4 Prepared by Dr. Jalpa P. Harsora Active Methylene Compounds (J) __ Introduction 2) Characteristics of Tautomerism (3) _Keto-enol Tautomerism in Ethyl acetoacetate (4) _ Difference between Tautomerism and Resonance (5) Acidic nature of methylene group (6) Evidences for structure of Ethyl acetoacetate [ Frankland ~ DuppaStucture&Geuther Structure] (7) Evidences for structure of Ethyl acetoacetate [Clalsen Condensation with reaction mechanism] (8) Physical Properties of Ethyl acetoacetate (9) Chemical Properties of Ethyl acetoacetate (10) Applications of Ethyl acetoacetatei stein ny {The misrotens in methane practically do not exhibit aie character. However when two ofthe hydrogens ae replaced ‘by lecron witherawing grou, the rest ofthe hyérogens become acc In nature. The electron withering BOUPS resent on both sides attract the election towards themselves and thus weaken the -CH bond of methylene. Thus ‘hydrogen atom can dissociate to give a stable anion. This same phenomena apalis to EAA, the two hyerogen atoms bonded to methylene group become acide and reactive due to twa electron withdrawing functional groups ie. acy and ester atached o methylene carbon ‘Thus methylene group attached to two electron withdrawing funcional groups is termed as reactive methylene ou. ‘Some examples of compounds containing reactive methylene group ar given Below: (1) Ey sectonectat ty Lovo buanete) (2) Malone ser Dea = alt conc me toe —- ress "a Examples of actron withawing 00 ae; -Lo«r her -cooR teen -2n(Gn001 40500) Characters of Tautomeriam (1) Wen two structural mers are mutually intrconverle and ext in dynamic equilibrium, they are calles “rauToMeRs (2), Tavtomersare discrete chemical entities, captble folio under sutable condos. (©). Tostomers fer from each other in stably The ess table oem scaled lab frm, The relative peoporton of {bo for na tautomeric mitre varies from compound to compound and ao wth temperature, len te “Tastomerc ansfomations ate ao ctayes by ace and ase, “Tavtomer exit namic equim, Tel separation can be achieved oly by speci methods ‘eto enlTavtmeram in Ey acetoacetate (EAA) Alsi, toes and ether catonycompourds exit thi special type of tautomer. Ths typeof tautomerism hasan obec in EAA R involves migration of poten rom a-carbon to carbonyl onygen by the flowing mechs Page?{ PreprdyO Jaba aor ayy — Ket form form es cauemer comaing carbon group (>) i desgated as hte frm, and the eter one cntning {reron run (OM) attached toa doubly Bonded aon rete el om: Ths hind ftom termed as keto enol tautomerism, Diference Between Tautomerism And Resonance Asa matter of fact there no escbing the dynamic equi ‘molecules. Some ofthe impo ointof smarty between tautomerism and resonance. The former ithe phenomenon um between isomers whereas the liter a concept for representing structure of rat eiferences hae ben pointed out below (D Teutamersm iovohes tautomers which have real existence whereas the resonance involves conteuting structures which re hypothetical and donot xs (©) Teutomerism involves the migration of atoms wheres for retonance to actu all the atoms must occupy the ‘same positon nal the contributing strctures. Contributing structures cfr from each other in the placement of electrons ony (©) The tatomers arin dynamic equilibrium. Since the contin structures in resonance are hypothetial hence no such equltrium posible (4) The resonance notes shortening of sing sin tautomerism (5) The resonance ower the ener of real molecule. sabes but this doesnot happen in tautomerism (6) The molecule soul be plana for resonance to ocr whilst necestary ntautonersm, (0) Alltve molecules of compound exiting resonance have the same structure reaver of the fat whether that ‘canbe represented or not, whereas compounds exiting tautomerism have two or more types of molecules resent as equim mii, (8) Te tautomer & shown by placing reversible arrows (As resonances depicted by lacing double ended arom) ond lengths and lengthening of double bond lengths bet this is nat ian of equitbrum) between tautomers whereas between contributing structures. Aci nature of methyene group Page 325 forthe structure of EAA, ‘Prepared by Or Japa Harve offers a classical and mest thoroughly vestigated example of keto-enol tautomerism an Dupo showe ‘This compound was fst prepared by Geuther who assigned the enol struct, whl Frankland vd Dupe hat CAA hadleto structure, The presence of each fhe eto ander formsnEAA was supported by t90 eso reactions (1) Reactions supporting Ket form (Evidences In favour of Frankland and Duppa formula (a}EAA Forms ston products with HCN and NaKSO, neeating presence of carbon! (>C=0) sow. Reaction Mechanisms SON — (2) Wrest with hyéronyamine (NHLOM) and phenyl hydavne (PHNHNM, "especie Formation of oxime and hysrazone i characters of ‘reaction inate presence of et group in EX 4) to form oxime and pheny!hydrazone compounds containing ketone group. This this namie Pages“A wenn tm Prepare by Or, pa Hare wt = Lb (@1EAA shyarohyse to acetone when treated with lute aor alll wich indcates presence of CH» €rOUP ° + CO; + C:HSOH Aca ‘ocn,cH, Se en (a) !tforms mono and aly! drat indicating the presence of active metylene Ero¥: the sbove reactions indicate that &AA ens in KETO for. {0) Reactions supporting enol form (Evidences nfvour of Gether forma): (a) wth meta Sedum, EA forms the sodlumdervative slang wit the evolution of hydrogen ges, whch indicates presence of dry grou in EAA 1 Rreian OF ne FAcenen (2) produces reddish oe coor wt FeCl slulon. This pints to the presence of C=C-OH, {3)dscharges the color of etna, sluton ging adn reacton which shows presence of olefinic double bond we one » * ‘ I we Nic we Poa he (4) ntrestment wth phosphorous pntachoride (PC) forms ethyl ester offhlororotonic aid Pls used forthe ‘conversion of hyarony group into chore functionality. Hence it has been again proved from this reaction that ron groups presentin EAA i A a 6 a ‘ocncr * ely ——e een etorccrtanc ait ragessaat nest a emai po fc 101 coo hay tan "lating Both tautomers in pure frm and showed that the tao foe i rene We Every, eee, Ena frm fehl acest ‘ort (2911), who succeeded in olatin WEboth forms. He cooled a solution of EAA n ight petro to 74°, and obtained Ata which melted at-38 This substance gave no cloration with 78° and nat combine with bromine, and wan ‘eretore the pure ketone form corresponding to Frankland. Dupp formule ‘nom then suspended the sodium derivative of ENA night petrol to-7°C an wee ths suspension wth at enough HO ‘decompose the soxtum salt He now obtained a product wich didnot stalls, tv to agi al whe cooked. Ths ‘utstance gave anintense coloration wie, and was therefore the pure hao frm comesponing a Geuther formula ‘he stability of eno! form is ascribed tothe formation of intramolecular hydrogen bonding CHE cic oc, OH ‘Acids and bass catalyze the interconversion of tautomeric forms ang the mechan fr acd and base catalyeed ‘transformation may be written as follows: ‘Ald catalyted tautomeric transformation Lge Papen pom ev for tl form ‘ase catalyzed tautomeric transformation {€)Proo for structure of EAA by lls Condensation ‘tase catalyzed condensation ofan ester containing an hydrogen atom witha molecule of ‘one to gv sto esters known a Clisen condensation. © ehygen of tasteam Prepared by Or Japa Harr general accepted mechanism forthe Caisen condensation is shown here. iw - cmon Se He Swan, ne 4 oon, Following steps are inoWed inthe above mechanism ‘Step 1 Removal of an ahydrogen by base gves resonance sabilzed anion Step 2: Formation ofrew bond betwen ena. nudeophie ad tony carbon of nother melee of thy acetate Step 3 Breaking of bond to ie stable molecule of EAA Physieal Properties of EAA (1) ty acetoncetat is coors quid and hs uty odour 6% (8) Sparinay st (4) Neutral us (5) Soluble in atte NaOH and tis enol form which dsoles to give Nast (6) Retracve inde 3.4232, ing points 181°C inwater but readly solble in ethanal, ether and most organic solvents. (7) Gives edsh volte color with FeCl, ‘Chemical properties of EAA (A) Reactions due to Keto frm (1) Reduetion EMA on redveton with Na-He amalgam OR LIA n presence of pyridine gves ethyl fshydrory butyrate, whereas in Drevence of LAH, and ethanol the product of reaction i 1.3-butanedio. "Mechanism of eduction using UAlMs in presence of pyridine as solvent is gven below. Ove to higher reactivity of LAM ‘redueton i arled out in aprotic solvents (in the absence ofa proton source). The neutral AIH bind to the negative ‘nrgen stom of EAA forming an ay aluminate, which canbe performed three adatona times producing a tetas ‘shaminate, This complex is then hydrolyzed ina separate step to yield the final alcohol. This reaction involves hyde ‘i (raster of negative hydrogen) from LIAN, to carbony| carbon of EAABo. Rm ceentaees TY |r " Co Ne es Yr yt doy byt ew oer eet nt ‘Mechanism 2p 0 ai Ally aie . one ute © Tetra aluminate Irs Pe: ag we For mechanism refer rection (1) under the heading reactions supporting Keto form. Ae eA ey soyns 0 cme Boalpe (2) Adation reaction (3) Reaction with itrous acid: EAA on reaction with nitrous acid gives a-oximino devatve Resction we anteyf - Prepare by Or. Japa Harsora OND, TQ, wo rr’ A When alkyl group i attached with ‘i, which on hydrolysis ives aeti “7 H a sa SP ¥ (4) Reaction with phen! hydrate and hydrazine hyrate Feactive methye ne Group, then It gies nitroso compound on reaction with nitrous 13d and oxi 1 compound, “fer reaction (2) under the heating evidences n favour of ranand-Dupp formule (©) Reactions that EAA undergo due to presence of Enolic roup (4) Reaction with Ammonia and 2° amine/2" amine Mean Meatmant with ammonia 1 amine or 2 amineges fain cotoniceser by removal of wa vol: Ny See _ ae Pedjon with acetyl chloride In benzene Is treated with acetyl chloride to ample of electrophilic substitution reaction, wow ace, EL cic, —CUsCoet Prepared by Or. Jalpa Haraora form O-acetyl derivative of enolic form of EAA. This reaction is an Macantn run soe en i NK me Acne a: Aa (3) Reaction with base inst The arbanion thus Inthe presence of base ike sodium ethoxide, EAA looses a proton to form corresponding sodium salt. The cab formed ie tabiized through resonance. pcu.ca, one Nha B (4) Reaction with Grignard reagent sensen pat ocarbon derivative 35 the yon Reaction with Grignard reagent results information ofits corresponding hydrorarbr enol form acts as source of active hydrogen. Reaction An te cn te al frmof ety econeieS. Grign reaget AT Soon, at (Ro mt osonetne teen wh dot msn erent — "ol form of ty aonente et fg — can gc 9 ae! \ acta S Aces (©) Reactions of synthetic importance (1) Reaction with Halattanes ‘The sodium salt of EAA reacts with 1° and 2° hlealkanes to frm corresponding sly derivatives. The reaction can be used to prepare both monoaltyl as wellas daly dernatives of EAA patie, °: wh. on, oe ne cri Sota as EAA s:0n| none © 9 on coe MOMKO. Exh we ewes om 2 Ne nd Yon & 8 Diy derive of EAA, Pages‘Prepared by Dr. Jalpa Harsora the hydrogens of methylene group cannct be replace ina single step simultaneously by the base. Thus to prepare derivative, ay groups are introduced one atte. Incase two cfrent alkyl groups are tobe introduced, the 70up is introduced fist due to steric reasons Hideo of EAA in presence of KOM, the hydrhss of EAA may occur in two way eter ketone or carboxylic aid a the ial product Based on the product obtained, the hydrohss can be categorized as ketonic hydrolysis and acid hydrolysis tonic hydrolysis Heating EAA with dilute solution of aqueous or ethanalc KOH results inthe formation of P-keto acid. This acid on heating undergoes decarboxylation (removal of CO) toyed ketone a the final product. dyn A ew A ‘hed hydrolysis Heating EAA with concentrated solution of ethanolic KOK results inthe formation of potassium salt of acetic acid. This ‘ciification gives free acetic acid asthe final produc. ts to be noted that in various synthetic strategies from EAA, Involving ac hydrolysis, the EAA contributes two carbon units tothe produc. nab we | Applcations EAA and its alkyl derivatives react with a number of other reagents toyed different functional group derivatives, Some ‘examples oftheir use In the synthesis of funcional group derhatives are mentione here. EAA | an important too! to yield various types of organic reagents. Its importance Is based on the presence of active methylene group and the ability oft to undergo Ketone or acide hydrolysis. Ove tothe acidic nature of methylene hydrogen, fe form salt wth sodium ethoxide base). This salt act as nucleophile which can takepart in Sy reaction. (1) synthesis of monocarboxylic aclds [EAA on acid hydroyss ges acetic aid The monoaly| and daly derivatives of AA on acid hydrohss vel corresponding higher monocarboxylic and substituted monocarborlc acid especialy. For example: Page-12ee of Butyic acid and Valerie acids Prepme by OF Jeon Marne tytn | GOB * j oh aw ‘The structure of Valerie acd i given below: ‘CHsCH.CH,CH.COOH In above reaction propy! bromide s taken instead of thy bromide then the produc of reactions Valerie aid (2) Preparation of cotonic acid (,f-unsaturated acid} Knoengel condensation teacian mp O l Ake cy, bon manne omen Bfojs ace ey on tan te poet epee oo ncn loss of water molecule after addition of the ‘Aili dervatne of FAA 20Ne Methylene compound to the carbonyt {0up. Weaker bases are used to avoid side icon Kon ERCION Othe aldehydes and Ketones, such at ° the aldol condensation EAA on treatment with acetaldehyde f= F—cooH Inthe presence of pyridine or dethyaine a ‘catalyst gives aliyliine derivative of EAA by Knoengel condensation. Ths derivative on ‘nydolyis eves croton acl which is B-unsaturate aid. The detaied reaction and mechanism ofthis reactions pven herery et a (3) Preparation of Higher Diarborylic ald Prepared yO. dpa Haren Higher dicarbonvlic acids suchas glutaric acid, adipic ac, imc ai, an the like, are prepared by reaction of two ‘moles ofthe sodium salt of EAA withaialoalkanes (having halogen atte terminal carbons! followed by acid hydrotss ‘This shown in the following reaction. Reaction Hes ‘dnd o=d K Sem Oyen 2+ ae — aes EE i ‘en, Diane cari . wet eum * rod = wal ” =~ Dee S pre ating om E00 sets He—COOH Tea KOH ay, Page-iayr A ek Prepared by Dr, Jalpa Harsora on treated with acid chloride (®-COCA) in presence of Me and the re , pve 3-lketone derivative Le acety acetone. sulted products subjected to seston - dram 9, 2 fl ee AA AAW j coen, ibn sete 2S Panne (5) Preparation of Acetonyl acetone Sodium salt of EAA on reaction with | gives acetodethy| succinate, which on hydrolysis followed by decarbonyation fives acetonyl acetone, Reaction ne ports Ca met toooe: ya" whe on ST ep pee Bar {6) Preparation of2-pentanone eure aat of EAA on reaction wih ey bromide ges c-ethy derivathe of EAATHis derivative on hydrolysis eves 2: pentanone, Reaction Ww (80% iy BB wc (WDAKOHS — cHycHLeH,Cocmy o_o wont “Peano ouput | Pagers