oliw Reactions Carbo Gadsd act @Acid- Base Properties of Carboxylic Acids ‘o-H @Fischer Esterification @ Conversion to Acid Halides @ Formation of Acid Anhydrides @ Reduction with Complex Hydrides @ Hell-Volhard- Zelinsky CHVZ) Reaction @ Decarborylation of Prketo-carboxyic Acids @ Formation of Amides @ Activation of Carboxylic Acids with Carbodiimides @naucreophitic Reackons of a Carbowlate Arion Code: ATIEEREACTIONS of CARBOXYLIC ACIDS ohaw a Acid Base Properties of Corsenis Acids R- R= + H® “Typical pa =4+0 oy a gpa’ P P So-n 74) -ypical pKa of the Rc ss HC ROL protonated acid is ‘OH ‘OH ‘OH -6+-3 é 2) Fischer Esterification P ROH P R- = RCL th ‘OH H® Ccat) OR 8. Conversion to Acid Halides er PBrs, & R=-c. ———> _ R-o + POBr + HBr \ N ‘OH Be eo sod, re Re 3 Rh + so, + Hes ‘OH a 4. Formation of Acid Anhydrides er xB Heat f R-c + a nel RCL _C-R + 130 0 other OH HO or Wd, 4 eq) oO side products or (Cod), Cred a depending. on the “ method 8 5. Reduction with Complex Hydrides H 4 P+. LiAlHy \ 6 & Hoc? t R-c = —- R-c-o R-C-0-H Ou ' workup i H Ashiasis Tyg Sov Code: ATIEE© Hell-Volhard- Zelinsky, CHV2) Reaction alin H oO Re- + Hee o —b— P Bry " See be OH R= CHC > R-6-¢ o. OH P (cat) v ae Se H Pp QR-C-c_ + Her 1 Sor & % Decarborylation of fo-keto-carboxylic Acids OH °o 9° °° tl T Heat p Keto-Enol t Cc. c. Cc. + CO, _————__> RNa Noy RO Nc, * 2 “aatomenaahon Rey 8) Formation of Amides ° NH, p Heat P ao > M M R-CL RC gg TT RCL 0 ‘OH SE Ruy, Ny, 9 Activation of Carboxylic Acids with Carbodimides ° é oO c ow > R-¢ i e Dec Pow a ~oR osu Re eee Tey pm i ed a I“ ‘° wh Ns gd! e x Nye oO 4 40 Nudcleophilic Reactions of a Carboxylate Anion ° ° f R-CH- Be t © R-<, ———> _ R-e. -R +B \e Sud Ng He Ashiasis Tyg Sov Code’ ATIEE4. Acid-Base Properties of Carboxylic Acids alin Dissociation of carboxylic acids: “Typical pka=4+6 ° ° ge but can be lowered Re Rg RM | + Ewe's in the No-H Se So & chain of the. acid. Resonancely Stabilized Anion Cearboxylate) The presence of Electron- Withdrawing Groups CEwe's) stabilizes the carboxylate via induction: a t 2 a do Bae (or Son a or “OH of a a pKa = 4.90 2.80 4.24 °. Since the stabilization effect here can only oecur via induction, it is the element (group clectronegotivity. & tS distance fom the carbouylate is vohat raters the most. © *t Electronegarivity Effect : F-CH,-COOH = CI-CH,-COOH © Br -CHy- COOH TL -CH- COOH Acid pKa 2.00 2.8 3.80 Ba Element Elecbonegatity. 3.08 Bao 2.90 a.wo Distance Effect: The distance effect is most promiment when the EWS is on a ~ & atom of o le Q Carboxylic acid & is ne, Ki when the on Ay us EWG is ‘Biether aww in Ae cain. a ° °° ° gs fF pKa= 3.83 3.98 Now ef Relative chain positions Carboxylic Acids Acting as Bases : ® e —, e we nmi Qc +H Rc =< oR. “Typical pka * -4 ‘OH ‘O-H So-H Resonance Stabilization of the cationic species Protonated carboxylic acids are storg Brgnsted acids & only exist in equilibrium at extremely Low concentratons even when protonated ey sheng, adds such as H2SOy, Ashiasis Tyg Sov Code’ ATIEE2. Fischer Esterification /° H®, reflux ° R-c + H-O-R sores R-c? + H,0 O-H Yo-k Mechanism: e@ ‘OH <> OH OH O-H Nudeophilic aHack “Tt 4 — YF —“t-bransfer LC® OH \ Resonancely. Stabilized Antermediate. Leavir 8 C OH On er ¢ <—— Cor athtransfer 0" Sos a on ay ° Se VY ~ ester Resonancely ‘Stabilized Intermediate, Fischer Esterifeation ° Pattern ° +H +Nu -H® +H® -La -H ROH) (H,0) -H®. =Lé +H® -He Nu +H? Ester Hydrolysis Examples: Patra ° L H© coat ° on HOA Non ———> [CEP + 1,0 — Cactone Ceyolie ester) ° © 9 Apo . se H' Cat) Aho + HO Note: Fischer esterification is an equilibrium, so to shift the equilibrium towards the ester product, according to Le rat iers principle, water has +o removed usi either Dean-Stark Trap or 4A molecular sieves to physically. Temove | tap 1,0 away, fiom the equilibviam Ashiasis Tyg Sov Code’ ATIEE3, Conversion of Carboxylic Acids into Acid Halides oli Pr PBrs L mn R-Cl * POBr + HBe OH Py Coptienal) Br eo sod, PP R- & Ss R- a + SO, + Ha OH Py-Cophenal) a Mechanism with Pad TPE rs, Pay, 8 PCs are alternatives for this rxn] © Be ae ‘ FF Nudeophile Pr~X Pee CHa TP CHs—C. Be <> CHC Br oh AS Attack No- Sg2u Resonancely, Stabilized Kewe o- a Interinediate Be H-transfer Leavin gPy ee ” JB Group rw” Nudeophite Po. CHCl sos e——— cH c*o sha Be 4 Be Dissociation ce Attack oNS f &e Tetrahedral Be 'o Intermediate ‘ Reaction produces Br during the elimination step which is used aS © nucleoghile in the previous step , thus Br acts as O catalyst for the second part of the mechanism. Reaction can be thus further catalyzed by the addition of KBr fo the mixture, Mechanism with SOC: ° 2» L » ma a Leavin, _f PN Nucleophilic. 4 L 4 & Groupe Pa CH os CHs— ——— cas, = Nou RT Attack = No-H — Dissociaton Ny fo ° | e gol “a a °° a o- o-S. Nucleophitie. Ps, Hebron: Pe cH LQ use Ny ebromsfie oy ai Attack — “BPX sess ic) 2°? ° Leavi ON 7 Returns back os a > Diseociation o @ Catalyst similar te OF om py. CH how PBrg works ° Since Cl" is Q weak nucleophile in acidic conditions therés some debate regarding the Asisiste Tgpesinn Of tris reaction Code: ATIEEa o a Mechanism with eo Covaly| chioride) # ohiw — op OE Step A: Chlorinating agent generation © Sea a % a ° © Yen we Ne CoS ——> we ° ° | (pur -cot) oo” 2 ' oO Now ie chlovinaking Agent d 3 NN q do, a+ co+ co, + NE a | of Dey Step 2: acid chloride formation | Re ved Catalyst Qo cl ¢ 8 oy on / i Cc / 7 CHercy er CHy-C +O che Ve yee Con 7 rey This reaction is favored man, thelic chemists as it produces Oo cH-c” CO & CO, which aw at & oe bss noxious to work with B Nog than 802 & Hel that ate formed in the reaction with SOCl,. Examples: PBrs OH oa Apt ey ° ° Sod, M qaoc-coce mw — + CO, + 0D + Hee re DMF Ome Aslaeas Typgy S&oO* & setvent) Code’ ATIEE Be + O=P-Br + HBr4. Formation of Acid Anhydrides r S Heat RQ-c + Ro > or Other N, / NO? ‘OH HO or Wa, 4 eq) products or (Cod), reg’ depending on the method Heat- promoted dehydrations yielding acid anhydrides general ceed via. self protonation & Smsequert Sacer atiacl! 8 o Pe Reactions with SOCl, or similar reagents convert> half of the carboxyic Acid sample into an acid chloride which in turn reacts with the other hal -egui of the carboxylic acid te form the anhydride: Oo a au a 2R-CL + SOC, R-c + RCL SO HS ‘OH ‘ ‘OH ‘ O°, PW Roc, ER +Ha Total Balanced Reaction: o ° eC a Jeg QC * Ye SOCy. ————> R-C_ ER + SO, + ane 4 Sou ‘4 a Nov 2 Mechanism of the acid chloride reacting with the acid: 2 cp oO. Nucleophilie Pe ° ee -CH, ———> |CH,- C-O=C-cH, <—= CHy-C-0-c-ay ‘ v Attack I I u oe OH O-H @ a) Leavin, Resonancely. Stabilized Grou Intermediate, ‘Dissociation Hel 4 a % cay, fe bransfie CH, Lo H Ch Cgc. CH, <———— CH a e 3s NA 3 ' 3 \ B00 6 “ou Mechanism of’ Heat- Promoted ‘Dehydration: Code: ATIEE5. Reduction with Lithium Aluminum Hydride abu 4 Q PP 1.LiAlHy 2 Tg ake { - Oe ogee -C-0- Now T° workup R t s H H Mechanism: r | Hetransfer SP Nudleophiie i CH &, Ho ASH CHa CAS) > CHC H1 NQu © = HH (gas) @ ee AIH Attack Noa 8 G 18 of aid H Leaving. Ny Group H Dissociation \ H e e y 6 g ww § 9 | Nucleophiti “ cHgre-n SUceeptie c. ' Attack N\ \ Geisie Workup ae auH 4 nofer OFA or H- ASH ewH ' © Tt is statistically likely thot each pucleopniic atack is done with a HU new Al-containng species. Important strichiometic relationship is that 40g. of R-CooH quires OS of LiflHy So there is usually an excess Of “the nucleophilic HP in the aioe that needs to be neubalized along with the alkoxide product. Practical Note: LAH veacts viclently. with Acidic hydrogens So this reaction Should be done with extreme coutions LAH is a very atong veduci ent & ik will reduce all polar C=* & C=X bonds in the molecule lke’ C=O ACen so You need to plan your syntnesis According! & use Bris reduction at te correct hme or use protecting groups for vainecetie ‘flnctional groups in your molecule. Examples: a. “7 C=O was reduced +e an alcohol along. f ' !. with the carboxylic acid. Boome > AKG workup HoH owe n® C=O is safe Eso Tihs Hac® workup takes off the acetal rotecting oup Vid Acetal hydrolysis, oe P amy! C rou? Borkup g no alktant step is necessary. Ranieat pap owe Code: ATIEE5a Reduction of Carboxylic Acids with Boranes ohiw e BH, THE q R-cL ——— _ R-C-OH + Boron derivatives ‘OH or By SMey 4 Mechanism: Theres @ considerable debate about the exact mechanism of this reaction. H H @_8 PX H Bis 7 H HOCH 1 CHC -0- re 1 Z 4 4 what hay 1 8 NaH here is unclear 4 Aqueous 1 Workup H 4 1 CHy C-O-H H The advantage of this reaction is that it is chemoselective towards —COoH, meaning tat” you can do +4his reaction in re presence of other functional Qrups- Examples : (7 TO is untouched! o 9° BHa- THE f SR, SO Ashiasis Tyg Sov Code’ ATIEEoe Hell Volhard= Zelinsky. CHvZ)_ Reaction Hoo TT I 1 a 4 we ww & by 1 2 eo be Br R-C-C + Hee \ ‘OR R-c-c RCH. ——— > e-c-¢ R Non oan T Sg. ~£Qy This reaction has both histpric & synthetic significance. Be esis thesis of" a Amino Acids a funchonaed carboxylic acids Mechanism: Step: formation of a brominating agent BP + 3B, ——> APBry a simple red-ox renction Step 2: conversion of a carboxylic acid into the acid bromide &e Be 7 ee p. ae oe Bg "> Br KT er Sn2 Nudeophili 7 | \ lu ie mou ME oF Wudeophite ~Bow Ree kee G Alback ° ee Be This is a slightly different mechanism of this veaction than vohat is chown in the previous section. Als both of those Show up in textbooks, both are shown in this set. + Acid-catalyzed a ~Bubstituction Cure eH cH Nudleophite FS Por oO - Oo r tebas Ad Sent Ak oS i mae We ~ ee Intermediate Cobre ary Oe Electrophiie Atback by On o eS He i iebansfer IL —T br te Be Ashiasis Tyg Sov Code’ ATIEE‘Step 4: workup oli HV2 Reaction mixture is commonly quenched with either water or aleshots 4 yield an acid of an ester ceapectively + 2 Leavin, ° CR. Nucdeeohil Vow t P B, Nucleoghilc BH Group, 4 Nee He! Bikack Con Dissociation “1 SOS Beer ee O a) Bag te Room Be carboxylic acid ° Sane Le ! v Be HO wee hi Broo Hy ° we vonsfir tr Ao + Hite be eater Note: POBr from Step 2 reacts with Bry regenerating PBrs thus P is often used in this reaction in catalytic. qush it Examples = ° PP 1.PCeat), Be, er NH Ces) ° P CHA-C. —— Hy-C., ————> _ HaN-CHy-C. 9 Noa HO 1? Son SNS Br Amine acid glycine Hoo ° i aon Hal Pa ayo 4.2, Bea on a ary Lee arc Cimnamic acid te ae on cas) ‘Su RM @)-phenylalanine- Ashiasis Tyg Sov Code’ ATIEEoliw OH g z Heat 7 «co, __fetorSent g a-Sc*on RON cH, * “automenzakon 2 ~cHs Mechanism: HS eu This reaction is : ° ace Pe 2 SE Ef oe Cnkatan of Pn“ cH No Ph" cH * Coy Caasd ° C ence ® intermediate H™ Cfforn another acid molecule.) ent, Keto -Enol & Base ° Taxrtomerization C. H-bransfer cw CkeT ) Pa“ SCH, Pn“ cH ketone Crore thermedynamicas stool > Examples mes». 2 “TS Pro Kon moos + “~o™~ ethyl! malonate any! acetate Cester) oo a ° Ltt 4 KeT iL wo Non wos + How Matonic acid Qeetic acid Spek e Sac OH A oy KET cr © pair of le —— Co, ———> cr \opoww enantiomers Tf O molecule. had @ chiral tom in the ci-position, the atom will undergo Facemization during the Keto-Enol Toutomenzation step. This reaction has a tremendous synthetic importance as the last step of the multistep synthetic procedure. Enouon a8 ‘matonic ester ayntnesis’ Ashiasis Tyg Sov Code’ ATIEE8) Formation of Amides ali © NH. p Heat P a ‘> M M R-c R-CL gg oR ‘OH S Ruy NHy, The exact mechanism of this reaction is debatable & probably. includes some Sork of Gey) aubstitation Ammonia. The reackon is ener driven ey. the remoyat’ HeO due ‘ the excessive heating uhich Voften Suases a decomposition of tie motecule & tua is not a "Yacticat aynthetic procedure. Alternacive methods of an amide syntresis include the acyl substitution Of acid chlorides with excess of ammonia: Z oe g 20% yield Aon Eieat oy, < Bi Ceesec) 2 fo} So e 1. S0cte 5 — ~~~ on NH Gey A ity PaC%% Yield The detaited mechanism of the acid chlorides reaction with amines & Ammonia is disused in the “Reactions of Carboxylic Acids Denvartives" notes Geparate set ). Another important altemative method of’ amide ayntnesis is Q carbodiimide coupling described on tre next page. Ashiasis Tyg Sov Code’ ATIEE@ Activation of Carborylic Acids with Carbodiimides abu “A a 1 PBS got & Dec e yw se 8 on ; R-c R-c + O=c OH Noe ~Roy, a- Nut J his syatet opprean is extemal. oO Es a usefil synthesis Of carboxylic acid deriuatves 8 solid state polypeptide synthesis when harsher techniques might not be Soe due to adverse interactions with Other -flinckonal Groupe in Ore molecule or a. eubsteate. Mechanism: Step 4: carboxylic acid activation g R Hetra ° i me ns for t R ely scan ww ~e Nueces NJ 4 “actuoted yo HK carbonic. ne Ao Leavin : R: Gros Step 2: reaction with a. nucleophile 4 H R ° WR Nucleooh Se. ww Leaving, Swe lucleophilic 2. Group Ae “peo Attack Fors Disscciaton ON C BANP HO Rg ~ 8 a~ASet Q UH . La dialkylurea, —> BN AA AKAM amie product Bide- product. ‘ 4 , Ashiasis Tyg Sov Code’ ATIEECommon Carbociimide Coupling Agents: oho Ch cen pec Solid = easy to hande. =o N,N-Dieyclohexylcarbodiimide First coupling agent of SO Be Se igre N=CEN. Dic yy NN-Ditsoprpylcarbodiimide —gyntnesizer use rece EDe ~~ ul PEthyS-Grdimetrglaminopropycarbosimise Water-Soluble = ideal -for synthesis of hydrophilic peptides Examples: anos. P 4.Dee e P 'Fmoc + NH- CHC —~ 9 Frmoc- NH-CH,— ©. cH. \Feoe: ou f SN 2. Hanne E Ne nt Protecting grou oa A 3 ome Le new amide bend Dic i Hom Ot CP new eater bona on ERC oye / HN —$§$§ = (Brew amide bod NM H Ashiasis Tyg Sov Code’ ATIEE4Q Nudleophilic Reactions of a Carbowyate Arica P R-CH,- Be r e > 2c cR ° Sn2 ° Carboxylate anions are weak nuceophiles & undergo SNZ substitution reactions with primary, allylic, & benayte atkythatides Examples: Oo { CN ©: ~ YT ~~? Ts ° H-bransfer oO SN2 6 Nucleophilic Attack x eo Oo -CHs—| —Y Ph-CHsr Br ye Ph ny O-H a apere —_—> ey 4 H- transfer Cnromoleculac Su2 Nuckeophilic- Attack Ashiasis Tyg Sov Code’ ATIEECARBOXYLIC ACIDS REACTION NETWORK Craioe braefinnatosti Sao the -CCOH flznction| R-OH , H®Ccat) carboxylate, anion R-CH,-OH mimMars Pleo Ashiasis Tyg Sov Code’ ATIEE