{5 Reaction 0 Y & Enols FA @Acid-Promoted Enolization @Aldol Addition @Baxe- Promoted Enolization @Aldol Condensation i @Halogenation @daisen & Dieckmann @tlaloform Reaction Condensaions @Michael Addition @Alkylation @Robinson Annulation 7. = w Tyg Sov Code: ATIEEREACTIONS of ENOLS & ENOLATES abu 4. Acid-Promoted Enolization oO @ OH IL eo CHa een, enol 2, Base-Promoted Enolization R Base & g acu, RS ca, area, Resonancely, stabilized enolate anion ENOLIZATION 2 Halogenation ° 82 pf singe aubstiturtion ° acid catalyst ‘cu, Conly, one H is substituted) a R-c | chs ° br Br, Gs) _d exhaustive substitution base. Catalyst Nef Call ou hye jens will be ) u~ repla ca 8 the halogen Be OS 8 4. Haloform Reaction A-POSITION SUBSTITUTION REACTIONS Oo # Bey xsd P 7 beomofoom Ro Nak Caq) RC gg 7 NCES As % ‘O'Na 5. Alkylation Creates an enolate (Nucleophile) 2, nok, P Reaction works best _ Se _ PRX acti Roc 2. ROLBr RG cHaR ieee ‘les "e% CH © ph 2 7\ New bond Electrophile H Aslasens Tyygi Sov Code: ATIEE@ Aldo) Additen —> P-hydroxy carbonyl alin ° ° New bend r P Base a on Reaction is reversite Roc RoC R-c. i & iS deen in mani CH, 7 CHa CH C~CHs biopatnways, eg ae V aly SiS. R 4. Aldol Condensation —— of,6-unsaturated carbonyl ( enone ) O cH P Pp Base 7 8 . R-c. + Re ———> _ 2 ql fS + H30 CHS 2 cH, 4 C NR RQ ae New bond 9 5 8 Claisen & Dieckmann Condensations ——> fo ketoester Z Clisen= Intermolecular (2 molecules) ct « oo, A New bend ¥ e-cn P e P EbONa . chow —CH-C, + — CHy- C. CCH. CHa + Eto W a" Soe ‘rs “ort Ra “oa ~ Z ee a i 8 3 4hs position must have a H in the final product. Dieckmann = Intramolecular Ceyclizaton) fe bond I Eton, cy + ELOH 4 Michael Addition ———> 1,5 -dicarbony! New bond f Ba g (a g CH. H (Se CH, C. ce ao~™ Cla a4 ™~ R— “cs Hae” ow RNa CH eH 3 10. Robi Loxk Michael By tt b insen, Annulation Csequence of a Michael adtathon | Petes an dy ee de ee do ~ © Cichaet) € / CAldol) No COMPLEX SEQUENCES Aslasess Tyygi Sov Code’ ATIEEAh, Stork Enamine Synthesis Can alternative to ct-alkylation , R aldol reaction , or Michael addition), i ; o~ee 9 New bond Hes enamine Substitution altemative p ingermesiata, SHAE route 4. aye A ake °° 2 Ha 2. Hs0' workup oR ° > “worl © oA i © 1 Re Rt te hy 7 Base CU Michael addition BR Heat alternative route Aldo! reaction / condensation ¥ alternative route y | Mannich Reaction 3 g 4H puss f Cc. Ro +NHst C = Cc. R + H,0 Nee Ane a Ro cH 4 RON x ad WY | i Matonic Ester Synthesis a alg g gg g C. é 4. ELON f C. 4, ELON i t Eto~ ScHY oet 2. Rx boc Nock ERX eto ot Malonic. ester H~ OR Re’ ~R “This reaction represents a powerfid |n2 | synthetic. creating highly- heat heat qenetonlaed Swe Shas’ ¢ 4 Cor ketones if the acetylocetonode ° i 2 is used as a starting, material) Roc Cn R-E-e R sco, 44. Monta- Baylis- Hillman Reackon O° ° ° Daaco pte —_ po phe © eke Row HoT R oc R-K Aslasens Tyygi Sov Code: ATIEE4, Acid- Promoted Enolization ohiw ° © OH Acid- promoted enolization cxn u He ccat) do UR Converts aldehydes & ketones Ros cHy Ro Nett into corresponding encls ketone. enol Mechanism: conjugate. base Of the acid used. , e eH 7 OH Ee Pol c Ph cll, H-bransRer ph7~ Sc%! Hebransfer pa cH ketone 44 enol Notes: + Acid- catalyzed enolization favors a more Ehermodynarnically stable enol: ® Ay He ~_ + \ +r ° On OH On ior enol “product Cmost stable) + This eguilibrium has a very Low equitibrum constant Ctypicalt Ol ot Smale => the system wil generally have a very low cot tantrotton of the enol at any given Hime. + Certain factors stabilize the enol: * Extended conjugation of the T-bond OH 2— extended on oO ®, ~ H™ Cat) yated prt en BEE Pn 8 er congugs * Hon ° AM, <— H-bondin TR H Coat) ER extended conjugated system Keto-enol tautomerism equilibrium can be used te exchange all H's on &- carbons with Deuterums CD's) + 9 D jou Wiel also lose any stereochemist q ones D0, 0.0. ? ~~ UGE the a position US the © atom G oeied D CHy is ap% hybridized in the. enol form n cos be used AbtasiclgSivcan also be performed in Code: ATIEE basic Conditions2. Base- Promoted Enolization ohiw ° oe Base- promoted enolization rxn é R bee R Converts aldehydes & ketones a "5 Ro cH ROS a4 into corresponding enslate anions. ketone ~ Lats "8 ne. enolate anion . . Minor Mechaniern: major Lo conte ° eK Smbivutor 3 be cy Wl —— <> pn“ Sey enor pao 7 WO ao: Bose y i H H Resonancely Stabilized Enolate CLMPORTANT: equitoruen constant & enolate regicisomer depend on the re Of the base used fir this enolizaton Aeidity of carbony!s: ° ° 9 ° 9 9° a e u t W i iy aor R07 Se RNS Ro Nc Nok “a WW wy WoW ~49-30 “33-35 -q nA aldehydes esters 4,3-diketone 4,3- diester ketones Regular corbony's are very weak acids | (,S-dicarbonys are significantly more, & Pogue strong bases Be complete acidic & can be easily deprotonated enoliZation wen by weak bases oS © Base | 9 ° q <> J AL = as “”AS More stable conjugate bose major minor J =? sbonger ook compare to ° ° 9 9 9° oO 2 9 Base c RA Se [AR TL — LL] major minor major Resonance stabilization in A S-dicarbony's shows 2 major conbibutors & ‘(minor contributor vs 18 4 for regular carbonyls. Aslasens Tyygi Sov Code: ATIEEEnolization carbony's using different bases: aration off carbonyls srg ore nm 1 Cc, + Bose c + ys Acid RO cH ne ees wo cory, acid pkansa_-( NHe ~10 NH, 4.3 pka too weal or ~ 10° HO 415A weak bases { 3 4 RO 740 bo 10 ROH 40-48 e NH, ~40% NH, 30 song bass{ LBA ~ 10" Auk as ° H 4 H, as 10 N Equitionum constant When weak bases are used, the enclization equilibium constant is « emai, So the % enclization is small => you only have a very small concentration of Gn enolate in the solution at any gen ime Weak bases are also called oan wases. Equitibhum bases tend to give more Ehermodynamically stable Penolates as major? enclate species in the Solution: e ° Onn | co F BY oy + Ay +n major J enolate species Strong bases enolize carbonyls with an extremely high equilibhum constant , giving vicbuall 400% enoclization. Thus, strong, wed are. ofen veferrea to as ~ equi ium bases. Tf OQ carbony! is added to a non-equilibrium base (so that the base is Oleoads in excess), @ kinetic enolate” is formed. Base size in this case contol fer ioselectivit deprotonation: "8 % + «<—~ sterically hindered H Nat A HOA = ib Om ~ 7 at Lhe aiffeutt “for. LDA + o small base _g® gee Sey, reach it tshile His W mall and not sensitive ee ak € ° tp steric hindrances. yt e stencally open Ms oO oul ey base ° Aslasens Tyygi Sov Code: ATIEEa Halogenation ° eo pf singe qubstitittion ° acid catalyst cy, (only. one H is substituted) a 2 RC — Br cA, ° BeOS 9 fg. exhaustive substitution base Catalyst Nef Call a-hydrogens will be u~ replated By the halogen) Br i) Mechanism Cacidic conditions): te @_H ° wont 3 HOOCCHs OF re, oS Nuc. c. = C. 5 =————! Pr“ Scat, Hetronsfer pr“ Scr" Hebansfer ph” Sc, wu Acetic acid CCHgCoon) is Electrophitic | Bech Elect: often used as a solvent / catalyst Attack the Qcid- catalyzed halogenacion a i egw i T c c. Br ON Hbronsfier Bae HOH an Mechanism Crasic conditions): “eC . 7 at — 1 q il {l Cup HY Base ¢ el ile Wy Due t the aN as ax Pn TK Hetransfer PP C CHy Attack = Pn ce \ Bes these 4 Be ~H JHs are more Bee acidic. than H- transfer |] Cee in the Sm! : Base © il o ce SQ Electrophilic oD C. Zs iw Pn Hee Ge ey cic TT duct the BUGS BeBe ewes Hal on in basic conditions give exhaustive halogenation Ctubstitde all a-Hydragers) Code: ATIEE4. Haloform Reaction ° ° Haloform pK Gd, ad nee - - * 5 Nc, Naou Caq) Non? Mechanism: very, Aecophilic, e ° ce Of OH D or - camgly CDH as —= AN pave Ph a, Pr CBr. yN H-bransfer 3 HoH fe ° Bre- Be for basic OH & halogenaton Nucleophilic carboxylate Attack 9 anion ° ; Grant o 2 ul l — Cf Ces Ph—b— cee, mor & H-bransfer Ph Or Dissociation ra J oH + HCBry tetrahedral intermediate beromofarm Reaction is typically done in an on ages solution of NaOH with an excess of the halogen gradually, Suse to misture. Reackion gives a carboxylate anion as a product . EF you wart a carboxylic Ocid product, youll need to neutralrze the reaction ensues Be Gs) . eee + yr NooH Gs) Kae ° 3 3 carbouglate ‘anion Examples: 9 Zz Gis) g one NaOH GS) mn, Om a. CHa group => ehauctoe regan on NO Hees — auae wl ere 5 2s) peoK st” ass terminal = Ashes Typgi Sov Noa” haf rec © H30 oH Acidic 1 workup § carboxylic. aed ‘OH : Code: ATIEE5) Alkylation oho — Creates an enolate (Nucleophile) & 1 Be P ction works best ce. ° . - -C che ir RX acting as RoC eecaBe RG ote Blectophiles. ° ZU New bond ‘Electrophile, HOW Mechanism: major resonanee TO N contributor ° Note: while both @ fe SD t conibutors a valid C. H Cc. Cre resentation , ph7 Se” Ph ca pr Ex, | erate be alae iv \ R showing the mechanism H-transfer ashy esonancel oceuring via the mi ag Stabiizes 9 contador skeuctuee non-equilibrium base Nudeophilic Enolate e NaH, Lit, LDA is usually Attack CSN2) 4 . used for deprotonation ° reaction & it works best with [rect alkylation is an Su2 primary, allyic ,& benzylie, halides F enolate anions have two nucleophilic sites: 5-—Nudeophilic 0 FD Nudeophiie C Cy YR = CO Ser Re’ Ne 4 Resonance hybrid of an enolate ion Thus two nucleophilic attacks are possible: ve © Hs _, o PF Ngys Sat Fe Pr7 Scig Pn Schiy Your choice of the we. compare to base & elecbrophilés 2 C-attack 9 leaving group determines c oc re aN +LG the major product. Pn~ Sc, Pro cy cH, ® e 2 Metal /counter Lon { NRa< enact favors C attack Leaving Group ~OTs 6-1 e- BeeE favors O-attack Aslasens Tyygi Sov Code: ATIEEControlling the alkylation position hwy You can contol the position of the alkylation forming different enclates using mali CLiH) vs boulky (LDA) base: 8 g ee wo 88 x een an ae “Gqnail base een compare eu — Ee BFP Pret YS Alikylation off fendicarbonyis fr Dicarbony's are Serifeonty more acidic than regular ones, thus they dont require a sbong base to form an enolate. eo 5 o S ° op ® P 9 uf EtONa, é ot nS CL f. > ANE c: He ‘4 Nets Hee™ ee, Hae Sea Woy u is NOT formed! pka=9 + E£OH Pp diketone. O° ° e ° S ° qt w 2 ® 1 T 1 t ASS, ExOna. ow Brn, Hac’ “ef O-et Hye 7 okt Hye7 cue ort H . 4 is NOT formed | Kaze + EtOH rketoester Also, due to the acidity difference between the Hs in between the carbonys youre not going to have “O competition between Une different enolate anions un the uitoakion making this enplization & thus alkylation “ee regiceel Big woe. RR Be ~~ SR OEL ROH Ce OEt HOR yy \ OEE same. Note: when youre working with the j-ketoesters, make sure youre using the same alkoxide a8 youl ester to dooid trans-esterifieation. Aslasens Tyygi Sov Code: ATIEEG) Aldel Addition [makes hydroxy carbonyl] oliw ° ° New bond Y P Base t of Reaction is reversite Roce RoC SRL & iS Seen in mani CH, =? CHa or Acid Scag t- Hs Bopathionys, 12g ao 7 2 Blgrogeness - Mechanism Coasic conditions): me — — (oe Neem ° WOH Ph-c, an “pe H-bransfer ‘CH. Nucleophilic New /\ Hebransfer 1, Nudleophilic yes New 4 Cenolizoction) Or Attack “on. SNe pn GH Hae Ph Hac a4 Biecbeophile Sy H- transfer Since the reaction uses the starting material as both a nuciophile (via enolizahon) & r an elechophile, weak bases Like NaOh or Ph—-c. EtOna are gpicaty used. bases would NcHy ote gan encli youll need Ho. / add So ie OS 2& do an adetitiona} SP sorkup te wpe ose the resulting, Hac7P ph mixtare. Weak bases, however, can be used in catalytic quantities, hydroxy ketone Mechanism Cacidic conditions): mmon Aame= aldol i™ o A on Po Hgo,caty SPH on gor -c = n-c. 7 Nucleophill Non Boome PSSA IE MG |r {%, H-Eronsfer au wu “ Lg oeeeeie Nucleophilic oe Attack 7C- Ph Hae 4 -H1 - Ph—c y S o-H CH Se - transfer CH co Ph CHs, cH, Pr hydroyketone New bond Ashocaw Tyg Sm Code: ATIEEMixed Aldol Addition oliw When you react two different compounds together in basic or acidic conditions youre gong te get a mixture of all possible” products: Qcid or Base oO OH ° ° ° Ki AK ee Ke AY + ° Ho Ho" plus 5 more products ! af You want to selectively react two different carbony! compounds in an aldel addition, you need to first convert one of them into an ensiate & Qdd the second carbony! to it: Examples: z ipa 8 tags Oo OH maior ~~ = ADS © AS preuck 2. HO workup eo ° New bond : a AK . : ua or co _— proauck Of 2, HCP workup OH OP New bend Mixed aldel reactions are a litle more predictable as aldehydes are more Uectrophilic & ketones often make dlighty more stable enolate anions: ° Qcid or Base OHO ~ + ety A mnqjor product O° You can also perform a reaction with a non-enolizable aldehyde or a ketone that can only Oct as an clechephile: Examples of non-enclizable aldehydes & ketones 9° °° il} W c c ee “™~N “on Pao PPh Ar ete. None of these exampks have a hydrogen in the a-position, thus NONE them can an enol or an Sroike. > thus they can ONLY serve os Ueckophiles Gnd NEVER Os nucleophiles in the aldol redction. Aslasens Tyygi Sov Code: ATIEEoliw 3, Aldol Condensation [makes of,6-unsaturated carbonyl Cenone) | Oo cH Base 3 Rc + RC ac a + H30 CHy 7 CH, 4 oN aeee H ~New bond Mechanism (acidic conditions): — eH 6 ° - : i HgSOx Cat) oF . cr =——— e —— Ph CH, H+bransfer Ph KX Hetransfer Pn” ScHy aH HOH i) < Ny REP 4 Nudleophile Pr 3 Atkock . H “OH e& a oH v HW ee A SS SS HSOy Pr te H-bransfer Pa“ Sc H-bransfee Ph“ SO eo i. ( Pn—C OH, Pa—C-OH soy Ph—c-oHn cH, cH, ' 3 C 3 CH, Leaving @nol intermediate Group Dissociation CH20) a) aye 4 Cs, 4 ° ns, il 1 wl 1 c C= c c Pn~ c% Ph H-bransfer Ph~ C7 Ph 4 4 dt, p-Unsaburated ketone Cenone ) Key points to remember about acid-promoted aldol condensation: @ The avivi ce for the reaction is the formation of a conjugated tem. R fe 1S Also entopy-driven => it requires heat wes je the equitionum towards the product. Water removal via Dean-Stark bap tsPalso common. @ Reaction fares the formation of a more thermodyramically stable. double bend when multiple products are possible. 2. Elimination step happens via an enol intermediate. sca Tyra Sov Code: ATIEEMechanism Coasic conditions alin ® o ° ce We OH 5 T c ——— c —= c. Pa Hebransfee Ph“ Seti, Nucleophilic Ph“ CHs oH rN 3 Attack { h&- HOH ° Ph—c-o® P Pn ~cHs | H-bransfer ©. CH, roe w ; Poe ‘Ou c H Ph c7 py == Ph oor Ph7 Soy Leawi - 4 soon Proccow POET po on a turated Dante a 1G ! _pounsatural i 4 P ketone a He He Cenone) enolate intermediate Key Points to remember about the base-prometed aldol condensation: @ Reaction requires heat to drive the equitibium towards the product: Removal of °H20 using Dean- Stark ® also common but unnecessary. @ Leaving group disecciation occurs via the enolate intermediate. @ Reaction is easier to conbol Cregicselectivity wise) since basic conditions allow or different enclote anion ~-formation Intramolecular aldol condensarion is @ convenient method of creating 5 & lo membered rings Smaiter or larger cycles generally dont form. Examples: S(O q 9 O _NaoH [a i — 1 + HO oxeyrey Heat Sat 9° 9° L Ph Rowe, Nod ates Ly Pro Heat \4 ° Ph Code: ATIEE8. Claisen & Dieckmann Condensations | makes pr keoester] ohaw Claisen= Intermolecular (2 molecules) ° 04, OF New bond 2 e P EtONa e cen =CH-C. + RCH S CCR cH, + Eto ly BN ot ‘Oct 7 Set R* ow RQ OF Le g this position must have aH in the final product. Dieckmann = Intramolecular Ceyclization) ° fee bond ° ° il ° a Etona cet ns Eto wr Koet * EON oo , Ne Mechanism: Le) pucleo lic. enolate > ELONa £ L “Tebrohedral om “Seo “Rudeoprite Oo Intermediate Hs H-transfer les Attack

workup couse Ol + etd fe ketoester enolate pkox aa intermediate, Notes: Reacton is an eqgitbem resulting in an enolote intermediate because the p-ketoester @) is More acidic than the starting material SD, which sheans that you need to do the acidic workup get the final Pr ketoester @. @ When multiple products are possible , the ones without the | in the ol-position will easily go back te SMs & Ore not observed as the final product cs). Aslasens Tyygi Sov Code: ATIEEExamples: ‘Dieckmann Condensation one o 8 4. Etna sche “arte ao™ “BHO” St oy workup +EtoH NoT formed Mixed Claisen Condensation L es ck 9 4, CHaOk cr 7 i Se oO Aw + cre Z. Hee? OW ccnoy —— OH workup =" Not formed Claisen- type Condensation ° ge cy 4, ELONa, cr ae Cow * rs 3. HO LU seton = A worl f bka=24 “e Since aldehydes & ketones are more acidic than esters, enolize easier & act OS nucleophiles im these reactions. However, since est are alsd less electrophilic than aldehydes & ketones, is better tp do a complete enolization of @ carbony! oefire adding the ester. . Oy pF ee FE 2. Hee workup Note: When youre working with esters in basic conditions, make sure. youre using matching’ alkoxide base to Quoid bransesterifcation | o. Ss Oy © a + rr +eto =——= TT EtO same as starting ° ° materials Compare to 2+ 44,0 ———= ON + EEF different minty 0 == ifferent mixture i? “ye due to transesterfienti Aslasens Tyygi Sov Code: ATIEE4 Michael Addition [makes 4,5 -dicarbong|] ahi New bond f Ba: g g CH. (Se cH C. iC. ™~ Nd ~ RSH, Hac” c RN ens > cH SH a New ©. ° 2 © g Nudleophilic. bond u e858 CNA Atkack ° Akh To ol Zenon Oe DD Ph co H-transfer = Ph OH, O aN Enolate @ =P O Cx HH nolate f CNucleophile) 4 p-unsaturated eS Michael Donor | compound EEO CElectrophile ) Note: when multiple equally enolizable Michael ° H-bansfer 2l+ positions awe Db it, use the Acceptor A Same approach as in mixed condensations Ph" 5 by quantibatvely turning one cartong) into a. on ponding enolate dig a strong base tke 48- carton “ LDA or Li compound. Best results are obtained when the enolate (Michael donor) comes from a 4,3 dicarbony! , So theres No competition betioeen the enolizable Positions: °° °° Oo oN N o 2 how i Ll @ N. a @ RR aN Acg a7 4 aA Examples of good Michael donors [minor resprance contributors shown with © on C] oO ° I Etonaccat) 4 =o EtOH 2 bohen chiral boses are used you can make. Chiral atom O mixbice with Oo NO competition Significant enantiomeric g ° ¢ g excess of one of the Oke arm ELONa (cat) C Ph enantiomers. EtOH Aslasens Tyygi Sov Code: ATIEERegioselectivity of Nuceophilie. Attack on dip-Uneaburated Carbony's_ alin [ 4,L- v3 A,4- addition] aan e A Hybrid resonance 2 4 ® & tt <> c C = structure of on “a “eZ i 7 Sow ~ S atb-unsaturated me carton! compound Position of the nudeophile attachment tn the final products depends on equrionaen conditions & nuceophile nature Chard v8 soft). In addition +o +hat, nature of the oi/o-unsaturated compound plays role in regionelectuity, @ Nature of a nudeopnile Hard Nucleophiles favor reaction with hard elecbophiles [ 4,2~adaition] eshile Soft nucleophiles faver reaction with soft dlecbrophiles [1.4- addition | Typical Hard Nucleophiles: RMg®r, ALi , HyN-oH Typical Soft Nucleophiles: Q,Culi’, FR, enolates Examples: i, HOP g 9 4, Phogec ca compare. ca A. Ph Cui CO Ud tae to —~— a Ho® ~Ph workup workup N- & Scnucleophiles tend to odd 44 te the d,p-unsaturated carbonyls fo} a oH ° W Avg Tao Aner MQ )or~ @ Steric hindrances in the substrate @ Noture of a substrate be much steric d,p-unsaturated aldehydes ‘dea to give 12> adetion ucts Significantly more than the ketones. Aslasens Tyygi Sov Code: ATIEE40) Robinson Annulation (sequence of a Michael addition followed by an — Shin oa aldol_ Condensation ) Re R Ais ny cate GOOF ee Crane Ro $ Cmichael) So / CAldol) SNo Electrophile Mechanism: ae" once D z 79 oe — = 3 Be bransfer CS —— s ao Nudeopitic. Attack ws Sond 2 Enolate. = Cmichad donor) Those Jog H-bansfer “Nuceophite byt § ROHN Bi banshee ‘Attack 3 oa 5 et 2 age u § transfer H- bran: © ° Note: reaction is driven by the 8 H,O removal during the = co aldol condensarton pact of the wee Leauing mG mechanism (Le Chatelers principe) oe Group ‘Dissociation This uence works best with 4,5-dicarbonyls with only acidic H in the ot-pobition , Otherwise multiple Michael rentbons may © prior to eydizaton via aldel condensation Le. r RK 7 eee “e. ox Uminium Detaken . HO: | ion intermediate. ihe - ‘OH H-bransfee 2 i “on AAO Nucleoptilc L@ . Nucleophitie N Attack GN’) __Altack 2 OS TD sO Ph Be enamine Pro iminium ion G intermediate. ENAMINE FORMATION al c 4 cet oH wl JF Sb FO 5 ‘Dissociaton HYDROLYSIS 2 Stork enamine synthesis is a usefd alternative to the regular a- alkyledion a! as it requires mild conditions & helps “Y= New bond — avoiding "Unwanted side reactions NUCLEOPHILIC ATTACK & Aslasens Tyygi Sov Code: ATIEEExamples: ~ o R Sere Pn Be RL —~ PCat) J 3. H,0® J ples > workup Ph More stable E-isomer is fosored too much oN steric hindrance om © QO oO f 4—+too much steric ° — hindrance I 4 ~ cr H° (eat) oo; “ or pHs major minor —— ° ep c I aH, Zing OT + Enamine intermediate favors, Qa more stable molecele as the major Product Wee eons que causes a lot of steric interactions with the amino group. Anythi bigger than a wn simple —H Sore hs Cunt duoras = unitkely, \ tp tiem. + Stork enamine synthesis is usefil when the molecule is sensitive towards bases os the entre Sequence, is performed in acidic conditions . * Unlike enolates, enamines are stable molecules => trey can be isOloted & Stored for future use. Aslasens Tyygi Sov Code: ATIEEAldo! reaction /condensation alternative route abu R R zy oy ty RE RE gis OC St OV SEES Or OO H® Ceat) 2. Ha® R Base Hee enamine 2% Has Heat p intermediate workup Mechanism: nl NY @_H ZH OH, Z § Pccaty e ed * Hetrans ee G | ~~" Fe bransfer ~ Nucleophilic Sy E fe 4 toe Lys 5 4 & OC ooh oR vo 7 & ARE ee we AA w Hu > ee oy H-bransfer ) 3 40 Uminium Seeiaken “on Mion intermediate. ‘OH, € " 6 | Hebraic co HVe 5 AO. Nucleophile Nucleophilic oS RIA\, __ Attack ao Aiktack 0 — » enamine Ph OH Ph OH : 3 Ph“A8-H Ef He why ° . HoH Be] OL. ~ Ao ae er 5 oa ran = “Leaving ng yw He bansfer iD w Pr on = Groups Ph ‘Dissociation lnm | E OH Protonation of -ol, ° Zz r H cata! tte elimination M Zz 2 orjugate aii , = Leto feo depiction 4 " +H,0 enol | deprotenacion d Ph” “OH nuctomerization PP OH (Oe ise conaensation PA eee for the details) Ahseas Tyga Sov Code: ATIEEMichael addition alternative route oli R VaR Riv to v4 ak R Ova OT: ® H® Ccat) 2, H,0® ples enamine 3 intermediate workup Mechanism: ay eH 4 “On é ~3 Peeat) — pete - Bo oosfe H- bansfer Nudleophilic. NN f sfe “Ur dep ay | 5 4 ; Coa ee 4 H REY) “Rae =r ~OrYy “Treake Aw w u er \ q : iminium Detiaken z HOI] ion intermediate. € H-transe- . So. o pO, Nusleophie ° nO , iu Atk o——— TO “yeD “ Pr EQ eramine H- bronsféc Ww 5 To nes wo She y Wo Nudeophitic 3 Attack < , Cs “OH, a 4 NS "es! € > é re ( | o \ —S ~ ss y = {i H- transfer C “Hetransfor J O = a Leavin mr~ So m7’ 3 (Ee ZHO: ‘Dissociation 2 ° 5 H, ac Ce Ga He bransfer e mo Code ATIEENotes: olin Stork enamine - Michael reaction has two main advantages: 1) Enamines are stable & neutral compounds => they can be stored & used for fdure reactions. Being neutral also ns that youre not concerned 4 any acid- Feackons that may be bggeres by basic enoiates. > Regular enolates give poor yields in Michael reaction, However, AB dicarbonyis & Ohamines demonstrate excellent results with minimal Sde-reactions & unwanted products. Examples: — l oC» fo) SW 9° f " | oll T Je sO On Ore Ce “ROH Ceat) a. Hy New bond — uporku.p 1) l 6 a 1 4 ANON prt —— py, maw 7BOH Cat) a. Hs? a workup “This sequence can also be modified into @ Robinson-like cyclization: 5 DY i ° , an Py ee © CO New bonds TBOH Ceat) 2. Ha heat or Ett & Neat Aslasens Tyygi Sov Code: ATIEE48. Mannich Reaction oO i u . ane ® TNH pues Cl UR +H eo Hou Z Na Mechanism: Step 4: Reaction of NHy with CH,O0 4 H os om Ye °og tin oH if B/S, ey ZN, He tran: ZS, Nudeophilie "77 4 Seen Matto a H- bransr Ay _o/H WN iminium ion Group Seo intermediate ‘Dissociation H” ‘y Step 2: Enolization of the carbony! ny eo-H Ou Ne Bw Tow KA WS “Fetransfer 4 Fe transfec enol intermediate Step 3: Reaction between the enol & the iminium ion intermediate O62 HF aot H. 9H A Non i oS Seek goo CN SS Conte 7oCSNu Nucleophifle LY y Ly SH Nuclecpnite Ws H- transfer Notes: “In Step 4 ypu can use any aldehyde oc 4°/2" amine to form the iminium ion intermediate. The trick is to make sure that the aldehyde iS more eleckophilic than the enolizable carbonyl to avoid cross - competition. + The reaction is usually done in a single pot mixing atl reagents together at the same Cor akmost same) time. 8 8 8 Aslasens Tyygi Sov Code: ATIEEExamples: olin cH, \ Hac Hs, © -RoMceat) gv ils Cl + noe tee ey 4 cH WO Je eH New bonds a. { gf CH; — nv? OH G HatscO 1 CS oO H iminium ion Hs to intermediate enol intermediate Mannich reaction can be used to build complex bridged systems vio multiple Mannich reaction cascade: He ° nN 9 wero RA cca, + Hgc-NH, + Nome, \ & Hse Coat) aS 4 Meo Re 2 Hyc-N&D. ° mcoO A . CF 4 4 ot | Hc Hy ot HCO) ~_OCH, EO Is ls ¥ S oes sOH oO Mannich reaction makes a went guest in both synthetic & biochemical reactions . Enzyme ackve sites Containn "S lysine amino Acid are often involved in similar Chemisty « Aslasens Tyygi Sov Code: ATIEE1S. Malonic Ester Synthesis ° ali 7 & 2 ge t A, ELON t c 4. ELON w t eto~ cue oct Dae eto Se Noel eto ot Malonic. ester HR RR This reaction represents o powerful Hy? Hye ‘Synthetic. creating highly ~ heat heat [errmnndlotonge Seiae’ ¢ H for ketones if the acetylacetenode ° 1 ° is ured as a starting material) R-CHy-C Roe-c + CO R +) Mechanisi Step 4: Malonic ester enolization & ol-substitution C29 eo LE —_ ~ eto RI Noet TT cancken geo Those Nucleophive eto "Noe He Attack = Pr Ce ° Step 2: Second enolization & a-substitution Coptonat but very common) co 9 Bo e 9 eo“ SY Nost Trae she EPO Ort Nadeopne Eto’ O& Ph Ph ry PhS Step 3: Ester hydrolysis ao ™ Ca ‘ oO % e oom ZOH, oOo Oe A q te A Qe & l OH, Eto ee Fitronsfer LO So jucleophile. cto oe PhoS PhS Mthack PhS H-bron cn any 9° Lg iseotiorkon GCeou tt tl < 2 Dseatn et Hors pot === Eto ‘OH Eto7 >< Bog Repent H AS Set ow mS ca Tyg Sov steps Code: ATIEEStep 4: Decarboxylation oli 4 onset untermediate- ao ao oy 104 © REP ve AT te! HO we H Forse Hof Ph Keto-enol Ph ukomevizartion + CO; (gas) ber While dicarboxylic acids require some heat, ° - ketocarboxylic acids decaPboxylate ey ‘spontaneously Ho Ph Examples: 9 9 ° 7 4, ELONQ i f ELONa cto oct 1 ky Be ERO et LO Ot matonic ester a g eS" zt Intramolecular © cL Br 7 Cydizarion os 4 Malonic ester synthesis is a very useful Hac? these. route. Soards righty RMctonatized = % OH He hact gyce carboxyic acids may be (a Ester Hydrolysis aiff It to Synthesize otherwise. & Decarboxulation 4 4 2s Note: when we say malonic ester, we enerally mean diethy) malonate. However, dimethyh malonate 1s just OS useful. These esters are onterchangeatse in iS Synthetic, Sequence ° ° 9 Et= —CHZCHs eo oct Meo “ome — Me= — CHa diethyl malonate dimethyl malonate Structurally similar to matonates esters are also usefixl in this Sequence: 99 gear, 9 AK 3, EtONa + Oy 4. 2B engl 5. Hx0®, heat Hl acetylacetonate, Aa So Code: ATIEE4, Morita- Baylis- Hillman Reactor olin fo} ° Daaco Ag ———> Re o pte Q P R R t R- Oy he oc R-K% nv DABCO = Digzobicyclooctane = Ay = «Co 'N’ Mechanism: ca Nudeophilc. f oO, BP) ‘enolate’ ion co ye Pharr, =—_ hae = Ph q ® 2 Nudeophie io th Nadeophie AND S a) PnP kore ee” Distiaten nde Sis = “Dek Ph N: Ohh Ph A Notes: @ Baylis—Hillman reaction is, essentally, a convenient tm do a Substitution in the ot- position f the op. unsaturated compound. @ While DABCO is the most common (& the best) cotalyst / base this reackon, other amines can also be used. The amine of choice should not have any Hs on N & be suffeiently nucleophilic like Mean, EtgN, or pyridine. @ In reaction with aldehyies & ketones a dehydration in the last step Cease p dissociation) iS not Observed 3s —RL is a much belter goa than —OH. Aslasens Tyygi Sov Code: ATIEE