Acid Catalyzed Reactions You Should Be Able To Write Arrow .

1Acid catalyzed reactions you should be able to write arrow-pushing mechanisms for.OHHOOSOOOHOOSHH2SO4 / H2O(-H2O)HOSHOHOORROTsOOOHOOH(-H2O)(-H2O) ROTsOHRROHRHO(-H2O)OHOOHOO HO(both ways)RR(-H2O) H2O(THP)OH2SO4 / OOH2SO4H2OHOH2SO4H2OCOH(both ways)H2NOHROpH 5HOTs(-H2O)ORNiminesROCH3OH2SO4 / H2OOHNH2H2SO4H2OOHOTs(-H2O)OHOTsONOCH3RH2SO4 / H2OOR Hketones &aldehydesR C or HZ:\classes\316\Organic mechanisms overview\316 arrow pushing practice.docNpH 5HOTs(-H2O)pyrrolidineH2SO4 / H2ONRenamines

2Examples of acyl substitution reactions, you should be able to write arrow-pushing mechanisms tsreactionsOHClHOOOOHROHONClHH LiRNHAlHOOHOLiRCl(cuprates)OR 1.OH (DIBAH)H (DIBAH)H2. WKOOOOClOH2. WKHvery slow reactionAlAlClHNaHOO1.BOCuONHRHNOHOundesiredside rxn.2 eqs.O1.OROOLiOHR2. WKR(Grignard reagents too)ClOAlCl3Rriedel-CraftsreactionsOROOO1. H2. WKNaROROOHOHOOHHOOONO1. H2. WKNaOHNOHZ:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc

3Reaction Mechanism Worksheet Guidelines1. 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 weakbase 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 ofsimilar acidity.b. Usually an anion (often the conjugate base of the solvent) acts as the strong nucleophile, strong base or goodleaving group (RO --)6. Are free radicals or one electron transfers involved? Often a photon or neutral (or reduced) metallic compoundis 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 electrons2. Show all formal charge, when present3. When resonance is a factor in the stability of an intermediate, draw at least one additional resonancestructure, 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

4Mechanism for “Fischer” synthesis of ester - Has catalytic toluene sulfonic acid with removal of water to shiftequilibrium to right.tosylsulfonic acid OOOHOOOOHHRHOOOOORHHOOOMechanism for hydrolysis of ester in acid - Has catalytic sulfuric acid in large excess of water to shift equilibrium tothe right.H2SO4 : aqueous sulfuricacid (and lots of HOHHOHOHOOOOOHOHOHHOHOOHOHOHOHOHHOcarboxylic acidZ:\classes\316\Organic mechanisms overview\316 arrow pushing practice.docHH

5Mechanism for hydrolysis of ester in base (also called saponification) – Aqueous sodium hydroxide (NaOH).HesterOOHOHOOOOOO2. workupOOHHOHHOHOHHOcarboxylic acidalcoholOProtecting 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 equilibriumto right.OketoneHH remove H2OHOOTsOHethylene OHHOHOOOOORHZ:\classes\316\Organic mechanisms overview\316 arrow pushing practice.docOketal

6Possible mechanism for hydrolysis of ketal or acetal addition of water with catalytic amount of sulfuric acid.HOHOHOOOOHOHOOketalHHOH2O(water ylene glycolImine Formation from Aldehyde or Ketone Reaction with Primary Amines R-NH2 derivatives (primaryamines and hydrazine)1. Follow by reduction with sodium cyanoborohydride (NaH3BCN) to form 1o, 2o and 3o amines, orStep 1 - making an imineacid cat. TsOH(remove water)HOHNHOHNprimary amineOTsOTsHHcarbonyl groupOTsONHHH2O (remove)HHOHOHNNNimineHStep 2 - reducing an imine to an amine with sodium cyanoborohydrideNaNimineHH2BCNHBHCNHONHsodium cyanoborohydride(reduces imines to amines)Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.docHRNsecondary amineOTs

7Possible Hydrolysis Mechanism of an imine (if not reduced to an amine) addition of water with catalyticamount of sulfuric acid.HHNHHOH2NNNOimineHH2Oprimary amineHHOOOHHH2OHNHNHNHHOcarbonyl groupOH2OHHPossible Mechanism for reaction of hydrazine H2NNH2 with aldehydes and ketones in strong base leading toreduction to a methylene group (CH2) Wolff Kishner Reduction.HOHROONOHHcarbonyl groupONH2Nprimary HNHHRHHHNNHONHNOZ:\classes\316\Organic mechanisms overview\316 arrow pushing practice.docRR

8Possible Enamine Mechanism – Secondary amine plus carbonyl compound with removal of water (we’ll alwaysuse pyrrolidine).acid cat. TsOH(remove water)HOHOTsHONOORHHNNcarbonyl grouppyrrolidineH(remove water)HHOHOOHHNNNenaminePossible Mechanism of Enamine with an Electrophile, (allyl bromide used in this example), Followed byhydrolysis of imminium ion back to a carbonyl HalkylatedketoneresonanceZ:\classes\316\Organic mechanisms overview\316 arrow pushing practice.docOH2OH

9Wittig 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 and3. Add a carbonyl compound (aldehyde or ketone) which undergoes an addition / elimination reactionto alkenes (we’ll assume usually Z stereochemistry).Possible Mechanistic steps for preparation and reaction of a Wittig reagent.1. Make the Wittig salt.PhPhPhPPhBrSN2 reactionPhPPhRX compoundtriphenylphosphineBrWittig salt2. Make the ylid.PhBrPhHPCPhLiPhPhHCH2CH3Phacid/baseproton transferPhn-butyl lithiumWittig saltPCHPhCH3PHCPhCH3ylid and its resonance structure3. React the ylid with a carbonyl compound.OPhPhPCHHH3Cdipolar ylidCH3Aldehydes andketones ate"oxaphosphatane"HPZ:\classes\316\Organic mechanisms overview\316 arrow pushing practice.docOHCH3CCH2CUsually the Z alkeneis the major product.CH3

10Nucleophilic hydride reactions: with organic electrophiles such as: aldehydes, ketones, esters, epoxides,nitriles and RX compounds.Common forms of nucleophilic hydride used in this course. (Remember NaH is always basic in our course.)AHHLiAlHHHNaBHHHHNaBCHNHSodium borohydride, NaBH4 (somewhatreactive, reduces aldehydes, ketones,epoxides, and RX compounds)Lithium aluminium hydride, LiAlH4,(LAH, very reactive, reduces manyfunctional groups in our course, includingaldehydes, ketones, esters, epoxides,nitriles and RX compounds.)HSodium cyanoborohydride, NaBH3CN(used to reduce imines to amines in areaction similar to the reduction ofaldehydes by sodium borohydride).Diisobutylaluminiumhydride,DIBAH (or DIBAL), used todiliver a single hydride to esters,nitriles and acid chlorides whichbecome aldehydes after the workuphydrolysis step. This hydride isdifferent from the others in that it isneutral and only has a singlehydride nucleophile.Hydride nucleophiles (e- pair donors) organic electrophiles (e- pair acceptors), WK work up acidicneutralization (electrophilic “hydrogen”).a. formaldehyde (methanal) reduced to methanolHHAlLiHHH2. workupHCOHHHLiCOHHNaBH4 works too.HOH2COHHb. general aldehydes reduced to primary alcohols (like an ester or carboxylic acid with LAH)HHAlLiHHH2. workupHCOHRHLiCOHRNaBH4 works too.HOH2COHRprimary alcoholsd. general ketones reduced to secondary alcoholsHHBLiLiR2. workupHHRRCROHCRLiAlH4 works too.Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.docOHHOH2CORsecondary alcoholsH

11e. general esters reduced to primary alcohols only with LAH (like the aldehyde or a carboxylic acid)HHRLiAlCHLiROHCRROCHOCOOHHORH3AlRHHO2. workupRHOH2RTwo equivalents of nucleophilic hydride add to the ester carbonyl carbon.One equivalent of electrophilic hydrogen (acid) adds at the oxygen atom.Only LAH will reduce esters at a practical rate under normal conditions.HCprimary alcoholsROHf. general carboxylic acid reduced to primary alcohol (like the aldehyde or ester)HHRLiAlCHRHROCHAlHCOHHOOH3AlLiOHOAlHHH2. y alcoholsg. ethylene oxide (epoxides) reduced to ethanolHNaHHBNaOOHOOH2H2CH2CH2. workupHHHf. imines (made from primary amine and ketone or aldehyde) reduced to amines with sodium cyanoborohydrideNaNimineHH2BCNHBHCNHONHsodium cyanoborohydride(reduces imines to amines)Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.docHRNsecondary amine

12NaHNHH2BCNBHNCNHiminium iontertiary aminesodium cyanoborohydride(reduces imines to amines)g. nitriles reduced to 1o amines with 1. LiAlH4, 2. lHHHHAlXHH2. workupHHHRHCHHCCH(neutralize)primary amineRNHOHXAlXCNHHXAlXHOHHHNHHOHHHHNHRHRHXXXHh. esters and nitriles reduced to aldehydes with diisobutylaluminium hydride, DIBAL (text c mechanisms overview\316 arrow pushing practice.docHHRAlHROHHHAlRHOHHNCHHHAlONHRRCHHOAlRH

13i. hydrolysis of nitriles in HCl/1 eq H2O to amidesj. hydrolysis of nitriles in H2SO4/excess H2O to carboxylic acidsk. hydrolysis of nitriles in NaOH/H2O to carboxylic acidsZ:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc

14Possible Mechanism for some of the cuprate reactions– Supply all necessary mechanistic details, including lonepairs, formal charge and curved arrows to show electron movement.a. Formation of dialkyl lithium cuprate2 equivalentsorganolithium reagentLiCuLiBr1 eq.CuBrLiCuCuBrLiA transmetallation allows the more electronegative anion (Br) to pair up with the moreelectropositive cation (Li), producing a better salt. The less electronegative anion (C)then pairs up with the less electropositive cation (Cu) to produce a better covalent bond.dialkyllithiumcuprateb. Conjugate addition to α,β-unsaturated carbonylLiOLiCuOOHH O HCu2. WKc. Acyl substitution with an acid chlorideLiOLiClOOClCuLiCuClThe ketone is LESS reactive than theacid chloride and does not react furtherwith a cuprate reagent. (It would reactfurther with an organolithium reagent.)d. Coupling reaction with an RX compoundLiLiBrBrCuCuThis reaction can be viewed as an SN2 reaction,but free radicals are likely involved. Lithium andmagnesium reagents produce a lot of sidereactions that make this coupling poor for them.2 "R" groups are coupledtogether with both comingfrom RX compounds.Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc

15Possible Mechanism for Formation of Organometallics – Supply all necessary mechanistic details, includinglone pairs, formal charge and curved arrows to show electron movement.Grignard (Mg) gMgMgRBrRBrLi Li Li LiLiMgLiRBrLi LiLiBrcarbanionnucleophileLithium reagentsLiMg 2RMgRLiLi LiLiLiPossible Mechanism for Reaction of Organometallics with typical Organic Electrophiles – Supply allnecessary mechanistic details, including lone pairs, formal charge and curved arrows to show electron movement.HHR(MgBr)carbanionnucleophileR C OC OH(MgBr)C OBrR'R'C OR C OR"ketones 2MgBrR"R(MgBr)MgO 2MgBrepoxidesH1o alcoholHZ:\classes\316\Organic mechanisms overview\316 arrow pushing practice.docHHH O HR C OH OR'2o alcoholH2. WorkupHR'H O HR C OH OR"3o alcoholHH2. WorkupHROH O HH OHR C O2. WorkupH 2R C OORBrH OHR'(MgBr)MgHH O HmethanalR'aldehydesR 2HHR2. WorkupHit dependsHH