Chemistry 2 Organic Chemistry: Lecture Notes for Week 6 (University of Melbourne)

Chemistry 2 (CHEM 10004) Organic Chemistry Lecture Notes for Week 6 Prof Richard O’Hair Room 554, Bio21 Building Textbook: Blackman, Bottle, Schmid, Mocerino, Wille (BBSMW), Chemistry (5th Ed). All referenc...

Chemistry 2 (CHEM 10004) Organic Chemistry Lecture Notes for Week 6 Prof Richard O’Hair Room 554, Bio21 Building Textbook: Blackman, Bottle, Schmid, Mocerino, Wille (BBSMW), Chemistry (5th Ed). All references are to this edition. 1  Types of Aromatic Substitution Reactions in Chemical Synthesis week 6 2  Types of Aromatic Substitution Reactions in Chemical Synthesis For electrophilic substitution reactions to occur, we need to generate a hot electrophile (highly reactive and electron deficient, usually has a +ve charge)! (a) Bromination: Br+ from Br2 + FeBr3 (catalytic amount) (b) Chlorination: Cl+ from Cl2 + FeCl3 (catalytic amount) (c) Iodination: I+ from I2 + CuCl2 (promoter not catalyst!!) week 6 3 (d) Nitration: NO2+ from HNO3 + H2SO4 (e) Sulfonation: HSO3+ from H2SO4 (f) Friedel-Crafts alkylation: R+ (carbocation - watch for rearrangement!!) from RCl (alkyl halide) + AlCl3 (catalytic amount) (g) Friedel-Crafts acylation: RCO+ from RC(O)Cl (acyl chloride) + AlCl3 (catalytic amount) week 6 4 (d) Nitration: week 6 5 (e) Sulfonation: week 6 6 (f) Friedel-Crafts alkylation: 7 week 6 7 (f) Friedel-Crafts alkylation: “Wrong” product! What is going on? week 6 8  (f) Friedel-Crafts alkylation: We know that carbocations have different stabilities. Primary carbocations, if formed, try to rearrange to more stable secondary or tertiary carbocations. Rearrangements occur via “H-” or “R-” shifts: week 6 9 (g) Friedel-Crafts acylation: week 6 10  Substituent effects: reactivity Electron donating substituents make the aromatic ring more nucleophilic, and therefore more reactive with electrophiles! week 6 11 Substituent effects: regioselectivity OH OH OH OH HNO3 NO2 H2SO4 NO2 (NO2 ) NO2 ortho meta para Which product will form? The reaction outcome is ‘directed’ by the existing substituent, not the reagent! week 6 12  ‘Directing group’ effects withdrawing donating week 6 13 Using resonance: way #1 How is intermediate stabilized or destabilized by group? 14 14 Directing effects of substituents Can use resonance to predict the site of attack by considering INTERMEDIATE. EDG favour ortho & para attack!! “+M” effect stabilizes +ve charge Try meta and para attack by E+ 15  Directing effects of substituents Can use resonance to predict the site of attack by considering INTERMEDIATE. EWG favour meta attack!! “-M” effect destabilizes +ve charge Try meta and para attack by E+ 16 Using resonance: way #2 Which sites are more or less nucleophilic by group? 17 17  Electron donating vs. withdrawing groups withdrawing donating 18 week 6 18  Directing effects of substituents Alternatively, can use charge separated resonance forms to show reactive (unreactive) sites of reactants: -ve sites direct o and p +ve sites direct m 19 week 6  Summary of EAS Aromatics do not undergo addition reactions (would lead to loss of aromaticity) Instead they undergo electrophilic aromatic substitution Highly reactive electrophiles are required Electron donating groups increase reactivity and are ortho,para-directing Electron withdrawing groups decrease reactivity and are meta-directing Halogen substituents are exceptions! week 6 20  Organic reactions This week will cover the last 3 reaction types (6 - 8): 1 Acid-base equilibria; the relative strengths of acids and bases. 2 Nucleophilic substitution (displacement) at a saturated C atom. 3 Elimination reactions. 4 Electrophilic additions to multiple carbon-carbon bonds. 5 Electrophilic aromatic substitution. 6 Nucleophilic additions and substitutions at unsaturated atoms (carbonyl compounds and acid derivatives). 7 Reduction reactions. 8 Oxidation reactions. week 6 21 Nucleophilic Addition and Substitution at the Carbon-Oxygen Double Bond The type of the products of these nucleophilic additions depends on the nature of the carbonyl compound! But they are all ionic reactions due to the fact that the carbonyl group is polar. week 6 22  The carbonyl group: C=O Most chemistry involves the breaking of p- bond (similar to alkenes) Reactivity due to highly polar nature of C=O bond (different to alkenes) week 6 23 Reactions of the carbonyl functional group d_ O acts as an electrophile C d+ Revise functional groups! week 6 24  Examples O H2N H H NH OH O O HO HO3PO HO H NH estrone NH (a steroid) O H2N N O N O HN OH H OH CH3 HO NH O O H N pyridoxal phosphate N (enzyme cofactor) HO OH H O N OH caspofungin O (an antifungal) HO HO paracetamol (an analgesic) week 6 25 The electronic nature of the carbonyl group The double bond is comprised of sigma (s) and pi (p) bonds p-orbital C O C O C O Most chemistry involves the breaking of p bonds week 6 26  Carbonyl groups and alkenes Most chemistry involves the breaking of p bonds Differences in mode of reactivity is due to polar C-O bond! week 6 27 The electronic nature of the carbonyl group The large electronegativity difference between C and O means that the carbonyl bond is strongly polarized d_ O C d+ acts as an electrophile week 6 28 O δ Reflects the 2 resonance forms (A) and (B) C δ+ O O C C + (A) (B) week 6 29  Notes on attack of C=O The carbon is electrophilic and thus susceptible to attack by nucleophiles O O C C + Nu Nu nucleophile week 6 30  Notes on attack of C=O.. while the oxygen is nucleophilic and thus susceptible to attack by electrophiles (e.g. H+) electrophile E+ E O O C + C + week 6 31  Aldehydes & Ketones Nucleophilic attack can occur under basic or neutral conditions or can be acid catalyzed. Either way, these reactions are two step polar reactions NOTE that overall there is a change in hybridization of the carbon and that these reactions therefore involve the formation of tetrahedral intermediates! week 6 32 Nucleophiles that can react with C=O week 6 33 week 6 34  Nucleophilic Addition Under Acid Conditions: H H O O O + H+ C C Step 2 + C Step 1 Nu + Nu H H Step 3 - H+ H O C Nu week 6 35  Nucleophilic addition reactions with water In aqueous conditions, aldehydes and ketones are in equilibrium with hydrates H2O OH O C R C OH R R' R' ketone or a hydrate aldehyde Mechanism: d_ O O OH C d+ C C R R' R R' R R' O HO H H H2O acid/base equilibrium week 6 36 Nucleophilic addition reactions with alcohols Similar chemistry occurs with alcohols, and this process is catalyzed by acids O R"OH/H+ OH R"OH/H+ OR" C R C OR" R C OR" R H H H aldehyde a hemiacetal an acetal of of an aldehyde an aldehyde O R"OH/H+ OH R"OH/H+ OR" C R C OR" R C OR" R R' R' R' ketone a hemiacetal an acetal of of a ketone a ketone week 6 37  Examples O H2O, H+ OH C CH3CH2 C OH CH3CH2 H H O CH3OH, H+ OCH3 C CH3CH2 C OCH3 CH3CH2 H H week 6 38  Acid-catalysed generation of a hemiacetal NB: a ‘hemiketal’ is a subset of hemiacetals, derived specifically from a ketone week 6 39 Acid-catalysed generation of an acetal from a The substitution of hemiacetal OH for OR occurs via an SN1 process; The oxonium ion The combination of these intermediate is a mechanisms shows the stabilised conversion of an carbocation aldehyde/ketone to an acetal O O R R NB: a ‘ketal’ is a subset of acetals, derived specifically from a ketone week 6 40  Variations: If the nucleophile contains H atoms (typically H2O, RNH2), then the product can loose water! O N + NH3 + H 2O C C week 6 41 week 6 42  Nucleophilic Addition Under Base or Neutral Conditions: E O O O Step 1 - E+ C C C Step 2 Nu Nu Nu week 6 43  Nucleophilic addition reactions (aldehydes and ketones) Attack of a nucleophile leads to the loss of the p-bond and formation of a new s-bond d_ O O C d+ C Nu Nu Hybridization at carbon changes from sp2 to sp3 week 6 44 week 6 45  Nucleophilic Addition to C=O Two very important reactions involve form alcohols via the attack of: H- O O O H + -H C C C Step 1 Step 2 H H H H R- O O - H+ O C C C Step 1 Step 2 R R R week 6 46  How do we generate R- or H-? We know from week 3 that these are very strong bases (their conjugate acids are very weak acids!). Generally we cannot form bare R- or H-. Instead, we use them complexed to other species: RMgX is known as a Grignard Reagent and is equivalent to R NaBH4 is equivalent to H week 6 47  Nucleophilic addition of hydride, H– (aldehydes and ketones) Addition of hydride leads to an alkoxide Protonation of the alkoxide affords an alcohol d_ O O H3O+ OH C d+ C C H H H an alkoxide an alcohol This process is a reduction week 6 48 week 6 49 Common reducing agents (H– sources) Lithium aluminium hydride: LiAlH4 Sodium borohydride: NaBH4 Examples: O 1. NaBH4 C RCH2OH R H 2. H3O+ aldehyde 1° alcohol O 1. LiAlH4 OH C R C R' R R' 2. H3O+ H ketone 2° alcohol Sodium hydride (NaH) and potassium hydride (KH) are not reducing agents – they are strong bases week 6 50 NADPH: Nature’s reducing agent Nature used NADPH as a reducing reagent to transform a wide range of substrates in “biosynthesis”. Examples include cholesterol synthesis, lipid synthesis, and fatty acid chain elongation. week 6 51 NADPH: Nature’s reducing agent Your turn #13! Use curly headed arrows to show the reduction reaction and then draw both products week 6 52  Addition of carbon based nucleophiles, carbanions, R– (aldehydes and ketones) Addition leads to an alkoxide Protonation of the alkoxide affords an alcohol d_ O O H3O+ OH C d+ C C H H H an alkoxide an alcohol This process involves carbon-carbon bond formation week 6 53 Addition of CN– Upon protonation, a neutral cyanohydrin is formed! week 6 54  Addition of acetylide anions Revision: acidity of alkanes, alkenes and alkynes Due to charge stabilizing nature of orbitals week 6 55 Addition of acetylide anions week 6 56 Grignard Reagents can readily be prepared from alkyl halides (RX) using magnesium and an inert ether as a solvent: Francois Auguste Victor Grignard 1871 - 1935 Mg Show change in RX RMgX polarity of C for Et2O the R group!! Your turn #14! week 6 57 Grignard reagents: carbon nucleophiles Grignard reagent: carbon nucleophile Carbonyl group: carbon electrophile Nucleophilic addition reaction generates C–C bond! week 6 58 week 6 59  Grignard reactions: examples 1. 2. 3. Ketones and Grignard reagents give tertiary alcohols. week 6 60  Summary The carbonyl group is a highly polarized functional group Carbonyl groups are electrophilic at carbon and can undergo nucleophilic addition reactions Nucleophilic addition of hydride leads to reduction of carbonyl groups Nucleophilic addition of water affords hydrates Nucleophilic addition of alcohols affords hemiacetals; SN2 substitution of hemiacetals affords acetals. Both reactions are catalyzed by acid Nucleophilic addition of ‘hydride’ leads to reduction to give alcohols Nucleophilic addition of Grignard reagents generates a C–C bond week 6 61  Other important carbonyl compounds d_ O C where X R' or H R d+ X O C carboxylic acids R OH O C amides R NR'R" O C esters R OR' O O C C acid anhydrides R O R' O C acid chlorides R Cl week 6 62  Carboxylic Acids & Derivatives: Important starting materials that can be used to synthesize a wide range of compounds For example, used in the Friedel-Crafts acylation reaction [ RCO+ from RC(O)Cl + AlCl3 (catalyst) ] Can undergo reactions involving nucleophilic attack then elimination – overall a substitution week 6 63  Polar nature of the carboxyl group Like aldehydes and ketones, the carboxyl group is strongly polarized Nucleophiles can add to the carboxyl group – but with an important difference… d_ O O C d+ C this is a R X R X leaving group Nu Nu “X” can act as a leaving group: O O C C + X R X R Nu Nu week 6 64  Polar nature of the carboxyl group Like aldehydes and ketones, the carboxyl group is strongly polarized Nucleophiles can add to the carboxyl group – but with an important difference… week 6 65  Nucleophilic addition vs nucleophilic acyl substitution 66 week 6 66  Nucleophilic substitution The overall result is a nucleophilic substitution reaction that proceeds through two steps (addition and elimination) We can write the overall reaction in a shorthand fashion as follows: O O C C + X R X R Nu Nu These reactions are called nucleophilic addition/elimination week 6 67  Carboxylic Acids & Derivatives: The mechanism is related to that discussed above for aldehydes and ketones! O O O Step 1 Step 2 C C C R Cl R Cl - Cl- R Nu Nu Nu sp3 hybridized! tetrahedral intermediates week 6 68 Carboxylic Acids & Derivatives: O O O Step 1 Step 2 C C C + R Cl R Cl - Cl- R Nu Nu + H Nu H H Step 3 - H+ sp3 hybridized! tetrahedral intermediates O C R Nu week 6 69 week 6 70  71 week 6 71 week 6 72 week 6 73  1. Reduction Hydride (eg from LiAlH4) can perform a nucleophilic substitution The reaction first forms an aldehyde, but this is rapidly reduced d_ O O O C d+ C C + R'O R OR' R OR' R H H an aldehyde H+/H2O H RCH2OH + R'OH LiAlH4 1° alcohol RCH2O week 6 74  Examples CO2H i LiAlH4 CH2OH ii H3O+ O i LiAlH4 2 x CH3CH2OH H3C OCH2CH3 ii H3O+ O i LiAlH4 CH2OH Cl ii H3O+ week 6 75  2. Preparation of acid chlorides Acid chlorides can be prepared from carboxylic acids and thionyl chloride Acid chlorides are useful reactive intermediates for the preparation of esters and amides week 6 76  3. Preparation of esters Acid chlorides react readily with alcohols to yield esters O O C C RCO2R' + HCl + Cl R Cl R O R' H ester R'OH Example week 6 77  4. Preparation of amides Amides can be prepared in an analogous fashion from primary or secondary amines O O - HCl O C C R' + Cl C R Cl R N R NR'R" R" H primary or secondary amide N R" R' H this hydrogen is lost Tertiary amines are unreactive week 6 78  5. Reaction of anhydrides Carboxylic anhydrides have a similar reactivity to acid chlorides O O O R'OH C C C + RCO2H R O R R OR' anhydride ester O O O R'R"NH C C C + RCO2H R O R R NR'R" anhydride amide Note: one equivalent of carboxylic acid is released week 6 79  6. Reactions of Esters with Grignard Reagents Esters react with 2 equivalents of a Grignard reagent to generate tertiary alcohols Nucleophilic acyl substitution generates a ketone intermediate The ketone undergoes nucleophilic addition with the second equivalent of the Grignard reagent week 6 80  Summary The carboxyl group is present in carboxylic acids, amides, esters, anhydrides and acid chlorides The carboxyl group is highly polarized and undergoes nucleophilic substitution through an addition/elimination mechanism Nucleophilic substitution of esters by hydride results in reduction to primary alcohols Acid chlorides can be formed from carboxylic acids by reaction with thionyl chloride Alcohols and amines react with acid chlorides or anhydrides to give esters and amides, respectively Grignard reagents don’t stop reacting after the first substitution. They react further to give an alcohol product week 6 81  Organic reactions Reactions covered so far: 1 Acid-base equilibria; the relative strengths of acids and bases. 2 Nucleophilic substitution (displacement) at a saturated C atom. 3 Elimination reactions. 4 Electrophilic additions to multiple carbon-carbon bonds. 5 Electrophilic aromatic substitution. 6 Nucleophilic additions and substitutions at unsaturated atoms (carbonyl compounds and acid derivatives). 7 Reduction reactions. 8 Oxidation reactions. week 6 82  Oxidation and reduction reactions Oxidation and reduction of organic compounds can occur with a wide variety of common inorganic oxidizing and reducing agents, and some carbon compounds. Oxidation refers to the loss of hydrogen (-H) or the addition of oxygen (+O) to an organic molecule. Reduction refers to the loss of oxygen (-O) or the addition of hydrogen (+H) to an organic molecule. Oxidation is the opposite of reduction. week 6 83 Oxidation state of organic compounds week 6 84 Reductants: Common Reagents Used A reagent that causes an organic substrate to be reduced is called an reductant or reducing agent. Common inorganic reductants include: NaBH4, LiAlH4, SnCl2, metals with acids, H3PO2, Na2S2O4 Hydrogenation by the simple addition of molecular hydrogen occurs catalytically over Pt, Pd or Ni. week 6 85  Oxidants: Common Reagents Used A reagent that causes an organic substrate to be oxidised is called an oxidant or oxidizing agent. Common inorganic oxidants include: H2O2, KMnO4, CrO3, FeCl3, S, Se, SeO2, Ag2O Dehydrogenation by atmospheric oxygen can occur catalytically over Pt and Pd. week 6 86 Important Reduction Reactions used in Chemical Synthesis (1) Reduction of carbonyl compounds The two commonly used regents are NaBH4 (less reactive) and LiAlH4 (more reactive). In general, the final product is an alcohol. week 6 87  Reduction of carboxylic acids LiAlH4 will reduce carboxylic acids directly to alcohols It is not possible to stop at the intermediate aldehyde as these are more reactive than the acid O 1. LiAlH4 C RCH2OH R OH 2. H3O+ carboxylic 1° alcohol acid Sodium borohydride (NaBH4) does not reduce carboxylic acids week 6 88  Reactivity order for reduction of carbonyl compounds Reduced by NaBH4 O O O O C < C < C < C R OH R OR R R R H Reduced by LiAlH4 week 6 89 (2) Reduction of Alkenes This involves addition of H2 using a catalyst such as PtO2 or palladium loaded onto charcoal (Pd/C). Alkenes are more reactive than other functional groups present in the molecule! Catalyst delivers both hydrogens to the same face: 1,2-dimethylcyclohexene cis-1,2-dimethylcyclohexane week 6 90 (2) Reduction of Alkenes week 6 91  Reduction of aromatic compounds H2 in the presence of Pt catalyst Requires forcing conditions – high heat/pressure Much harder to achieve because it results in loss of aromaticity week 6 92 Examples illustrating selectivity week 6 93  Summary: Reduction The addition of hydride to a carbonyl group is a reduction Aldehydes reduced to primary alcohols Ketones reduced to secondary alcohols Carboxylate derivatives reduced to primary alcohols Hydrogenation of double bonds uses H2 and a catalyst Hydrogenation of isolated alkenes is easy with Pd catalyst Hydrogenation of aromatics is difficult and requires Pt or Ni and high pressure/temperature Hydrogenation occurs in a cis fashion week 6 94  Oxidation Reactions used Synthesis A reagent that causes an organic substrate to be oxidised is called an oxidant or oxidising agent H2O2 KMnO4 CrO3 K2Cr2O7 hydrogen potassium chromium potassium peroxide permanganate trioxide dichromate CrO3/H2SO4 Jones reagent (organic-soluble Cr(VI) oxidizing agent) week 6 95 Important Oxidation Reactions used in Chemical Synthesis (1) Oxidation of Alcohols The outcome of these oxidation reactions depends upon: (i) the type of alcohol used; (ii) the type of oxidizing reagent: week 6 96  oxidation of primary alcohols Oxidation of primary alcohols proceeds through aldehyde to carboxylic acid Strong oxidising agents (CrO3, KMnO4) will promote both stages to give acid (cannot stop reaction at aldehyde) PCC can be used to provide aldehyde (requires low temp, dry conditions) Aldehydes can be oxidised by mild oxidants such as Ag+ week 6 97  oxidation of primary alcohols The oxidation of ethanol can occur to either an aldehyde or a carboxylic acid Oxidation of wine to vinegar: oxidation O CH3CH2OH C CH3 OH Metabolism: ethanol O aldehyde O CH3CH2OH C C CH3 H CH3 OH dehydrogenase dehydrogenase week 6 98 The ‘Breathalyzer’ Detection of ethanol content (by oxidation to acetic acid) Early models used visual observation of colour change upon reduction of Cr(VI) to Cr(III) Modern equipment uses an electrochemical cell week 6 99  Oxidation of secondary alcohols Tertiary alcohols in general are not oxidised: there is no H at the tertiary C to be removed H3C OH [O] H 3C CH3 week 6 100  (usually Na2Cr2O7 or K2Cr2O7) alcohols example methanol formic acid (methanoic) 2- 2- O Cr2O7 O Cr2O7 1° alcohol carboxylic acid CH3CH2OH CH3C H CH3C OH 2° alcohol ketone ethanol acetic acid 3° alcohol no reaction an aldehyde - further oxidized to carboxylic acid CrO3 HO O Jones' reagent cholestanol cholestanone (2° alcohol) Jones' reagent OH CH3(CH2)8CH2OH CH3(CH2)8CO2H Jones' reagent no reaction CH2OH CO2H 3° alcohol CrO3 Ph Ph 1° alcohol "phenyl" substituent 101 week 6  Oxidation/reduction summary increasing oxidation state oxidation RCH2OH O RCO2H 1º alcohols C carboxylic R H aldehyde acid O R2CHOH C not oxidized 2º alcohols R R ketone R3COH not oxidized 3º alcohols reduction week 6 102 Important Oxidation Reactions used in Chemical Synthesis (2) Oxidation of Aromatic Compounds (a) Oxidation of alkylbenzene side chains. KMnO4 is a strong oxidizing agent which reacts with alkylbenzenes to cleave their side chains to yield carboxylic acids. Note that H atoms are required to be present on the C atom attached to the benzene ring for this reaction to occur (tert-butyl groups are not oxidized)! week 6 103 this bond cleaves tert-butyl group week 6 Not oxidized! 104  (b) Oxidation of phenols. Phenols and o- or p-bisphenols (hydroquinones) can be oxidized to quinones Quinones can be reduced back to hydroquinones O MeO Ubiquinone (Coenzyme Q10): Important biological a component of the electron processes MeO H transport chain O 10 participates in aerobic cellular respiration, which generates energy in the form of ATP. week 6 105  Summary: Oxidation Alcohols can be oxidised with oxidising agents – Primary alcohols oxidised to aldehydes then to carboxylic acids – Secondary alcohols oxidised to ketones – Tertiary alcohols are typically unreactive towards oxidising reagents Alkyl-substituted aromatics are oxidised to benzoic acids by KMnO4, unless a quaternary carbon (e.g. a tert-butyl) is next to the aromatic ring Hydroquinones can be reversibly oxidised to quinones week 6 106  Organic reactions We have covered all reactions we need to: 1 Acid-base equilibria; the relative strengths of acids and bases. 2 Nucleophilic substitution (displacement) at a saturated C atom. 3 Elimination reactions. 4 Electrophilic additions to multiple carbon-carbon bonds. 5 Electrophilic aromatic substitution. 6 Nucleophilic additions and substitutions at unsaturated atoms (carbonyl compounds and acid derivatives). 7 Reduction reactions. 8 Oxidation reactions. Final lecture: putting it all together for organic synthesis and inventing new reactions. 107 week 6