CHE202 Structure & Reactivity in Organic Chemistry: Reduction Reactions and Heterocyclic Chemistry Semester A 2016 Dr. Chris Jones [email protected] Office: 1.07 Joseph Priestley Building Office hours: 9.30-10.30 am Monday 1.30-2.30 pm Thursday (by appointment only) Course structure and recommended texts § Coursework: Semester A – week 9 5% (‘Coursework 3’) Semester A – week 11 5% (‘Coursework 4’) § Test: Semester A – week 12 15% (‘Test 2’) § Recommended text books: ‘Organic Chemistry’, Clayden, ‘Oxidation & Reduction in ‘Heterocyclic Chemistry’, Greeves & Warren, OUP, 2012. Organic Chemistry’, Donohoe, Joule & Mills, Wiley, 2010. OUP, 2000. Don’t forget clickers Overview of Reduction Chemistry lecture material § Reduction: - Definition (recap.) - Reduction of carbon-carbon double (C=C) and triple (CΞC) bonds - Heterogeneous hydrogenation - Homogeneous hydrogenation, including stereoselective hydrogenation - Dissolved metal reductions - Other methods of reduction - Reduction of carbon-heteroatom double and triple bonds - Reduction of carbonyl derivatives, addressing chemoselectivity - Stereoselective reduction of carbonyl derivatives - Reduction of imines and nitriles - Reductive cleavage reactions - Hydrogenolysis of benzyl and allyl groups - Dissolved metal reduction - Deoxygenation reactions - Reduction of heteroatom functional groups e.g. azides, nitro groups, N-O bond cleavage Selectivity is a key theme of this course Reduction: definition (recapitulation) § Reduction of an organic substrate can be defined as: - The concerted addition of hydrogen. e.g. O H2 (g) H O H Catalytic hydrogenation (e.g. H2(g) & Pd) - The ionic addition of hydrogen NB: Dr. Lebrasseur’s & Dr Bray’s carbonyl lectures. e.g. O "H " then H Hydride addition then protonation H O H (e.g. LiAlH4 then acid w/up) - The addition of electrons. e.g. H H electron transfer 2nd ET Dissolved alkali metals (e.g. Na in liquid NH ) + 2H 3 H H one electron added Overall two electrons added ‘OIL RIG’: a helpful mnemonic... § Consider the reaction from the point of view of the electrons: OIL Oxidation Is Loss RIG Reduction Is Gain Question: reduction or not? § Which of these transformations represent reductions? A. All of them ✔ 1 B. 3, 4 and 5 C. 1, 3, 4 and 5 D. 1, 3 and 5 E. 1, 4 and 5 NO2 NO2 NO2 NH2 2 3 N N N N O O O N 4 NH2 CO Me CO Me 2 5 2 Reductions: why are they so important? § Reductions appear in almost all synthetic chemistry: - in Nature: e.g. important metabolic pathways (e.g. reduce pyruvic acid to lactic acid). H H O H O O enzymatic H OH NH2 + + NH2 CO2H reaction CO2H N N NADH pyruvic acid lactic acid NAD+ - in pharmaceutical synthesis. e.g. O O O Me Me Me N N N H2N reduction H2N OEt HN N N N N O2N H2N n-Pr n-Pr n-Pr nitro group amine group O2S Sildenafil N N Me § Reduction of carbon-carbon double and triple bonds Reduction of carbon-carbon double and triple bonds § Catalytic hydrogenation - Concerted addition of hydrogen across a π-bond. - Use hydrogen gas: H2(g). - Transition metal (TM) catalyst promotes the reaction. - Catalyst can be heterogeneous or homogeneous. H H Metal Catalyst H H2 (g) H - Hydrogenation has a different mechanism of reduction compared to hydride reducing agents (e.g. NaBH4), therefore different chemoselectivity is often observed. e.g. O O Pd/C (10 mol%) H H H2 (g) Aldehyde not reduced (c.f. NaBH4) NB: 10 mol% = 0.1 molar equivalent (or 10:1 substrate:catalyst molar ratio) Reduction of carbon-carbon double and triple bonds § Heterogeneous hydrogenation - Catalyst insoluble in reaction medium. - TM (e.g. Pt, Pd, Rh) adsorbed onto a solid support, typically carbon or alumina (Al2O3); e.g. Pd/C. § Reduction of alkenes: - Reactions generally proceed at room temperature (r.t.) and 1 atmosphere (atm.) H2 pressure, however, reaction rates increase when elevate T and/or P. - Hydrogenation is typically selective for syn-addition. e.g. Ph Ph PtO2 (cat.) (R) Ph Ph (S) H H2 (1 atm.) H (Z)-alkene syn-addition (i.e. H atoms added to same face of C=C bond) PtO2 (cat.) (S) Ph Ph Ph (S) Ph H H2 (1 atm.) H (E)-alkene - Need a polar reaction solvent to dissolve sufficient hydrogen (e.g. methanol, ethanol, acetic acid). Reduction of carbon-carbon double and triple bonds § Mechanism: - Complex and difficult to study (reaction occurs on metal surface and each catalyst is different). - Working model without curly arrows (explains syn-selectivity): i). H2 dissociatively adsorbed onto metal surface. ii). Alkene π-bonds coordinated to catalyst surface. iii). Alkene π-bonds adsorbed onto catalyst surface. iv). A hydrogen atom is added sequentially onto both carbons. v). Reduced product can dissociate from catalyst surface. syn-addition R R R R H2 H H ADDITION ADSORPTION then DISSOCIATION R R R R R R R R H H H H R R H H R R metal catalyst surface COORDINATION ADSORPTION - Syn-selectivity increases with increased hydrogen pressure. - Reactivity decreases with increased alkene substitution (more steric hindrance). Reduction of carbon-carbon double and triple bonds § Complete reduction of aromatic compounds: - Lose aromaticity so more forcing conditions required c.f. isolated alkenes. - Rh, Ru & Pt are most effective catalysts (i.e. Pd less active so use Pd when require chemoselectivity for alkene reduction in presence of aromatic ring). - Carbocyclic and heterocyclic aromatic rings amenable. HO O HO O OH OH Carbocyclic ring Pt/C (cat.), H (4 atm.) NB: carboxylic O 2 O acid untouched OH AcOH OH O O NB: increased H2 pressures H 10% PtO2 (10 mol%) H2 (5 atm.), HBr, r.t. Heterocyclic ring N NB: syn-addition N 74% of hydrogen Bun Me n Me Bu (±)-monomorine Question: reduction of carbon-carbon double and triple bonds § Which of these structures 1 to 5 is the correct reduction product? A. 1 O B. 2 ✔ Pd/C (10 mol%), H2 (1 atm.) ? C. 3 MeOH, r.t. D. 4 E. 5 OH O O H H H H H H 1 2 3 O O H H H H 4 5 Reduction of carbon-carbon double and triple bonds § Reduction of alkynes to alkanes: - Standard heterogeneous hydrogenation results in complete reduction to alkanes. e.g. H H O Pd/C (10 mol%) Ph OMe Ph 2 moles of H added overall OMe H2 (1 atm.), MeOH H H O 2 1 mole of H2 added Ph CO2Me H H alkene intermediate - Alkynes to alkenes, is it possible? - Require chemoselectivity to differentiate between reduction of alkyne and alkene. - Require control over cis- or trans- geometry. Reduction of carbon-carbon double and triple bonds § Reduction of alkynes to cis-alkenes - Lindlar’s catalyst: affords cis-alkenes. - Pd is poisoned with Pb and an amine – makes a less active catalyst that is more reactive towards alkynes than alkenes (NB: alkene reduction is still possible so reactions often require careful monitoring). e.g. Herbert Lindlar O Ph CO Me Pd/CaCO3 (10 mol%) 2 Solid support – CaCO3 or BaSO4 Ph H2 (1 atm.), quinoline, Pb(OAc)4 – deactivates catalyst OMe H H Pb(OAc)4, EtOAc Quinoline – competitive cis-(Z)-alkene binding to catalyst surface e.g. in the synthesis of a complex molecule O N O Z Pd/CaCO3 (10 mo%) O O H2 (1 atm.), quinoline TBSO O Pb(OAc)4, hexane, r.t. TBSO R R O 86% - Mechanism: two hydrogens added to same face of alkyne, leading to syn-addition. Reduction of carbon-carbon double and triple bonds § Homogeneous hydrogenation: - Metal-ligand complex is soluble in reaction medium. - Phosphines are common ligands (i.e. good electron donors). Sir Geoffrey Wilkinson (Nobel Prize in Chemistry 1973) e.g. Wilkinson’s catalyst, (Ph3P)3RhCl - Stereospecific syn-addition of hydrogen across alkene. - Less substituted and least sterically hindered double bonds reduced most easily. - Chemoselectivity (i.e. ketones, carboxylic acids, esters, nitriles, ethers and nitro groups all inert to these conditions. Least hindered alkene O O (Ph P) RhCl (cat.), H (1 atm.) O 3 3 2 O O benzene/EtOH O 95% NB: Heterogeneous hydrogenation (e.g. H2, Pd/C) is non-selective and leads to over reduction NB: This mechanism is beyond the scope of the course – for a full explanation see ‘Ox & Red in Org Synth’ p. 54 Reduction of carbon-carbon double and triple bonds § Enantioselective hydrogenation: H2 (FYI only, beyond scope of course) - If metal-ligand complex (MLn) is chiral, then possible ML + to control to which face of alkene H2 is delivered. n WHICH FACE? - Discrimination between enantiotopic faces of alkene can lead to single enantiomer of product. H2 ANSWER: use chiral ligand. e.g. BINAP is a chiral & bidentate ligand for TM. - Commercially available as both (R)- and (S)- enantiomers (i.e. chose desired product enantiomer). Bottom face top face CO2H CO2H PPhRh(I), (R)-BINAP CO2H Rh(I), (S)-BINAP H 2 H PPh NHCOPh 2H2 (1 atm.) NHCOPh H2 (1 atm.) NHCOPh Very high facial selectivity (98% ee) NB: this is a ‘protected’ version (S)-BINAP of the amino acid - alanine - Beyond hydrogenation, homogeneous catalysis is an extremely important area of organic chemistry and you will encounter numerous examples in future lecture courses… Pre-Lecture Diagnostic Test – Feedback § Average mark: 18 / 20. § Excellent – no obviously weak areas. - individuals are strongly encouraged to revise any specific areas of weakness that the test revealed. Lowest scoring questions were on hybridisation O sp2 state and pKa values (these concepts are fundamental to understanding organic chemistry, so please revise if necessary). O sp3 sp Revision: N Put the following species in order of increasing acidity (i.e. least acidic first) O O OH O O O F > > OH > OH > S > HCl Me OH F Me OH F pKa = 10.0 4.8 4.2 –0.3 –2.6 –8.0 FEEDBACK: each week please use QMplus “Lecture feedback quiz” to comment on which area of the last two lectures was least clear – I will then revise that topic at the start of the next lectures.