Week 12 - Reading Notes
Week 12 - Reading Notes CHEM 2321
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This 25 page Class Notes was uploaded by Hayley Lecker on Friday November 13, 2015. The Class Notes belongs to CHEM 2321 at University of Texas at El Paso taught by Dr. James Salvador in Fall 2015. Since its upload, it has received 114 views. For similar materials see Organic Chemistry I in Chemistry at University of Texas at El Paso.
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Date Created: 11/13/15
Organic Chemistry Week 12 CDMMDM FUN39C TIl MAL GHDUPS Important Information Professor s Email isalutegedu Class Website organicutepeducourses2324 Class Code Ebook utep232Xfall2015 T5191 and mum Exampne Funmmmal mp mm Gammll Enrique mun II E H rm mrmmm WilliElm H Hm EH aw Alumni H C39IH H 4 43H a a 13 3 H 3 H IIlIIII HR m WWW acid H EH Dummy ll l lii 2 IR t V 343 H Jammyd2 H m r Eater ch Fl quot 1 1 43H Mme FL lll micalg Em H p H taro mg MW at A EH 3 y r V 130 name if a a H EH mumum Hemm H EM mm quot 39 A quh de amma nH E39lr my irtrie Fl CH 4143 an gm GE H H H mm H S H mfg cm EH 5 I lquot 3 Hie p mm WE 1TH thl E HlFL 11in la jaIl Elia EH s EH MlIE Fla Emarm H urFl EU m Hll39Illam m Hm 4H2 39I39IinEEIEI39 oosn warm mm H an EH i EH 3 i Notes for L24 M9 AND L25 R C DIil R C UE39 R C NR39 Cmbmgylic acid Ester Amidh if if H R C K R C U C R X Bf 81 The Aycl Tranfer Mechanism Nucleophilic reactions change direction based on the strength of the nucleophile Stronger nucleophiles will favor the product If quotE Nu Cquot Hui GTE Vii Q The example below is the reverse reaction the loss of a nucleophile to reform the original carbonyl compound M1quot quot39 Ez The nucleophile substitution at a carbonyl group of a carboxylic acid or derivative combines 2 steps In nucleophilic substitution the group that leaves is the electronegative group bonded to the carbonyl carbon so the starting and ending compounds are different A nucleophilic substitution involving a carbonyl group is often called acyl transfer reactions I EL 715 u K Nu 39 Lf U Li l E The ease in which a leaving group leaves is based on basicity thus the more basic it is the more it won t leave A strong base is more willing to donate electrons to the carbonyl carbon so the weaker the base the more readily it will leave Acyl halides work well because they are weak bases Acyl transfer does not occur with aldehydes or ketones because hydrides and carbanions are too strong of a base The leaving group and nucleophile are both bases weak bases are stable anions I I 39 n i H Jr KiwiEL quotquotquotEE 9 391 U Cilt H The behavior of the leaving group affects the reaction Acyl halides and anhydrides have most stable leaving group Ester and carboxylic acids have intermediate stability thus intermediate reactivity Amides are the least stable 82 Water and Alcohol Nucleophiles Esterifcation is the nucleophilic substitution reaction that converts a carboxylic acid or derviative to an ester The reaction requires a substitution of hydroxy group in the carboxylic acid with an alkoxy group from an alcohol Reverse reaction called hydrolysis Tl Esteli catim RWH EEKll Iii i l Cathoxylie acid Eater Equilibrium constants for esterfication reactivity are small Below is an example the constant is 4 f EliIg lg mam Illg The pKa of the nucleophilic and leaving groups helps understand the equailibrium constant Ethanol has a pKa of 163 and water 157 there is little difference so little thermodynamic preference between substrate and product EM5 I 2 5 H l H 39 E HalC HE Ei39 quot quottfce cmtmi o c gtj l Ho L l H g H QH P l t maniaquot H C j Hg Q In the 1st step nucleophilic oxygen of the alcohol attacks the carbonyl carbon In the 2quot l step of the reaction the proton bonded to the oxygen from alcohol is transferred to the oxygen that was the carbonyl carbon s oxygen Proton transfer requires a base so water is used to remove the proton from one oxygen to another In the 3rel intermediate the compound will lose a hydroxide ion thus an ester is formed In the 4th step the hydroxide ion removes a proton from carboxyl group to remove water from esterfication distillation is used Example of this below you should have done distillation by now in lab Te retrieve the water rem an esteri eatien reaetienI ehenusts usually use distillatien la the eemmereiall distillatien preeess the result ef the distillatien is an aseptrepie mixture The aseetrepe fer the reaetien atquot aeet39ie aeidl and ethanel hails at THEE audl eeusists atquot 33 ethyl aeetate 3 ethanell and water Eeeause the ethyl aeetate is largely inseluhle in the mixture ehemists simply separate it Earn the mixture andl puri r it Then they purify the ethanel frem the water andl reeyele the aleehel The laheratery preeess is very similar te the eemmereiall preeess Chemists re ux the mixture using a trap te remere the dienser water The apparatus returns the waterainsaluhle layer ef ethyl acetate ta the reaetien flask fer eelleetieu at the eudl atquot the reaetien See 31 31 Use at a trap in aseetrepie elisijllatien As the distillate lls the trap1i the leery layer stays in the trap and the upper layer ereri39lews hash inte the reastieu flask Hydroxide ion is a poor leaving group so to increase the rate of esterfication catalyic quantities of acid are added Acid pronates the leaving group allowing water to leave known as Fischer esterfication The acid increases reactivity of carbonyl group the acid pronates oxygen and enhances carbon s reactivity to nucleophile His He quot 329 FEE He HQ The pronoted carboxylic acid is resonance stablized look below Resonance allows serveral atoms to bear partial chage so ion has more stability and less reactivity than pronated aldehydes and ketones The 1St 2 reasonace contributors are equal in energy 3rel is minor The pronated carboxylic acid then adds the alcohol to form hydrate of ester CH3 H CH3 f m u i l n E Hgli Hg H quotquotquot if H CHEEHE QFC Q39H Ho ME Elm After proton transfer from alkyoxy group to hydroxy group the intermediate loses water to form ester fin quotEH U U 39 I Hat Hg o c UH CH gilC Hg D ilT UH H as III H QH EEK 1 31 13 V riff DI lefC H Emmi Equot E39HaiETIg Most popular acid to use CHM H A it 3 LR c a y 39 p T luenem onic acid Very strong It is very strong because conjuated base is reonance stablized with negative charge distrubed on 3 oxygen bonds bonded to sulfur Fischer works will for most primary alochols because not sterically hindered However secondary and teritary alochols are sterically hindered and usually have lower equilibrium constants and low concentrations of the ester at equlibrium So cehmist 1St convery carboxylic acid to acid chloride Cl is a good leaving group the acid chloride rapidly forms ester With ester hydrolysis reactions there are 2 mechanisms 1st step is the formation of tetrahedral intermediate that occurs in an esterfication in this the nucleophile and leaving group both bond to the same carbon however this has never been isolated so truly been identified A enggeetect alternate rearetiin n nteeha niem in re llred the tallaawing tranaitie n etate This mechanism aeeme mneh Simpler than the mechanient with the tetrahedral intermediate Iit Ill Elma Hen Ree me en alean 1 Rea H a 3 H H Hea he t E 391 39 39 Errata rt 7 a J labeled ethyllbeamxate Ethyl quotlama Base assited ester hydrolysis follows same path as acid catalyzed hydrolysis 1st in the reaction is the reaction of ester with nucleophilic reaction of base at carbonyl carbon 2quot l is the loss of an alkoxide ion 3rel is a proton exchange it leaves the alcohol and carboxylate anion Little reversal because alcohol is too weak to be a nucleophile I irmjl i m sinf I m a 39H lit ESQR RE QR h RE Q Q H tg l V I f 5 quot we 5 II n Lact ones are cyclic esters 56 membered lactone rings occur from compounds containing hydroxy group and carboxylic acid group 5 H idT EE E t i a id l Iydm ype tanoic acid lactone E iia39emlactonejl 36 Water and alcohols react very rapidly with acyl halides and fast with anhydrides Leaving group is a stable anion it is either halide or carboxylate RCOO anion Amides are less reactive than any other carboxylic acid derviatives Hydrolysis of amide with either acid or base equires heat and longer reaction time than others when producing carboxylic acid Below are examples of reactions 31 1 Eat mg a E ethymaheaenoic acid Whit 339 l V A ll CHECHEOH l V CHECHECOH CElgcggCOCEgCHg 3 la Ethyl propamate 99 l T l ll If U H234 l Pl mylpmpmmi acid Elva 83 Halide and Carboxylic Acid Nucleophiles Acyl halides and anhydrides are the most reactive members of carboxylic acid derviatives because they create the most stable leaving groups The leaving group for acyl halide is a halide anion example is CH and anhydride is carboxylate anion RCOO l l E 0 24 REC C 19 Acyl halide nhjrd ile Leaving group of acyl halide is a conjugate base of a strong acid pKa less than 1 Anhydride is a weaker acid pKa roughly 5 The equlibrium constant is more favorable of acl halides than anhydrides They are synthesized as intermediates than end products Usualy only acyl chlorides are used Q Q bromides and iodines are expensive to II II 39 CHECHECHECOH SD61 3 CHECHECHECCI SOB Hm make and unstable To syntheSIze acyl chlorides from carboxylic aCId thIonyl Emtamyl chloride 39 chloride SOCIZ or phosphous chlorides PCI2 PCI3 are used All 3 O reagents are acid halides or inorganic ll ll acid 92 POCI HC l BE E jll chloride 98 Mechanism Reaxtion of Carboxylic Acid with SOCIZ 1st step Produces a mixed anhydride consists of organic aicds and inorganic Cl IE rag l a 1 l quot R C 3 o E C t H 7 313 HRham n as 3 III I lit u R C gg 21 1 2 l step Follows typical nucleophilic substitution on carbonyl y H A 64 a or II J h 4 C I SEE R C g SK til I w I quot As the reaction progressed SOZ leaves and 2quot l Cl leaves as HCl Both are gases so they bubble out Oxalyl chloride CICOCOCI is a becoming reagent of chloride for synthesis of acyl halides because easy to handle The by products are C02CO and HCl ll Cl 3 c gt quot H 31 C C Gil v quot quot zLc xquot H 3H r f a 1 x a Anydrides are made limitly because acyl halides are readily avialable and more reacrive To make an anhydride it involves an acyl halide with a carboxylic acid in presence of nonnucleophilic base usually pyridine 39l It on N39 ll coo V Cyclopmentaneearbo ylic anhydride 95 Mechanism Anhydride A weak base such as pyridine reacts with acidic proton of carboxylic acid forming carboxylate anion The negatively charged oxygen reacts with the carbonyl carbon of the acyl halide Heating carboxylic acids does not form anhydride unless 56 membered ring can form This will be seen a lot in next week s Monday homework if MCOH j ECC J H lll O Succinic Acid Succi 11in anhydride 93 Many anhydrides form via anhydride exchange it involves heating the acetic anhydride with carboxylic acid 393 D on El Example of reaction til H H A Ilia valJ Hfm mo IRE afrawfc new if a l l l L xquot 7quot s F REVERE 84 Reactions with Nitrogen Nucleophiles Nitrogen nucleophiles studied most in carbonyl chemistry are ammonia NH3 and primary amines RNH2 and seconary amines R2NH All react with carboxylic acids to form amides To prepare amides most common is to react carboxylic acid or acyl halide with NH3 or amine O 31 CH3CHECHECCI 4 2 NH3 3quot CHgCI IECHQCNI Ig 4 NHqu Butanamide 99 Acid or acyl anhydrides react similar to acyl halides but less reaction 9 i ii if GHEQDCCE Ig li gjg CHgCNEHQE QHgCDII EN Di111ethylethanamide 35 o i r Pi petidinedi one Glutarimitlejl 981 The mechanism for formation of amide by reaction of amine with acid anhydride similar to above The amine Nitrogen reacts with carbonyl carbon to form tetrahedral intermediate Tetrahedral intermediate losses a caboxylate ion to form amide w V Wm g I m c gf C U h 1 H imlh 395quot Er H EH a Ll H3 1 Ema 1H3 c39 m3 ll Direct reaction of amine with carboxylic acid can form amide The water tie them Itemieredl tram the ammenium ealt ta predate the eerreepending amide D eh r ratiea requiree a high temperature Thie type at thermal ehy ratieh fie aeefall in in aetriall eyntheeie hat ehemiete eeldlem tree it in the llaherater r It iie eaeier ah eheaper te eentrel a high temperature ayatheeie an an indlaetria eealle than an a llaherater r eeale TBeneemidle we Laeta me are egrehe amidee Theee re and eiamemhered riage term eaeihr tram eempeundle that eentaia an amine greup and a earheayhe acid greup The equilibrium reaetierl if a latetam lie mere favearahlle than the ether reaetierle atquot aminee aadl fh i f aei e quot7 O HEN jaz 39tmt t i acid laetam IKEPipetide me 64 85 Reaction with the Hydride Nucleophile LiAlH4 course of reaction with carboxylic acid is a reduction It is a two step process where in step one the hydride first initiates a nucleophilic substitution follwed by the loss of the leaving group to form an aldehyde or ketone A second hydride comes in and reacts with the aldehyde or ketone to form an alcohol With LiAlH4 all carboxylic acid derviates except amides form PRIMARY alcohols 390 V 1 l 1 ELEIIIz H eja in ides reaet with tn fem amines Di sit IllI39m seams 39e The 7 I he sn3e it rednetien reaetien preeeeds in two steps The rst step is the new familiar rearden at the nnieleeph ile with the electrenhilie earhenyl earhen In this ease the nueleephile is a hydride in 5 y Fi L quot1 R lll L ed H The tetrahedral intermediate is unstable se the leasing gratin departs The tetrahedral intermediate farms an aldehyde heeause the leasing gratin is a weaker hase than the hydride inn i E H 3 K II E Ij L R C Il ken In the seeend step1 the aldehyde immediately reaets ta term an aleehel because the aldehyde is mere reactive than the starting earherylie acid derivative The aldehyde intermediate reaets as rapidly with 4 ts farm the aleshall that it is impassihle ta iseltate the aldehyde e y i 39 rte a I snares e a Chemists start the reaction in anhydrous ethyl ether and then add aqeous acid to protonate the conjugate base D II gt7 1 Lile i ether gt7 CCl W SHED 1 1 H30 Cyclopenlylmethanol High CI 1 LitiI Iqletl39er CH3CI I3CH3CDCH2CI I3 Ii CH3CHQCHQCHEDH CH3CH2DI I 1 H C j 3 iEutaeol 91 When LiAlH4 reacts with a carboxylic acid in an acidbase reaction the hydride ion is a strong base The hydride ion reacts with the acidic hydrogen in an exothermic reaction to product hydrogen gas D i LiAlH4 a wool w E l g JED H2 The reaction produces a negatively charged ion Anymore reduction requires a strong nuceophie LiAlH4 can react but with complications initial product is insoluble in solution so the rate of reaction is greatly reduced E E3 quot5 quot Lie 395 393 11 to l m H quot HL Eff Next the reaction mixture 13 treated with dilute aqueous acid to produce em aloohol product L1 Al F 4 L1 3 54339 I H ofquot Re o Q Liquot oeego m6quot 3 demon iquot Z i Elfquotquot5 ej H 1 H X quota Because of the slow rate of reaction chemists convert the carboxylic acid to a methyl or ethyl ester before the reaction with a hydride Amides with LiAlH4 react to make amines 0 l Lien14 RENEE g RCHgNHg o st The mechanism is not well known but it is belived to follow the pathway via an imine 1st A hydride and proton are added on the nitrogen to form hydrogen and amide salt 1 1 1mg Er EC 14112 1 E N m g L11 t rearranged to make k39 kh o D aEIEIE II E a the II E E1 IHAIlIg Li FE Lil l EEI m L1 i 1 v M H It then losses an oxygen to form the imine E E an 11 L EEC H I HR Since the imine is more reaction than an aldehyde it quickly reduces to an amine NH u Llama Haul Ito H P Emilia 3 H CH CHI 1 CH CHM1 0 3 EleiAII Iq I I 339 III EDI130 le c l ohexylethanamine 95 1 LEAH Ill W N 339 2 Ho N a 339 i a Py olidlne 31 To prepare aldehyde from an acyl halide tritertbutoxyaluminum is used 11mm 3 CH3ngon 1 Ml i sjah a 113 1 Lmiiocic 331th CHg II Cl l li CHQCH CH 1 H3093 I H3 CH3 Methylpropa al 74 Sodium borohydride is only used on acyl halides for reduction li39 CCI CI lgDH U 13 MB H4 0 E IIgCI39 f Cyclohea rlmethanol 35 Example of LiAlH4 reducing D H h H 23quot quot Hf H a HR 2 Hg whim H s w f H H H H 87 Nitriles i E l Nitriles RC N considered carboxylic acid derviative because reactivity resembles carbonyl group Nitriles hydrolyze form amides or carboxylic acidsderviatives To form carboxylic acid the nitrile is hydrolyze with water with either a base or acid catalyst if mild conditions hydrolysis stops at amide if vigous conditions hydrolyzes to amide then carboxylic acid vigous means higher concentrations of acid or base and heat HEB ill 1 H20 y m RIC ftpH DH IlljlI H3053 Hane H KEN quot39 RENE REDH To hydrolyse with base 1St A nucleophilic attack of hydroxide ion on the electrophilic carbon of nitrile group v A rF t tzii H R CEN a L E t picks up a proton from water and produces unstable isoamide and regenerates hydroxide catalyst soamides are unstable so the rapidly isomerize to form amide fquot 5 13quot a qull i gt NF39 fenm1 R R Ienemide The isomerize by transferring proton from oxygen to nitrogen There is a shift in the pi bond IL gal Lllill fir NH Eff NHL if ye E N r vfa getquot Hawquot iffy NH tntte ETEETE SEthyihenzemitle ne When an neiti ie the entn ll ret the reactinn hegine with pmtenetinn bet the nitrite nitragen aquot e 39 HLJ U Eff n nzn H R E EH The reaction is unfavorable equilibruim because nitrogen not very basic so does not pronate easily After Nitrogen nitrie is protaned water is added via a nuceophiic addition to carbon Intermediate losses proton and tautomerizes to form amide gal R CEN H 4 3513 4 Had H H215 39 It needs heat to proceed heat increases the rate of hydrolysis of amide ID I C zl l C EIH HgSDg r re mt E gmlop ltmeeatboxylic acid 84 Hydride addition to nitries used to snythesize primary amines Proceeds by 2 successive additions of hydrides LiAI hydride to carbon If If 39 i u r aquot i1 i It E 1 on r R EE N 1 J CNe 39 R c N a 39i H El l A H u H92 H E Addition of water to dianion hydrolyzes to primary amine am a CHHH z If E gmlohex mm m mmi 11 94 Nitriles with Grignard reagent and organolithium to produce ketones Ne R E a R E H Lin a quot3 i Iii 91 1 3 Rquot H Rquot g m R I 31 lel39 t 5 I quot1 H23 gr IlID E NH3 Egg C NHE u R r N H T quotj39 L1 tm mniim I if R R H HM R c E R 39lhe following is an example of this macti m ll an 2 m cm H DUI1311 if a 3 L I quot3 d4 I Methyl phm Iceman 3m M8 Mechanism The reaction of propanoic acid and methanamine with DCC 236 refereance pages 12091216 236 Peptide Synthesis Amides are readily synthesize from amines and acid chlorides does not work well for peptide chains because amino acids have additional functions groups that can react with acid chloride So protecting groups are added to protect active functional groups with protected groups the reaction forms an amide bond Two groups used to protect carboxylic acid functional groups are methyl esters and benzyl ester In H H393 NHngl39Z Hi f39IIg m I Na Him Hm R a Air h 3 If Mietllnyl eater NHECH oH mgf m I I a R Him He 1111th X a H M HH HCDCH I l HERE I Email cater Benzyl and methyl esters are usually removed by hydrolyzing in an aqeous base An alternative way to remove benzyl ester is through hydrogenation to cleave the weak benzylic CO bond To protect the amine end of the amino acid a carbamate ester group is used benzyl and tertbutyl esters most commonly used 390 I V Qt H w xiv x Ill Ill NHEI39IC HE39DH 39r if s CHEUC NH CHE39DH N Eenzyloxycarbon derivative of the amino acid I CH3 I 0 N3 ICUl CH3 Hi D D H CH3 H II I NHQE39HCUH 39l 39CHg I39CDES N fTICUH f 1L EH3 R NurerrmEutoxycamlbonyl imitative of till amino acid In 1st reaction the product is an Nbenzyloxycarbonyl derviative of the amino acid abbr NCbz or Cbz In the 239 the product is a Ntertbutoxycarbonyl dervative abbr NBoc or Boc t C CH L A V cooH 2 gu j cooH I H 1 C H wnu thmg fommm KKHW II at Alanine Nu mzyilommhmq almi e CheAlla You would write the Elm derivative of alanine as E 39 Cl EH3 Ny tIKF EHE ED H y cooH CH3 J H HEEHH 39 chgH fin E N g MHtoqftI Jill iCH3 lm N Iert Eutoxyc homylalami c BoreAla Benzy and tertbutyl esters are both good for protecting because stable carbocations or radicals Cbz is removed by treating solution by HBr in acetic acid H HE E v r r a t CH quot in III gt I EH3 NHvE iQ HZ i fa 1 quot I 39f 3Ci H r EUGH UH v 1 l 1C Y BEE Boc is similar but best acid to use is trifluoroacetic acid in dry methylene chloride or HCl in anhydrous ether Ei lii Cl DDH I H CH3 CH f iu ripF CH3 quot it n I 3 II If EH3 Q U H CH3 km H U in g H n zfcg mH 7 CHER NHE CH3 HI 0 ll 9mm H n M EFgCD H Formation of peptide bond is accomplished by reaction involving amino acid with protected carboxylic acid another amino acid with a protect amine and DCC fa f H r a Dicyclohex earbm imi e DCC converts unprotected carboxylic acid to intermediate with chemical proerties similar to acid anhydride On next page E f RIC UH prunt cttd amine 32M rm HH RTgq ai j RIC Div I 5 H N Cmb xyli amine