Pewee Reactions fp Ctdehyaes d& Ketones @ Reduction with Hydrogen on Heterogeneous Catalyst @Reduction with Comper Metal Hydrides @ Wolff -Kishner Reduction & Clemmensen Reduction @Reduction of Thioacetals @Arddition of Organometailic Compounds @bydration Reacton CAddition of Water 5 @Hemiacetal & Acetal Formation @ Thicacetal Formation R RQ @Formation of Imines \.7 @ Formation of Enamines C @Formation of Cyanohydrins e M @Baeyer-Villiger Oxidation Cc oO @Oxidation of aldehydes Q 7™N H Owitta, Olefination Code: ATIEEREACTIONS of ALDEHYDES & KETONES 4. Reduction with Hydrogen on Hetemgeneous Cortalyst rs oa —2_ PL 4 2, Reduction with Comper Metal Hydrides Y oO Hae on gZ A _NabHa Hs H 9 LOD ee GAIR4 ene workup’ ion 5 c 3 Wolff —Kishner Reduction w H x © 1 nHy,H® 2 2. KOH, S cn oO Q 4. Cemmensen Reduction 5 4 3 2? 2nCHg) a) Orage cre a 5. Reduction of Thioacetals s 4 2 WS SH ) Raney ni OP a Ch? fs cy “ thicacetal 4 3] © Addition of Organometallic. Compounds 5 e & ae — Hao” 3 OP Amer Cre wort KIB é g Askari Tyagi Sov Code ATIEE2 8. n 2 9 d u tt @ ov Zz 0 tl A | 0 a « w J oO} mm a of w > wW ov AZ) Hydration Reaction CAddition of woter > alin cr H20 { on y® Hemiacetal & Acetal Formation OR cy? aoe ROH Ki — Chee wap He pemacetal acetal Thioacetal Formation _ CP ESF HO sno thioacetal Formation of Zmines Ce Omar imine Formation “ Enamines sn oO ba +H20 2! ore enamine Formation of Cyamohyarins Or as cf cyan chydrin Ashiasis Tyg Sov Code: ATIEE2B, Baeyer-Villiger Oxidation I ao Oo RCOsH of Cm O 9 & | 14 Oxidation of aldehydes a a ° ° HaCrOu,0g b Ay Some ot) reagents mon or Ag, in Ni Cote Sdagent) or CuS0y Benedict Reackon) ol ® With. Olefination H Oo E on PhgP=CHR om e 3 Code: ATIEEA Reduction with Hydrogen on Heterogeneous Catalyst Ccararytic Hydrogenation) N H. \ Reaction has a conserted mechanism no peat R-~9 & proceedes via syn addition HH R R General Mechanism Hydrogen is adsorbed — iL on the surface of the St WRST/T/1 coraiyst & has & partially, WRAT/ Lr broken H-# bond making® i very, active This mechanism can also be shown as: ° o-H WH 1 ¢Reburns back t: reaction yy A Act Pax Ceatalyst regenerated) RR RR Examples: on oy He cy Ne AK He ax + Ac Pair of enantiomers ° HoH yoo oe atom Ph Ph Ph H. . . ve ——- aK + x Pair of diastereomers © HOH Ho" OH Note: due to possible prochirali of the carbonyl carbon , the catalytic hydrogenation reocsth can be Stereelectve when Chiral additives “to Gre catalyst are used. Ashiasis Tyg Sov Code’ ATIEE2 Reduction with Complex Metal Hydrides _ R A g H.0® \ Neso fly | pi ¢ @ = -c- 470 se NaBly BTS oorkup™ ROC“ P H HoH Lithium aluminum hydride CLAH or CHa) typical complex hydrides Sodium borohydride CNaBHy) used in this redudti however, other complex Mechanism: “eee can also be used. H le Electronegativities: H= B=2.0 Al=1.0 H- BH Due to a difference in “he dlectronegatiriy of i ° the elements, the formal negative chal H No Al & B respectively. is actually located® on “A - density. on H in both ee & Ne iq Makes? H meceoene 4 Gea Ap. y Nucleophiic cs H-bransfer 1 4 Attack a 8 ease. workup) Since both LiAlhy & NaBHy — ll Bye Al coordinates around contain 4 equivalents of rtvely Charged O, Audlesphilic Widvide ion , Jee 4S, however ie often’ ‘the: ogi can veduce ef to” 4 Not shown lalents of c=0 ants ° ot 4 4 Hoa LialHa H : Oo LNaBH: Oo OC aa TT" OBR ACR state IPH ate of enantiomers t, 2. Hx THs? oe Ortom 4. NaBH. Xo z theo AA» +4. “oH Pair of diastereomers Notes: LiAIHy + reacts violently with acidic Hs =7 it is used with ether for a solvent + is very nucleo ic & reacts with other @ecbrophi jes such as carboxylic: acid derivatives, epoxides , & alky! halides NaBbHy is a mild veduci ent & does NOT rac with weak acids such as HO or alcofdls CHgCH is @ common solvent. fer Na®H4 Ashiasis Tyg Sov Code’ ATIEE3, Wolff-Kishner Reduction ale R eR H Nea n AN2Ha, NZ =O TeGH, Be een Yo NGHy Mechanism: Hi a IN NC HEXEN, ry transfer, Ye a H Nudeophitic ~ zt ie x, : 4 azine = Attack : H Z Pe Ory a Qu <=} Reacton of an aldehyde or a ketone 2H° o£ | with hydrazine produces a hydrazone Proton transfer v fs Ha 33 cou Hace Q Hetransfer coupe NO & NOH SN Group a YT ONS Setranfer EN NH, Some Ch Hydrazone H ® on (ftom KOH) H- transfer Wo" y z ° g C HW at [~" Nge4 a“ \ i transfer AL NO, oF Resonaficely, stoabitized anion < Co. H- transfer 2 Hy ~H 8 Hoy beans 5 Leaving, I bransjer Grou < N Stout 4 ~ “tH “ “Qa “Dissociation ER This step is entropy-driven due to the ges formation => Bis high temperature is Examples: essentiag 4.NeHu, He 1.NoHa, H® > Oper: ade) AQ HA ACL, H Notes: ~ Welff-Kishner reduction is safe for other double bends , however it is Nor safe in the presence of electrophiles like acid halides or alkyl hatides ~ Instead of hydrazine , a hydrazine hydrochloride CN2Hy HC) is commonly. used * Reaction with KOH can be done neat bj baking & hydrazone with solid “KOH or using dighyme or other high-beiling’ seven Ashiasis Tyogi Sin Code: ATIEEBase-only Ceingle step) mechanism: abu “BX UH Nudleophilie Xe wet H-transfic > SN-N oe Zz eS HoH Attack evry Sy ‘o> us HON aa NH, H,N—NH, NI or SDH H-bransf? Tr Leaving. ben N. H rou. “SK = fans 7 - wee ONS Dissociation HOD TN-NH, io Siew, H H LY H _ S Tw. OT H-bransfer ae 5 Ne N Sii=u Sn on Resonancely Stabilized Anion H- transfer yur Py Leaving. < “NEN _ Group Le nN Hi-bransfer — (gas) “Dissociation RG Like in the previous mechanism, this step is entropy-driven (due te the ace formartion ) & is favored at high C200- Zse'c |) temperatures Comparison of both methods: Both methods are very, similar. Two -step method uses hydrazine hydrochloride (or sulfate) which is a solid & very easy. to handle. Singe-ctep method uses hydrazine hydrate CN2Hy HO! wohl iS @ Liquid with a rather unpleasant smell. Pure hydrazine is unstable & combusts/ explodes on air. The initial hydrazone formation is Generally, more favored in acidic conditions Cideally ot pH~S) Often, The cice OF Q method is a personal preference Ashiasis Tyg Sov Code’ ATIEE4. Clemmensen Reduction ag any ene 2n CH, 4 Seno eS cC + ance, (og) R- He Qn H ay Mechanism Cusually net tested in class) 4 o TI “Ke o En OS, ! At least & Zn atoms on De 2m surface Surface participate in this electron exchange Kx HOH ezn) H e Examples: H ~_ yoDeuble bond is untouched o 2nthg) 4 Hee (aq) oma fo} H. WL in dtigy cr Her (aq) Notes: Clemmensen reduction uses a strong acid CHa) => ih not be safe if acid-sensitive Groups are present ~—s 5 Reduction of Thicacetals CMozingo Reduction) ~~ Roig He SH RSS), Ramen Rt Rv # Rv Ss Hy RO ned aickel +hioacetal alkylated nich 4 s Mechanism of the veduction part Cstep 2) is not quite clear. The’ a thicacetal will be discussed later. ample: 1 Double bond is reduced col s 4 O 7) w cy HS SH hs He 4 H® Raney ni Note: Reaction will reduce other TL bonds in the molecule! Raney Ni is being ivreversibly consumed => must be used in 0 Strichiomebic CNGT catalytic) Quan ts Ashaasis Typgi Sov Code: ATIEEIAA Nebel Prize © Reaction with Organometallic Compounds CErignard & Organo-Lithium 2 © R no RM RL yo Hse Rot Re RR workue KR Mechanism: Ph* Ma Br Lo 9 ed oe Nudeophilic 867 “Ph Acidic Workup fo" son Attack, C CH- transfer) Be Note: NHyG Caq) is often used fer acidic UO workup in Grignard reaction as it is slightl H H Qcidic Hhus works as a source of protons > but not acidic enough te cause any adverse Examples : reactions of alcohols “Ce.g. Ei reackoh)) ~ OH ° Co .estate co 2 Het workup Phy ELMAR ph, Procifal 2 HS ip en) 4. PhMg Be 4 H SAY Linge A — Pair of diastereomers Ph Oo 2H? HO Ph workup Ph-> Pair enantiomers no et * Pou of Notes: + Common solvent that is used with Grignard & Organolithium reagents is THE Chetrohydrofurane) or Et,© Caietry! ether)” as they stabilize. Organometallic compounds. + RMBe & Qli are very similar in terms of reactivity. However, electronegetvities of C= 2.5 | Lis 4.0 }=> C-Li bond is more pdar Mg=4.3 than C-Mg bond thus RLi reagents are more reactive oS nucleophiles & dre more basic than Rmge& * RMyBr & RL are exbremely basic & will parkicipate in acid-base exchange ister than in any. nucleogl ‘te attack Ashiasis Tyg Siv Code’ ATIEEA) Hysration Reaction CAddition of H20) [Reversible Addition Reach] R ‘=o Ho RY OF Hydrates are generally unstable & his =—_ CC LX HCeat) 7 OH equilibrium favors thé carbonyl Mechanism Cacid - catalyzed): a1 H-bransfec “EO Nucleophilic —X ——_ + He pr CO ao Oe ° AS wet 1 H® “Te + HO When o hydroxyl C-CH) is present in a molecule Along with a carbonyl Cc= OS functional group, cyclic hemiacetals or acetals con fam: OH oH O OH ® OH oO, H Get a oe SS 4 OH OH OH ud >-4 Wo 1 Son SoU ]-membered rings are favored in such cydizations (ors) Senne Ronen sy oe “— C ‘y O° wo = ep ae Acetal formation & hydrolysis is an towards either acetal Cvia removal of H2©) according to LeChiteliers principle ook eqgilibriteen & can be shifted Hz) or carbonyl Cvia additional Ashiasis Tyg Sov Code: ATIEE@ “Trioacetal Formation | Reversible Addition Reacton] tiny R-2RSH_ RL _SR “The reversed reaction c=0 ON +H,O — Chydrolysis) vequires the Re HRT sR” renee ef HED tone tp ind Away RSH & remove it from the reaction. Mechanism: oD = transfer HS7sH_Nuc “vy Ses “Te > —petack we So 7 4 Oe (aq) Ha, $ H-bransfer ‘OH, = Le H- bransfer “TL ) DSe Gowns 167 ss H Gu & | ‘Oh, “4 ruc. Xo 9 OK 6 —— Sse eee SS a 35 SNA thioacetal Resonancel Reaction mechanism is identical +0 0 regular acetal Stabilized formation except theres S instead of Carbocation aucleophile. Thicacetal formation pattern +H. +Nu -H° +H -L6 +Nu -H® CRsH) © CHO) (sh) -H ~L6 +H af 4Nu =L6 +he Thicacetal atysrtane must have He" (ag) [ +H® ee x pen] Note: Thioaceta\ formation can be used as & “Semi-reversible” protection of carbony!s as thioacetals are stable in acidic media unlike reguiar acetals. Ashiasis Tyg Sov Code ATIEE40) Formation of Imines [Reversible Addition Reaction] R R R Sexo SN Deen + H,0 R H®CpH=s) R Mechanism: Ayr Hebronsfec ~~ — ph Nucleophilic 0. ue Attack Ho Pe 10 Cfiom cat) HH” 4 Neh H-bransfer Le H-transfer ate mn oy H e H | Of HSN® on —~T \ ae H-transfer NPh 8 N LImine L oH ns Reaction yields a mixture of syn & anti Cusually. major) imine + Ses N 4 See NO S Group Priorities 2 ‘Ss a « 4>Q-aoe ant (trans) syn Ccis) mine formation pattern +H? —_> + Nu ——> - H® —_> + H#®_ + -Lq ——> -H® ° CRNH,) (H20) —H®<— ~L6 <— +y® <—— -+%2—__ +nu_ =. + Imine hydrolysis Examples: nt pattern ee NK ot to aw kee H Ba a Aste i Taegu Sov He ie Code: ATIEEM, Enamine Formation | Qeversible Addition Reaction | abu é _RNH RV gk ° Tie aims) pies) RA Sa AA. Need at least 4 Rott hydrogen i Enamine Ne + H20 Mechanism: A setorefee H-transfec Lo ) 1 eg Attack Xe 2 6 Nt CH a 4 | FIO Le H-transfer Ac Dissociation Bo ep \ 5 H Z cNe UO | oO H Re - Enamine This reacton tends to © cm the more stable more substituted) double bond Enamine, formation pattern +H?» + Nu ——> - H® > + #® > -L@ ——> -H® CRNH,) (H20) —H®<——~ Le <—_ +y® ——__ -+p®2 _ ¢nu =. + ® Examples: Enamine hydrolysis H=S atten 7 aS tho re Code: ATIEEBi Formation of Cyanohydrins | Reversible Addition Reacton | alin RL HCN RY OH The reversed reaction is 0 SS Cotalyzed by the presence R R CN of an aquecis ease COH®) Cyanchydrin Mechanism: H-transfer Tr KS e_ “pita a oe yCten: H c= Wg is this reaction relevant ? Cyanohydrins are used in synthesis of Oxylic Acids Cvia hydrolysis ofthe nitrile flmckonal group) & in remit of carbohydrates a8 a way to extend a backbone chain of a carbohydrate, Examples: ° HON(agy «OH 2 ee —Hsc" Ay Aug 73 coon Cyanohydrin lactic acid ° HCN ne, OH Ho cn Pro pK pk Pair of enantiomers Prochiral carbon Ne, OH 9 wer 4 HN wo ws Pair of diastereomers Base - Catalyzed cyanohydrin reversal: 2e Leavin AN ow Wo# HOGS? Group? oN PQ Dee OE 4 CaN H-transfer H den Dissociation 4 Reaction is a quick equilibrium & can be easily shifted accerding te Le Mateliers principle. Ashiasis Tyg Sov Code’ ATIEEPATTERNS of REVERSIBLE REACTIONS of CARBONYLS’ +H®= protonation | Broten NU =Nucleophilic attack -H®= deprotonation J transfers ~LG= Leaving group dissociation Hydrate formation 4 4® > ny ——> -H® pattern =H° <—— -Lg <4?) Hydrate hydrolysis pattern Acetal formation pattern +H?» + Nu——> - H® +h® -L6. ——> +Nu——>-® ° CROH) Yemiacetol » GO) ox) =H ~L6 +1? =< af +Nu = -l6< +H? Acetal hydrolysis pattern Thicacetal formation pattern +H +Nu -H®. +H ZS) ay -H® CRst) HO) SH -H°. ~L6 +H? +e. +Nu -l6< +H? Thicacetal hydrolysis pattern [must have Hg" (2) + H® Cat) “b> happen ] mine & Enamine formation pattern ° +H?» + nu ——> - H®—_+ +H® = -LG —~ -1® CRNH,) © (20) —H?—<—— ~L6 <—_ +7® = 42 __ nu =. + mine & Enamine hydrolysis pattern Ashiasis Tyg Sov Code: ATIEE1B. Baeyer-Villiger Oxidation R RCO3H RQ °. Nee Neos Re Migratory ability: R + RccoH SRPZRP>PH>PROCHS tT ° Mechanise: e. —~ ome) Lo Nor nuceophite Ph Se el H-bransfer Ph "Sr = “6 ° Attack Lt 0, O_Hs ° Co-4 Cae we 8 r [Peron - Ph wc-coon + PRA hanefirn ‘kp, ® ester Notes: HaC-Coo * Baeyer-Villiger Oxidation is cotalyzed by Lewis acids such as BFs aS peroxy low pKa values & dort “protonate carbonyls easily. acids hha Pr P Ph P =15 tv + Hae Soy Ty, + CsCg Keg * 4x10 Pka= 8. pka=-0.2 ® . Migrating Qroup retains its stereochemistry : © mCPBA ©. ne LE ProR R * Most commonly used peroxy acids for Baeyer-Villiger Oxidation are: R Re awe cand a o-o-# ug* Sey So ou T “2 97 or a 44 mCPBA mmMpp Perouyacetic acid * Baeyer-villiger Oxidation is an excellent way off making cyclic esters Clacton) & mCPBA cy / Ashita Tyg Sov Code’ ATIEE44, Oxidation of Aldehydes gb Og Foe = - + compounds Sy HySOq 9) ou Other oxidizing Tellens Reagent! CA er shaff) in NHs)3 and Benedicts ent C CuSO, Cag) + can be used for san “8 iS Oxidation. ages such as H3CrOy (ag); K, Cr, O3 & HySOx ops Mechanism: , 5H fiom H580,) ®os" Nucleophilic. x co Ay Wtranstee “IN, Be , a . 5 Ot, 1 {CrO5 & 0} H H-tronsfer in the solution . rane o : ie hie OH 0=Ce-B2 on BUceontilic ba 5 ree OG. how OF 1 ws 5 4 hydrate ° ° Ci Red -Ox af P O= CAO, OH = OR ou | xy f OH } Ou | ™ +0 +4 +8 a +A Notes: + While Tollens & Benedicts reagents are selective towards aldehydes , other OxXidizin, agerts Such aS Jones reagent C CrO3/ HO, or HgCrOy or Kacnots 4) will oxidize” other filnekional groups such as alcohols CR-on), + Tollen's & Benedict's reagents are often used as Roe reactions for an aldehyde Functional group. Reducing sugars give a posh reackon in Tellers & Benedict's test 4 3 8 Ashiasis Tyg Sov Code’ ATIEE45 Wittig Olefination (1039 Nebel Prize) R PhaP=cR, R R Nexo = Neael = O= Phy Re R R phosphine oxide Mechanism: c edu ~~ bose + Bull +UB 6 PPh HOH uH + LiBe eS) AAg. 88, > E 5 GP Nudeophitic 6 hs Pens oe Attack Br { Rescranesly © Stabilized “~~ 9, Phospho 3 Slide. 2 Nudeophil oh = + PhPA~™ Nuc ili. PPhs > | Presa ° athak PM betaine. q 4 3 or = ° OF-PPhs, P| ods nah gilts, men one eo HoH 3 Note: Formation of a betaine or Sy | @ dived formation of on oxaphosphetane Reductive Cleavage of OPO, iS 0 subject of an ongping research Tt is Known trot the rohure of 4 the yilide , the carbonyl ,& reacien Ph Ph. H S| constions’ all great, influence. the »= + ~~ O=PPhs CX | reacton mechanient 4 H H cis alkene trans alkene Types_of_ ylides: + phospho ylides containing Electron- Withdrawing Groups CBW) are called stabilized du¥ to the extra resonance stabilization provided by the EWS. They are usually sabe & can be Stored for future use. Ss So @ cS @ [em —- \ “extra” resonance conbributer EWE phospho ylides containing Electron-Donating Groups CEDS) are called non-stabili: due to the d izing ePPect of the EDS on the nucleophilic carbon of ylide. These ylides are unstable & must be prepared immediatel before use Ashiasis Tyg Sov Code’ ATIEEStereochemistry of Witkig Reaction ohaw Renctiors with stabilized ylides generally. give E or brars alkenes: g er + Fm ——~ aren se ° -OPPha, E product Cemgior) Z product Cmninor) Reactions with non-stabilized ylides tend to give Z or cis alkenes: 9° I ey +N —_> ara +e er °Prs. Som, ar E product: 2 product minor) Crrajor) Selectivi Wittig Reaction Selectivity, of_Wittig Reackon Ww i Hig, reaction is ver; selective towards aldehydes & ketones & tolerate Other functional grog’ ° OH O Pha? CH ° LA, BLE + oom c=p CH. mA K BSE LEU + 07m Ashiasis Tyg Sov Code’ ATIEE