+ = strong, the acidity drives the reaction) + a. Usually use a strong acid to supply protons, often the strong acid is the protonated solvent. (ROH2 ), (nonproton Lewis acids can also be species with an empty valency such as BH3, BF3, AlCl3, FeBr3, TiCl4, SbF5, etc. which all complex very well with lone pairs.) b. There are no strong electron pair donors in strong acid (bases or nucleophiles are weak). Often the weak base or leaving group is the neutral solvent. (ROH) 5. Is the reaction in base? (The strong base/nucleophile drives the reaction.) a. Usually use a weak acid to supply protons, usually the neutral solvent, (ROH), or other neutral molecule of similar acidity. b. Usually an anion (often the conjugate base of the solvent) acts as the strong nucleophile, strong base or good leaving group (RO --) 6. Are free radicals or one electron transfers involved? Often a photon or neutral (or reduced) metallic compound is part of the reaction. Oxygen or a peroxide can also serve as a free radical initiator. In mechanism problems of our course include the following. 1. Show all lone pairs of electrons 2. Show all formal charge, when present 3. When resonance is a factor in the stability of an intermediate, draw at least one additional resonance structure, including the “best” resonance structure. 4. Show all curved arrows to show the flow of electrons (full headed arrow = 2 electron movement) 5. Any free radical centers if present (half headed/fish hook arrow = 1 electron movement) Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 4 Mechanism for “Fischer” synthesis of ester - Has catalytic toluene sulfonic acid with removal of water to shift equilibrium to right. tosylsulfonic acid = TsO-H H OHTs H OTs H H O O O O O H H H H H O O O O H H H O O H O H H H H R H O O O H O H H O O O H O O O O H H R H O O O O O R H H O O O Mechanism for hydrolysis of ester in acid - Has catalytic sulfuric acid in large excess of water to shift equilibrium to the right. H2SO4 : aqueous sulfuric acid (and lots of water) OSO H H H 3 H O H OSO H O O ester O 3 O O O O H O H alcohol H H O O H H H H O O H H O O H O O O O O O H H O H H H H O O O O O H H H H H H O O H O carboxylic acid Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 5 Mechanism for hydrolysis of ester in base (also called saponification) – Aqueous sodium hydroxide (NaOH). H ester OH H O O O O O O O O 2. workup O H O H O O H H O H H H O carboxylic acid alcohol O Protecting Aldehydes and Ketones as acetals and ketals with ethylene glycol (…and deprotection) Possible mechanism for synthesis of ketal - Catalytic toluene sulfonic acid with removal of water to shift equilibrium to right. ethylene glycol OHTs H H H OH H O H OTs ketone O O O O O H H H H H remove H2O H O O TsO H O O R H HO O O O hemiketal HO HO HO OH H O O O O O O ketal R H Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 6 Possible mechanism for hydrolysis of ketal or acetal = addition of water with catalytic amount of sulfuric acid. H OH H O O OH OH O O O O O ketal (water added) H2O H H H OH H2O H H O O OH O O OH O O OH H H H H H H O O H2O O O OH ketone ethylene glycol Imine Formation from Aldehyde or Ketone Reaction with Primary Amines R-NH2 derivatives (primary amines and hydrazine) o o o 1. Follow by reduction with sodium cyanoborohydride (NaH3BCN) to form 1 , 2 and 3 amines, or Step 1 - making an imine acid cat. = TsOH H (remove water) H OTs H O O O N OTs H H H N N carbonyl group primary amine H H OTs H2O (remove) H H H O O N H OTs N N imine H Step 2 - reducing an imine to an amine with sodium cyanoborohydride H Na H2BCN H H H O R N H B CN N N H imine sodium cyanoborohydride secondary amine (reduces imines to amines) Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 7 Possible Hydrolysis Mechanism of an imine (if not reduced to an amine) = addition of water with catalytic amount of sulfuric acid. H H H N H OH2 N N N O imine H O H 2 H primary amine H H O O H O H2O N H H H N N H H OH2 O O carbonyl group H H Possible Mechanism for reaction of hydrazine H2NNH2 with aldehydes and ketones in strong base leading to reduction to a methylene group (CH2) = Wolff Kishner Reduction. H H O R O O O R O N NH 2 H H N N carbonyl group primary amine NH H 2 H NH2 H H H O H O O O R N N N N H H H N H N H RO H H H H O H H O R N N N N N N O R H H H H H N H N N H H N O R Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 8 Possible Enamine Mechanism – Secondary amine plus carbonyl compound with removal of water (we’ll always use pyrrolidine). H acid cat. = TsOH H OTs H (remove water) O O O N OR H H N N carbonyl group pyrrolidine H (remove water) H H O H O O H H N N N enamine Possible Mechanism of Enamine with an Electrophile, (allyl bromide used in this example), Followed by hydrolysis of imminium ion back to a carbonyl compound. H2O O H H N O N N N H H H H Br enamine HNHR H HOH 2 H 2 O O NHR2 N O N O H H resonance alkylated ketone Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 9 Wittig Reaction (pronounce “Vittig”) 1. Form Wittig salt with triphenylphosphine SN2 reaction on an RX compound. 2. Use a strong base to remove a proton from the carbon alpha to the phosphorous atom and 3. Add a carbonyl compound (aldehyde or ketone) which undergoes an addition / elimination reaction to alkenes (we’ll assume usually Z stereochemistry).
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