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by: Brady Spinka


Brady Spinka
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This 171 page Class Notes was uploaded by Brady Spinka on Monday September 7, 2015. The Class Notes belongs to CH 318N at University of Texas at Austin taught by Staff in Fall. Since its upload, it has received 22 views. For similar materials see /class/181884/ch-318n-university-of-texas-at-austin in Chemistry at University of Texas at Austin.

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Date Created: 09/07/15
Lecture 21 The Claisen Condensation E5 CHscOCHZCHs EHz COCHZCHs Mn 3 2008 Chemistry 315w Y From Tuesdays lecture Nucleophilic Acyl Substitution This is a very IhPORTANT general reaction Understanding the mechanism allows one to explain and predict a large body of organic chemistry Chemistry 318N I It s all in the leaving group 0 The best leaving group is the conjugate base of the strongest acid 0 Egt The best leaving group is the most stable anion 0 Please review considerations of anion stability Resonace polarizability inductive effect electronegativity etc Chemistry 318N Y Familiar O AoA 1 X5 CH3MgBrTHF 2 dil H30 O i 1 x5 CH3MgBrTHF O o 2 dil H3O Chemistry 318N I Relative reactivities of carboxyl derivatives 5 E 5 a 5 an 4 u v Hydrolysis ofAmides in base 0 This should not work but it does 0 Hydrolysis of an amide in aqueous base requires 1 mol of base per mol of amide O 0 H H 0 ll CH3CNH NaOHheZaTgtCH3CO Na H2NO NiPhenylethanamide Sodium acetate Aniline Cheman Y Hydrolysis ofAmz39des in Base 0 Hydrolysis of an amide in aqueous base is divided into three steps Step 1 addition of hydroxide ion to the carbonyl carbon I 6 R c NHZ EH gt R lt iiH2 29H Tetrahedral carbonyl addition intermediate Chemistry 318N Y Hydrolysis ofAmz39des in Base Step 2 collapse of the intermediate to form a carboxylic acid and ammonia 6 R C H H gtR cl NH3 9H 0 3 L pH Tetrahedral carbonyl addition intermediate Avery rare event Why Chemistry 318N E Hydrolysis of Amides in Base Step 3 proton transfer to form the carboxylate anion and water Hydrolysis is driven to completion by this acidbase reaction R C O AH H39 oH gt R c p39 H p H Chemistry 318N Y Hydrolysis of Amides in Base In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion This makes the reaction irreversible 0 RCNHR39 H0 RCO R39NH2 Chemistry 318N I Hydrolysis of Amides in Acid 0 Hydrolysis of amides in aqueous acid requires 1 mol of acid per mol of amide CH CH HgNH H 0 HCI Mr 3 2 2 2 heat Ph 2 Phenylbutanamide H CH3 CH2 cHCOH NH4C39 Ph 2 Phenylbutan0ic acid Chemistry 318N Y Hydrolysis of Amides in Acid 0 Acidcatalyzed hydrolysis of an amide is divided into three steps Step 1 protonation of the carbonyl oxygen 39c3 II quot OH 39oH R CNH2 HUD H gt H r I Fll R c NH2 4 R cNH2 H20 Resonancestabilized cation Chemistry 318N E Hydrolysis of Amides in Acid Step 2 addition of H20 to the carbonyl carbon followed by proton transfer iOI Kl proton transfer 5quot I r 7 R iz H RcsNHJ I i H H 9H 19H Tetrahedral carbonvl addition intermediate Chemistry 318N Y Hydrolysis of Amides in Acid Step 3 collapse of the intermediate coupled with proton transfer to give the carboxylic acid and ammonium ion II OH 05H 6 R lrNH H Iquot I 3 Rquot 39NH3 R QH NH4 QH pH Chemistry 318N E Hydrolysis of Amides in Acid Hydrolysis of amides is also irreversible In acid solution the amine product is protonated to give an ammonium salt 0 0 II II RCNHR39 H20 H RCOH R39NH3 Chemistry 318N Y Some loose ends before we go on o Spectrosopy of acid derivatives 0 A selective reduction for your tool book Chemistry 318N I Reduction of Acid Derivatives o Acids page 659660 0 Esters page 709711 Please work through the example on p 710 o Amides page 711712 0 Nitriles page 714 o Selective Reductions with NaBH4 Chemistry 318N Y DI BAH Diisobutylaluminum hydride DIBAIH at 78 C selectively reduces esters to aldehydes at 78 C the tetrahedral intermediate does not collapse and it is not until hydrolysis in aqueous acid that the carbonyl group of the aldehyde is liberated 0 5 1 CH32CHCH22AIH at 78 1 CH OH C gt C 3 0 CH3 2 Di H3O H 0 A39R2 Stable at low l Qijc s temperature H Chemistry 318N I Infrared Spectroscopy CO stretching frequency depends on whether the compound is an acyl chloride anhydride ester or amide CO stretching frequency v 0 II o 0 CHscCI enacoccn3 CHsCOCHs CH3CNH2 1822 cm1 1748 1736 cm1 1694 cm1 and 1815 cm1 Chemistry318N Y Infrared Spectroscopy Anhydrides have two peaks due to CO stretching One from symmetrical stretching of the CO and the other from an antisymmetrical stretch CO stretching frequency V enacoccn3 1748 and 1815 cm1 Chemistry 318N I Infrared Spectroscopy Nitriles are readily identified by absorption due to carbonnitrogen triple bond stretching that is all alone in the 22102260 cm391 region Chemistry 318N I Chemistry of Nitriles o Nitriles and carboxylic acids both have a carbon atom with three bonds to an electronegative atom and both contain a it bond 0 Both both are electrophiles O R C E N R C OH Nitrile Carboxylic Acid Chemistry 318N I 11 Preparation of Nitriles o 8N2 Reaction with Cyanide ion The usual limitations apply N CEN 0 Br Polar apiotic Solvent Chemistry 318N E Preparation of Nitriles 0 Reaction of primary amides RCONHZ With SOClz or POC13 or other dehydrating agents 0 Not limited by steric hindrance or side reactions as is the reaction of alkyl halides with NaCN 0 CHacHZCIIZCHZCHC NHZ CHaCHZCHchZCHCEN so2 2 HCl CHZCHa omen3 soon IIHJZFHE39 3m Chemistry 318N I Mechanism of Dehydration of Amides o Nucleophilic amide oxygen atom attacks SOCl2 followed by deprotonation and elimination o o n Q Q o S CI 01 0 Cl 6 01 I J3 A H713 l Base R CN 502 i c R N R EN 12 an H H Chemistry 318N I Hydrolysis Conversion of Nitriles into Carboxylic Acids o Hydrolyzed in with acid or base catalysis to a carboxylic acid and ammonia or an amine O Q Chemistry 318N I Reduction Conversion of Nitriles into Amines Reduction of a nitrile with LiAlH4 gives a primary amine 0 EN CHZNHZ 1 MA H ether 2 H30 oMethylbenzonitrile oMethylbenzylamine I 88 Chemistry 318N 39 Reaction of Nitriles with Grignard Reagents o Grignard reagents add to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone N t 7W 7 VA H J VY RC CF 4 Nil Nitrile Imine anion Ketone Chemistry 318N 14 IR of Nitriles o Nitriles show an intense CEN bond absorption near 2250 cm 1 for saturated compounds and 2230 cm 1 for aromatic and conjugated molecules 0 This is highly diagnostic for nitriles Chemistry 318N Y 73C NMR Carbonyl carbon of an acid is at low field 8 160180 ppm but not as deshielded as the carbonyl carbon of an aldehyde or ketone 8 190215 ppm The carbon of a CN group appears near 5 120 ppm Chemistry 318N I Nuclear Magnetic Resonance Spectroscopy o Carboxyl 13COOH signals are at 8165 to 8185 o Aromatic and 0L3unsaturated acids are near 8165 and saturated aliphatic acids are near 8185 o 13C EN signal 8115 to 8130 0 ll C OH O ngTJszTOH CH3CH CHCOI I EN 9 25 181 134 128130 1291723 18 122 148 172 10 11 121 mmmmmmmmmmmm 12 Ch emistry 318N I Some loose ends before we go on o Spectrosopy of acid derivatives 0 Selective reductions for your tool bOX Ch emistry 318N I Reduction of Acid Derivatives o Acids page 659660 0 Esters page 609711 Please work through the example on p 710 o Amides page 711712 0 Nitriles page 714 o Selective Reductions with NaBH4 Chemistry 318N Y Infrared Spectroscopy CO stretching frequency depends on whether the compound is an acyl chloride anhydn39de ester or amide CO stretching frequency v 0 CHscCI CHsCOCCHs CHsCOCHs CH3CNH2 o 0 1822 cm1 1748 1736 cm1 1694 cm1 and 1815 cm1 Chemistry 318N Y Infrared Spectroscopy Anhydrides have two peaks due to CO stretching One from symmetrical stretching of the CO and the other from an antisymmetrical stretch CO stretching frequency V cnacoccn3 1748 and 1815 cm1 Chemistry 318N Y Recall our discussion of the Acidity of protons or to carbonyls o The anion is stabilized by resonance 0 The better the stabilization the more acidic the or proton o Acidity of a protons on normal aldehydes and ketones is about that of alcohols and less than water pKa 1820 0 Some are far more acidic ie Bdicarbonyl compounds that have quite low pKa s Chemistry 318N I pKa of some cchozH 475 HF 345 some oc protons Hcl 7901 CM 10 H 1 11 H C giciH 50 cHgoH 16 4 11 11 cHaccHzccHa 10 4 4 1 CH3CCH3 20 CH3CH3 50 Chemistry 318N Y Some Acid Base Chemistry ZCHSCHZOH 2Na gt H2 2CH3CH2039Na HA B HB A I I CHsCOCHzCHs CPBCHzO CHzCOCHzCHs CHsCHzOH pKa 25 pKa 16 f 1 EH CH3CCHCOCH2CH3 CH3CHZOH CH3CCH2COCHZCH3 CH3CHZO 10 16 n CH3CCH3 CH3CH20 CH3CCH239 CH3CH20H 16 20 Which way do the equilibria lie Chemistry 318N Y o Rainer Ludwig Claisen 1851 1 930 Born in Cologne and studied chemistry at Bonn and brie y at Gottingen He took his doctorate at Bonn under August Kekule 18291896 WWW Y Classical Claisen Condensation 00 II 0 1 NaOCH2CH3 CH3CCH2COCH20H3 20H3COCH20H3 2 H 0 39 3 0 Two moles of ethyl acetate condense to give ethyl aeetoaeetate 0r aeetoaeetie ester Chemixtry 31th Y 20 lnz ramolecular Claisen Condensation The Dieckmann Reaction Chemistry 318N Y Example CHscHZOCCH20H20H20H2000HZCH3 1 NaOCHZCHs 2 H30 0 0 COCHZCHE Chemistry 318N I via CH30H2000H20H20H20H2000H20H3 NaOCHZCHs CH30HZOCCHchchchCOCHchs Chemistry 318N Y via CH30HZOCCHchchchCOCHchs Chemistry 318N I 22 via 6 CH CH O 3 3 3 2 5 C H20 CHCOCH20H3 Hzc CHz CH30HZOCCHchchchCOCHchs Chemistry 318N Y via 5 CHscHzo 3 3 quot oo o C O H20 CHCOCH20H3 Hzc CHz Chemistry 318N I via D 6 CH CH O z z 3 2quot C H20 CHCOCH20H3 Hzc CHz 5 II 5 C CH30H29 H20 CHCOCHZCHs H20 C39 aemistry 318N Y A versatile synthesis of 3 ketoesters and symmetrically substituted acetones i t CH c7 OCHZCHj a A CHf c7 cm c7 OCHZCHj A 1w Heat o A 4 ACHfL CHZ co2 HOCHZCHJ Acetone A Alkylation of Acetoacetic Ester o o H o u H H 1CH CH O x H HaciciocHZCHg H cHaici jHiciocHzCHg 43 2 H 2 A 1CH30HZO39 l 2 87L 0 o o o 3 002 H H H30 H H CHaiciw CHaicicicicOOH W HgicicicioCHZCH3 ea Chemistry 318N Y 3 Haiciciciowzw3 Acetoacetic Ester Synthesis 0 R1 CH3C CH R2 Chemistry 318N E 25 Ketone Synthesis Let s work another example together 0 0 w CH3 0 CH3 CH7 Chemistry 318N Y Ketone Synthesis Let s work another example together From Ethyl acetate only let s make this HO Chemistry 318N I 26 318N Krische Lecture 14 Th 03509 Ch 22 We begin this lecture by discussing reactions of extra nuclear substituents of aromatic compounds Reactivity Oxidation of the benzylic position Exposure of alkyl substituted benzenes to chromic acid generated from K2CrzO7 and H2SO4 yields benzoic acids For example toluene aka methyl benzene is oxidized to benzoic acid under these conditions Remarkably isopropyl benzene is also oxidized to benzoic acid under these conditions However tert butyl benzene does NOT oxidize under these conditions thus indicating that at least one benzylic hydrogen is required for this reaction You should know this reaction but are not responsible for the mechanism Just as alkenes are subject to bromination of the allylic position benzenes and other arenes are subject to bromination of the benzylic position In class we discussed the mechanism SEE ONLINE HANDOUT FOR MECHANISM Benzylic halides are excellent electrophilic partners in SNZ processes and precursors to Grignard reagents Benzene is inert to conditions under which most normal alkenes would react readily This is due the resonance stabilization energy or aromaticity of benzene For example upon exposure to aqueous acid most alkenes will undergo hydration the alkene is protonated to generate a carbocation that accepts water in an SNl type process Upon exposure of benzene to aqueous acid no reaction takes place Why First reason the activation energy for the protonation of benzene will be quite high since aromaticity is destroyed in this process Second reason Rather than undergoing an SNl type reaction with water the cation will simply eliminate E1 type process and thereby reestablish aromaticity Using a deuterium labeled acid D2SO4 H D exchange can actually be observed The mechanism is simple 1 protonate benzene to 2 yield a resonance stabilized cation which 3 eliminatesrearomatizes Try converting benzene C H to deuterated benzene C D EAS NitrationSulfonylation In the deuteration of benzene under acidic conditions we have essentially substituted hydrogen for deuterium under acidic electrophilic conditions This reaction can be thought of as an Electrophilic Aromatic Substitution reaction EAS EAS works for a variety of electrophiles if the electrophiles are highly activated In class we describe how sulfuric acid and nitric acid are activated via dehydration to yield the active electrophiles protonated sulfur trioxide and NOZ These electrophilic species are attacked by a benzene pi bond ie benzene serves as a nucleophile to yield a cationic intermediate E1 type elimination of the cation reestablishes aromaticity to yield the mono substituted benzene Be able to write out mechanisms for the sulfonation and nitration of benzene Remember the same old EAS mechanism applies to all the reactions that we will discuss this chapter so don t think of each reaction as a unique case o Halogenation of Benzene Elemental chlorine C12 is not a strong enough electrophile for a reaction with benzene However if C12 is complexed by a Lewis acid eg FeClg the Cl Cl bond is weakened and the reaction will take place Once again the same old EAS mechanism applies The only thing we ve changed is the electrophile 318N Krische Lecture 11 T 022409 Claisen and Dieckmann Reactions Conjugate Addition to Enones o Esters also participate in basemediated condensation reactions The products formed are betaketo esters If this ester condensation reaction is conducted intramolecularly it is termed the Claisen Condensation If it is conducted intramolecularly it is termed the Dieckmann condensation o The Claisen and Dieckmann condensations are just additionelimination reactions The starting ester serves as the electrophile and the enolate of the starting ester serves as the nucleophile In the case of ethyl esters ethoxide is the leaving group SAME STORY 1 ADDITION ester enolate adds to the carbonyl carbon of the ester to form a TETRAHEDRAL INTERMEDIATE which 2 undergoes ELIMINATION by expelling ethoxide o The choice of base in Claisen condensations is important If you are using ethyl esters then you should use sodium ethoxide as base If you are using methyl esters then you should use sodium methoxide as base Why To prevent transesteri cation of your starting materials and products via addition elimination of the alkoxide base to the ester group 0 Crossed Claisen reactions are possible Use one ester with alphahydrogen and one Without In order to prevent selfcondensation of the ester containing the alphahydrogens use the one Without alpha hydrogens in large excess See online handout for examples 0 The products of Claisen reactions Dieckmann reactions are Bketo esters which are themselves useful intermediates in synthesis 0 The ahydrogens of keto esters are especially acid because they are doubly activated ie upon deprotonation the negative charge can be delocalized onto two electronegative oxygen atoms Anions of keto esters are good nucleophiles for SN2 reactions The acetoacetic ester synthesis involves the alkylation of a 3keto esters followed by hydrolysis of the ester to yield a carboxylic acid The Bketo carboxylic acid is unstable and will decarboxylate upon gentle heating The acetoacetic ester synthesis is a convenient way to prepare unsymmetrical ketones The malonic ester synthesis involves the alkylation of a betacarboxy ester the diester of malonic acid followed by hydrolysis of the diester to yield a dicarboxylic acid The betacarboxy carboxylic acid is unstable and will decarboxylate upon gentle heating The malonic ester synthesis is a convenient way to prepare substituted carboxylic acids We covered conjugate additions also termed 14addition to oc unsaturated carbonyl compounds SEE ON LINE HANDOUT ON CONJUGATE ADDITION Using resonance structures we were able to see that the Bcarbon of an enone bears a partial positive charge similar to the carbonyl carbon Since both carbonyl carbon and carbon bear a partial positive charge both positions are susceptible to nucleophilic attack Conjugate addition 14addition is favored for stabilized anions which can add reversibly to the carbonyl carbon 12addition For systems capable reversible 12addition eventually addition to the Bcarbon will occur The products derived from conjugate addition are thermodynamically preferred Why The CO double bond which is more stable than the CC double bond is retained in the product Malonic esters are the classic example of a nucleophile that prefers conjugate addition In fact the conjugate addition reaction of dicarbonyl compounds with aBunsaturated carbonyl compounds is known as the Michael Reaction Organolithiums are unstabilized carbanions and their addition to the carbonyl carbon is NOT reversible Thus for organolithiums 12addition is preferred Cuprates are special They will always give 14addition to enones 318N Krische Lecture 12 Th 022609 Enamines then Benzene and Aromaticity We conclude our discussion of carbonyl chemistry with the reactions of enamines Enamines are prepared from the condensation of a secondary amine and an aldehyde or ketone See online handout on the formation and reactions of enamines Enamines are isoelectronic with enols Enamines however are more nucleophilic than enols and will readily serve as nucleophiles in SN2 reactions with alkyl halides and additionelimination reactions with acid chlorides SEE ON LINE HANDOUT ON ENAMINES Through enamine formation the aposition of a carbonyl compound is nucleophilically activated like an enol The use of enamines occurs in stages 1 Enamine Formation the ketone is exposed to the secondary amine in the presence of an acid catalyst to provide the enamine 2 Enamine AlkylationAcylation the enamine is reacted with an electrophile ie alkyl halide or acid chloride 3 Hydrolysisupon alkylationacylation an iminium species results which is hydrolyzed to unmask the alkylatedacylated ketone In 1825 Michael Faraday discovers benzene and determines its empirical formula CH6 Benzene has 4 degrees of unsaturation yet does not behave like a typical alkene In 1865 Kekule proposes a structure for benzene cyclohexatriene This structure is consistent with the fact that all the CH s of benzene are equivalent Benzene yields a single monobromination product and three different dibromination products termed ortho meta and para Still benzene is much less reactive than an acyclic alkene The heat of hydrogenation of benzene clearly shows this to be case The heat of hydrogenation for cyclohexene which has a single double bond is 286 Kcalmol exothermic Based on the proposed cyclohexatriene structure of benzene we would predict heat of hydrogenation of 3 x 286 Kcalmol 858 Kcalmol However the experimentally determined heat of hydrogenation for benzene is 498 kcalmol Therefore benzene is 36 kcalmol more stable than expected This extra stabilization is termed resonance energy Lecture 18 Carboxylic Acids 0 0 R R quot RCeg H OH I O R c0 March 25 2008 Chemistry 318N Y Hyd rolysi s 0 0 H30 2 Chemistry 318N Y Ok more synthesis From Benzene any thing with less than 3 carbons and any other reagents that do not become part of the structure 0 O H3C CHa HBC 0 CH3 Chemistry 318N Y Addition of Nitrogen Nucleophiles 0 Primary Amines RNH2 Imines 0 Secondary Amines RZNH Enamines o Hydrazine derivatives RNHNH2 Hydrazones o Hydroxyl Amine NHZOH OXimes Chemistry 318N E Addition of N Nucleophiles 0 Formation of an imine occurs in two steps Step 1 addition of the nitrogen nucleophile to the carbonyl carbon followed by proton transfer 39539 39 Iii EyH CH2NR F IllR c llR A tetrahedral carbonyl addition compound Chemistry 318N Y Imine Formation Step 2 protonation of the OH followed by loss of H20 and proton transfer to solvent H H 3 337 Io H C lNR H HOH 1 quot HoHo Ck lNR lt2 NR 2 3 H Hk gr Animine H Chemistry 318N I Imines One value of imines is that the carbonnitrogen double bond can be reduced to a carbonnitrogen single bond H Cgto m0 Cyclohexanone Cyclohexylamine H CgtO CHO An imine Dicyclohexylamine Chemistry 318N Y Enamine Formation o SecondaIy amines react with the CO group of aldehydes and ketones to form enamines H Cgt 0 C Piperidine An enamine a secondary amine Chemistry 318N I Mechanism of enamine formation A H OH r 9H H OH A N 1160 ZggHz H 0le H 3 2 N q gig dejN H30 Enamine Chemistry 318N Y Enamines o The mechanism of enamine formation involves 7 formation of a tetrahedral carbonyl addition compound followed by 7 its acidcatalyzed dehydration 0 We discuss the chemistry of enamines in more detail in Chapter 18 Chemistry 318N I Example I 5 O C heat in benzene N N H H N OH via V nemistry 318N Y Hydrazones and Derivatives o The carbonyl group of aldehydes and ketones reacts with hydrazine and its derivatives in a manner similar to its reactions with 1 amines Oo H2NNH2 gt gtNNH2 H20 Hy drazine A hydrazone 7 Hydrazine derivatives include H 2 NOH H2 NNH Hy droxylamine Phenylhydrazine Chemistry 318N I Reaction with Derivatives of Ammonia HZN G cho R20NG H20 HzN OH R20NOH hydroxylamine OXime H2N NH2 R20NNH2 hydrazine hydrazone etc etc etc Chemistry318N Y Example 0 CCH3 H2NNH l phenylhydrazine WNH lt gt CCH3 H20 a phenylhydrazone Chemistry 318N I MECHANISM OF THE WOLFFKISHNER REACTION you are not required to memorize this mechanism II R 39 aH hquot N 0H quot RltI3 NHgNHz 2 NNH2 R HOCHZCHZOH R hydrazone ketone quot5H Rc NH quot R quot pquot H O H Ho sH R R FWD ROCNN R39c Roc fegoved 6quot gas ChammwN Y Keto enol Tautomerlsm fl H RH C c H C H3C CH3 3 CH2 Ketone End I H 50 O f H H OH H OH H ikbg ch k H3CCCH3 HSC C H F E ICHZ 1 1 Ketone H HOH no HO H If Deuterium Exchange 0 Deuterium exchange at an Xcarbon may be catalyzed by either acid or base o o CH3dCH3 6D20 3 CD3 CD3 6HOD Acetone or CD Acetoned 6 Chemistry 318N Y Keto Enol Tautomerism Ketoenol equilibria for simple aldehydes and ketones lie far toward the keto form Enol at Keto form Enol form Equilibrium O OH l 39 5 CH3 H 2 CH2 CH 6 x 10 0 0H CH3llCH3 lt2 CH3t39CH2 6x104 o OH 0 F0 4x105 Chemistry 318N E KetoEnol Tautomerism o For certain types of molecules however the enol is the major form present at equilibrium 7 for Bdiketones the enol is stabilized by conjugation of the pi system of the carboncarbon double bond and the carbonyl group O 0 ii Av ii 0 OH 13Cyclohex anedione Chemistry 318N Y KetoEnol Tautomerism in 3 diketones o Openchain Bdiketones are further stabilized by intramolecular hydrogen bonding 5 hydrogen H bonding 56 0 39 CH CCH CCH C 3 2 3 Hac f O CH 3 20 H 80 24Pentanedi0ne Acetylacetone Chemistry 318N E Al Ml ml bl l ml l ml l Tautomerism Acidity of protons or to carbonyls o The anion is stabilized by resonance 0 the better the stabilization the more acidic the CL proton o Acidity of a protons on normal aldehydes and ketones is about that of alcohols and less than water pKa 1820 0 Some are far more acidic ie 3dicarbonyl compounds that have quite low pKa s Chemistry 318N I CH3COZH 475 H 345 Hc1 9 OH CH30H 15 O O CH3CCH2CCH3 9 o H CH3CCH3 20 CH3CH3 5 0 pKa of some acids and some or protons A span of 59 powers of 10 Chemistry 318N Y ocHalogenation o xHalogenation aldehydes and ketones with at least one OLhydrogen react at an 0L carbon with Br2 and C12 action is catalyzed by both acid and base I o l QCCHa Br2 CHacozr F QCCHZBr HBr Acetophenone Chemistry 318N I ocHalogenation o Acidcatalyzed Xhalogenation Step 1 acidcatalyzed enolization my quot R 2 l R R39 R Step 2 Nucleophilic attack of the enol 0n halogen R r c BrBr gtfast c q R HBr 39 R v R R R39 Chemistry 318N Y What about Base Catalysis Hydrogens 0L to carbonyls are acidic O a H M C H0 H3c C H p OH H3C CH2 2 H Resonance stabilized O enolate anion gt H3C CQCHZ Chemistry 318N E ocHalogenation o Basepromoted Xhalogenation Step 1 formation of an enolate anion O H A b OH CH2 H H Z H20 I 0 Chemistry 318N Y Base catalyzed 0c Halogenation o Basepromoted Xhalogenation Step 2 nucleophilic attack of the enolate anion on halogen O O CHQ Brgr QJLCHerr Br39 Chemistry 318N E ocHalogenation o In base catalyzed OLhalogenation each successive halogenalion is more rapid than the previous one the introduction of the electronegative halogen on the occarbon increases the acidity of the remaining ochydrogens and thus each successive Xhydrogen is removed more rapidly than the previous one Chemistry 318N Y Haloform Reaction 0 Iodoform Reaction 0 A qualitative test for methyl ketones o A decent way to synthesize carboxylic acids O O O H 312 II 1 HO Rc gt R c agt R c HC13 CH3 NaOH hr 0 I Iodoform Chemistry 318N I ocHalogenation 0 There are maz39or differences between acid catalyzed and basepromoted othalogenation 0 Acid catalysis gives the most substituted product 0 The rate of acidcatalyzed introduction of a second W 7 introduction of the electronegatiye halogen on the 0 carbon decreases the basicity of the carbonyl oxygen toward protonation Chemistry 318N Y More Synthesis CHa CHQ N Chemistry 318N I 318N Krische Lecture 19 Tu 033109 Amines PREPARATION OF PRIMARY SECONDARY AND TERTIARY AMINES We can prepare secondary and tertiary amines via LiAlH4 reduction of secondary and tertiary amides Also we can prepare secondary amines via hydrogenation of irnines The formation of primary amines is more complicated Direct alkylation of ammonia is not feasible due to problems associated with over alkylation ie the products are also good nucleophiles To avoid the formation of poly alkylated materials we use azide eN3 as our nucleophile followed by LiAlH4 reduction of the resulting alkyl azide Note that the reduction of nitriles is another good method for the preparation of primary amines By exhaustively alkylating 2 aminobutane with methyl iodide we can form the corresponding alkyl trimethylammonium iodide We can exchange the iodide counter ion for hydroxide by exposing the alkyl trimethylammonium iodide to AgOH silver hydroxide Heating the resulting alkyl trimethylammonium hydroxide results in elimination to form an alkene In contrast to what we predict on the basis of Zaitsev s rule we obtain the less stable terminal alkene This is primarily due to steric reasons Using Newman projections we were able to rationalize this result This reaction is known as the Hoffmann elimination The Hoffmann elimination precedes through an anti periplanar transition state The Cope elimination involves the thermal elimination of an amine N oxide Dirnethylaminocyclopentane can be converted to the corresponding N oxide through exposure to hydrogen peroxide Cope elimination results in the formation of cyclopentene Note that the Cope elimination proceeds via a cis syn transition state Diazotization Treatment of a primary amine with a nitrous acid in aqueous HCl will deliver the corresponding diazonium salt These diazonium salts lose N2 gas to generate primary carbocations Generally a mixture of products is obtained However the Tiffeneau Demjanov reaction shows us that the diazotization of aliphatic amines can preparatively useful Try converting cyclohexanone to cycloheptanone using the Tiffeneau Demjanov reaction m rst you ll have to synthesize the cyanohydrin followed by reduction of the nitrile to the amine Arene diazonium salts are extremely versatile intermediates in the synthesis of aromatic compounds Simply heating an arene diazonium salt in the presence of water results in loss of N2 gas The resulting vinylic cation can be captured by H20 in an SNl sense to afford a phenol The treatment of arene diazonium salts with copper halides CuX X halide or copper cyanide CuCN results in conversion to the corresponding halo and cyanobenzenes This reaction is known as the Sandmeyer reaction The treatment of arene diazonium salts with hypophosphorous acid H3P02 effectively replaces the diazonium group with hydrogen Lecture 26 POLYMS 753 ril 24 2008 Chemistry 318N Y Natural Polymers a Natural polymeric materials have been used throughout history for clothing decoration shelter tools weapons and writing materials 0 Examples of natural polymers Cellulose wood Hair Silk Rubber 0 Modified natural polymers Nitrocellulose lacquer smokeless powder Rayon etc Chemistry 318N 39 Shellac wa Armstrong zoua 39f JULULV The History of Novolac CH Meyer and0r LH Baekeland Discovered Novolac ca 1907 1909 OH CH3 Baekeland Meyer Chemistry 31 8N Novolac Resin reductionll zerkleinert das Harz von Hand ca 1910 Chemistry 31 8N 39 Bakelite and Shellac Baekeland s Phenolformaldehyde resins which he called Bakelite The Association People Graham thought that cellulose and other colloids consisted of large numbers of structurally simple molecules held together by quotassociationquot also called partial valency 77 Thom as Graham 18051869 Chemixtry 31m Y Staudinger s Heretic Proposal Macromolecules O I o CHKCIZHCOCHZCHK gt 0 OH Chemistry 318N T Hermann Staudinger 18811965 theNnbel Pnzem chem stxy n 1 mm 31m Y Science Wins If the total mass of dissolved material is known polymer solutions could no longer be ignored or attributed to small amounts of a low molecular weight impurity mm 31m 1 Herman Francis Mark May 3 1895714191716 1992 Chemistry 31 8N I XRay Crystal Structures Mark and Staudinger ght over stiffness Chemistry 31 8N I Wallace Hume Carothers 18961937 Synthesis of Polymers Inventor ofNylon US patent 2130947 htt 39 t hall ff 28html see p www1nven org iofarne Ch 31m Y Commercializion of Nylon html Nylon was rst used for shing line surgical sutures and toothbrush bristles DuPont touted its new ber as being quotas strong as steel as ne as a spider s web and rst announced and demonstrated nylon and nylon stockings to the American public at the 1939 New York World s Fair DuFunt suld 5 mlllmnpau s ufstuckmgs acmss the u s unthe are generally avalable May is 194m Abuut d Y W a mlllmn were suld in their rstyear Chende 318W Y Notation amp Nomenclature a Show the structure by placing parenthesis around the repeat unit 0 n average degree of polymerization CHCHZ 6 Chemistry 318N Y Notation amp Nomenclature 0 To name a polymer add the prefiX poly to the name of the monomer from which the polymer is derived 7 if the name of the monomer is one word no parentheses are necessary 1ike polystyrene 7 for more complex monomers or where the name of the monomer is two words enclose the name of the monomer is parenthesis as for example polyVinyl chloride or polyethylene terephthalate 7 Many common monomer names are used Chemistry 318N I Industrial Influence Polyvinylidine chloride Saran wrap Polyvinylidne Fluoride Speaker membranes Kevlar Polyamide bullet proof vests Nylon polyamide rope and stockings Delrin polyacetal bushings Dacron polyester clothing sails etc Lexan polycarbonate aircraft windows Polyethylene bags bottles etc etc Polymers have changed the world Chemistry 318N Y Morphology Many polymers tend to crystallize as they precipitate or are cooled from a melt But they are very large molecules often with complicated and irregular shapes which inhibits crystallization and tends to prevent efficient packing into exactly ordered structures As a result polymers in the solid state tend to be composed of ordered crystalline domains and disordered amorphous domains Chemistry 318N I Polymer Morphology g Crystalline and semi crystalline Amorphous Ch emistry 31 8N I Morphology 0 Polymers With regular compact structures and strong intermolecular forces such as hydrogen bonds have high degrees of crystallinity 7 as crystallinity increases the polymer becomes more opaque due to scattering oflight by the crystalline regions for example te on CF2CF2 looks white 0 Melt transition temperature Tm the temperature at Which crystalline regions melt 7 as the degree of crystallinity increases Trn increases Ch emistry 31 8N 39 Polymer Crystals q n u iquot F El l l l L i J l l lg i ll 3 39 39 Chemistry 318N 39 Crystallinity some spontaneously form crystalline regions micelles crystalline 39 39 amorphous m lamellar l J M chain folded crystallite I J pl I V 1 i l 3 1353 f i tie molecule e l L i f 1 7 L I A w amorphous l H material spherulite surface proportion of crystalline amorphous strong in uence on properties PE carrier bag amorphous toughened pipe 95 crystallinsitemistry 318N 11 Morphology o Amorphous polymers are referred to as glassy polymers 7 they lack crystalline domains that scatter light and are transparent Polymethyl methacrylate 7 they are weaker polymers and generally more exibility 7 on heating amorphous polymers are transformed from a hard glass to a soft exible rubbery state Glass transition temperature Tg the temperature at which a polymer undergoes a transition from a hard glass to a rubbery solid ca 100 degrees for polystyrene Chemistry 318N 39 Differential Scanning Calorimetry Reference Pan Sample Pan Cylindrical fu nice Polymer T Thermoelectric Disc D39 Chemistry 318N l A DSC Plot Eu heat Endu temperature 4 Chende 31m Y Morphology 0 Example polyethylene terephthalate abbreviated PET can be made with crystalline domains ranging from 0 to 55 depending on how it is processed It can have the properties of drink bottles or Dacron ber 0 O 60on H n Polyethylene wrephlhalaw Chende 31m Y Morphology o Amorphous PET is formed by cooling the melt quickly 7 plastic beverage bottles are PET with a low degree of crystallinity o By cooling slowly more molecular diffusion occurs chains become more ordered and crystalline domains form 7 PET with a high degree of crystallinity can be drawn into textile bers and tire cords dacron Chemistry 318N 39 Wallace Hume Carothers Addition Polymerization and Condensation Polymerization Chemistry 318N 39 Carothers Definition Additon Polymerization Emperical formula retained A d d ition Condensation Polymerization c02H o OHH20 Hoc H gt H 2 H Loss of a small molecule oCondensation Chemistry 318N Y Problems with Carothers Definition Same product by two paths o H N c o oc NWoOJKN Ar H 0H gt o H NC0 Condensation if gt i ori o 0 Addition 0 Condensation Chemistry 318N I Paul J Flory 19101985 The Nobel Prize in Chemistry 1974 quotfor his fundamental achievements both theoretical and experimental in the physical chemistry of macromoleculesquot Chemisby 31m Y Flory Clears Things LJp nu Prmess Additiun 581mm Puiymerizatmn Puiymenzauun 5 O O O of HMJH HOYLOM Cunnensatmn Puiymer Process Structure Addition Ringrnpemng monomer polymer Nn byrpmducts V Degadaunn gives different Enmpnsitmn 5 e Hy a Basic Types of Polymerization Mechanisms Hexamer O O Step growth HogCHZVCHZVOH gt HltOHZCH239CH239OH H20 Chain growth 5 B gt O WWAO Ring opening 0 R0 of RONOgtH 318N Krische Lecture 21 Tu 040709 DielsAlder Reaction Cope and Claisen Rearrangement o DIELS ALDER REACTION Several unirnolecular reactions proceed through aromatic transition states ie reactions in which there is the concerted cyclic motion of 3 electron pairs 4n 2 electrons The decarboxylation of beta carboxyketo acids and the Cope elimination are examples The Diels Alder reaction is the 42 cycloaddition of a diene and an alkene to give a cyclohexene product The Diels Alder reaction has an aromatic transition states involving the concerted cyclic motion of 3 electron pairs 4n 2 electrons Note Related 22 cycloadditions and 44 cycloadditions are unfavorable as they would involve anti aromatic transition states o The Diels Alder Reaction The Diene Partner Dienes must be able to adopt an s cis conformation to participate in Diels Alder Cycloadditions For this reason cyclic dienes work the best The best diene partners are usually electron rich In class we ranked the ability of several 2 subsituted butadienes to participate in Diels Alder Cycloadditions o The Diels Alder Reaction The Dienophile The best dienophiles are electron de cient ie an alkene that is conjugated to an electron withdrawing group 0 Stereochemistry of the Diels Alder Reaction The Diels Alder reaction is a concerted process Because bond making and bond breaking occur simultaneously the reaction is stereospecifrc For example groups that are trans in the dienophile will be trans in the cyclohexene product Conversely groups that are cis in the dienophile will be cis in the cyclohexene product 0 Endo versus Exo Cycloadducts The Diels Alder reaction of cyclic dienes gives rise to endo and exo products In the endo cycloadduct the electron withdrawing group of the dienophile projects inward toward the alkene of the cyclohexene In the exo cycloadduct the electron withdrawing group of the dienophile projects outward away from the alkene of the cyclohexene and toward the bridging residue of the bicyclic ring system Be able to draw stereochemically meaningful depictions of the endo and exo bicyclic ring systems that derive via Diels Alder reaction of cyclic dienes Endo products are kinetic products while exo products are thermodynamic products See the on line handout on the Diels Alder reaction for an explanation o Intramolecular Diels Alder Reaction The Diels Alder reaction can also be conducted intramolecularly to give endo and exo products Be able to predict the stereochemistry of both endo and exo products ie be able to draw the products It might be helpful to use molecular models Lecture 6 Infra red spectroscopy SIIIGLE mus aono smEtcN nouns DouaLE nouns 044 I144 smEtcN w muss smEtcN mums 4nnn asnn annn zsnn n 2nn WAVENUMBER cm isnn mnn snn demin was Chzmixby 31m Y Oh noan unknown Solving nmr unknowns 1 Molecular Formula and unsaturation number C2H3O mass 43 17243 4 9 C8H1204 C8H18 CSHIZ H6 62 3 Three rings or three pi bonds or a combo of these Chemistry 318N Y Solving nmr unknowns N Number of distinct signals is 3 three different types of equivalent hydrogens 3 Integration ratio is 204060 123 123 6 126 2 The ratio ofhydrogens is then 246 4 Pattern of Chemical Shifts 5 12 42 67 5 Please read carefully pages 530 532 Chemistry 318N I Chemical Shift 1H1HR Type of H 5 Type of H 5 C H3 4 Si 0 ROH 05 60 RCH3 09 RCH2 0R 33 40 RCH2 R 12 14 R2 NH 0550 R3 CH 14 17 0 R2 CCRC HR2 16 26 RECH3 21 23 RCECH 20 30 O Arc H3 22 25 RECHZ R 22 26 ArC H2 R 23 28 Chemistry 318N Y Chemical Shift 1H1HR Type ofH 5 Type of H 5 0 Rice H3 3539 R2 CC H2 4650 quot R2 cc HR 50 57 RCOC H2 R 4147 ArH 65 85 RCH2 I 31 33 o RCH2 Br 34 36 chzH 95 101 RCH2 CI 36 38 quot3 RCH2 F 44 45 RCO H 1013 Chemistry 318N I Chemical Shift additivity estimates H Hi CH m 0 3 C1 Caution estimates only Chemistry 318N Y From last time a H3C O c1 JUL HT Chemistry 318N E Coupling Cumtam 13C Chemical Shifts 7Hlt H cc icicllw 13CNMR chemical shifts Type of Chemical Type of Chemical Carbon Shift 8 Carbon Shift 8 RCH quot3940 C R 110 160 RCHZR 1555 R3CH 2060 0 RCHZI 0 40 Rpm 160 180 RCHzBr 2565 0 RCHzCl 3580 liltiNR 165 180 R3C0H 4080 0 Ram 4080 RI 0H 175185 RCECR 6585 0 0 R2CCR2 100150 RI RICIR 180 210 Ch emixtry 31 W I 13C NMR Spectra i wii V d 4 lrcquellcy 13Cnmr Spectroscopy o Eachnonequivalent zc m o givesadifferent signal 1 Jim m 3 23 392 mm xmu xn 5n 4n 2n The DEPT Experiment 0 In the hydrogendecoupled mode infoImation on spin spin coupling between 13C and attached hydrogens is 10st 0 Distonionless Enhancement by PolaIization Tmnsfer is an NMR technique for determining Whether C signals are from CH3 CH2 CH or quatemary carbons o DEPT is an instmmental tIick that provides the means to acquire this infoImation 13 amm w Y The DEPT method 0 DEPT uses a complex series of pulses in both the 1H and 13C ranges with the result that CH3 CH2 and CH signals exhibit different phases 7 signals for CH3 and CH carbons are recorded as positive signals odd numbers ofH 7 signals for CH2 carbons are recorded as negative signals even numbers ofH 7 quaternary carbons give no signals in the DEPT method zero H Chemistry 31m 391 Broadband decoupled 13C nmr spectrum Frumoept CH m H m quotquot3 aquot quotW m w m tin 1quot m J ms t L mm m mi 39 22a zen we mu m nu me an m m 29 0 5mm Chemimy 31m T 13CNMR a and DEPT b spectra of isopentyl acetate 22 25 20 39170 62 3739 Odd CDCI3 l I l I a 22 0 Odd 12 25 I 20 r II 8 d c h EH37 62 37 Odd EH30IH2I3H23H a CH3 20 170 sz y 25 CH3 CH Even 0 Even 250 200 150 100 so 0 ppm Empirical formula C4H9 MW 114 13CNMR chemical shifts W T f Chemical p 39t39 39 DEPT i ypeo Carbon Shift 3 0S1 Ive In T RCH1 040 Rel2R 15 55 T 11ch 20 60 RCHZI 1140 T ncnznr 25 65 TMS Rel2C1 35 80 T nlcon 4030 RSCOR 40 80 T EEC 53985 Disa ears in nzccn2 100150 35 0 pp T DEPT Chemistry 318N 39 r I 220 Whatzit 139 C5H30 CH cncl1 I i l i l i i l 60 MO 20 100 ED SD 46 20 G 5c prm l 200 180 Chemistry 31m Y 13CN M R Spectroscopy review Each nonequivalent 13C gives a different signal Low abundance means weak signals CC splitting is insigni cant CH splitting is big and complex so it is turned off by decoupling Range of Chemical Shi s is large compared to H Some Coupling info can be recovered by DEPT Integrals of 13C spectra are not useful except under very special circumstances Chemistry 31m I39 3 i E 94 v 61 any Renesh Hm gemen Mme Hnslmy F va an swam jhanw pm Evam s a nndawaDda Bug s wmnm aUTWananReseath ruanic Strunan Elucidatinn Wurkhnnk m Unknowns Unlvexsny af Nam Dam 1992 m Bradley D Ennn myquot my m an nnnass Wm M Enumrmm Department 01 Ehemim n aincnemimv EE JZ IE5393VUEMM puny nivnmitv nf mm Dame cw mwm mm m manu wm W q nnv s nmm Awnaa m wan mm 0 Evans n a nmemen 4 In El gay gm ngnnles 1m Henp I quot 9 3 1 Q 1 5 Q a y meard Slap shesh Hume Seavch Fawnlgs Hulavy Punk Edd Dell Home Mvmxl huplwwwchmatuk aca lmmv j 201 m mmanfstalemiar gwmmumua 45 am We Web gems Elvaan g m wnmn Rexeaum Emup 31le cm b Dank Enadal Was 9 mm Basic Proton and C13 NMR A place to Practice httpWWWchemuiceduWeb1OCOLIIWINSPECHTNI G Chemixlry 31m 1 Mum zonnm wunm 500nm 2mm sown Chemixlry 31m 1 Infrared Spectroscopy Vibrational IR spectral region covers 7 25 x 10396 m 25 micrometers to 25 x 10395 m 25 pm 7 Human hair is about 50 pm in diameter Absorption of IR radiation in this region causes bonds to change from a lower Vibrational energy level to a higher one Q Chemistry 318N Y Infrared Frequency Scale IR radiation is commonly expressed in wavenumbers Wavenumber the number of waves per centimeter cm391 read reciprocal centimeters or Kysers Expressed in wavenumbers the Vibrational IR extends from 4000 cm391 to 400 cm 391 10000 m cm391 250 pm 10000 um cm391 100 pm 4000 cm391 7 1000 cm 391 Chemistry 318N I 318N Krische Lecture 3 Tu 012709 Aldehydes and Ketones 0 We begin by reviewing acetalketal formation and hydrolysis and the formation of thioacetals ie 13dithianes The mechanism for acetalketal hydrolysis is simply the reverse of acetalketal formation KNOW THE MECHANISM 0 Thus far we ve examined the addition of Oxygen and Sulfurnucleophiles to aldehydes and ketones Next we discuss additions involving Carbonnucleophiles Some carboncentered nucleophiles organolithiums Grignard reagents acetylides cyanide and dithianes The preparation of organometallic reagents was discussed in class along with several problem in synthesis that exploit such reagents o Carbanions will add to the positive end of the carbonyl dipole ie the carbonyl carbon The immediate product of addition is an alkoxide By quenching the reaction with a large excess of water one obtains the corresponding alcohol EXAMPLE CH3MgBr adds to formaldehyde to give ethanol a primary alcohol CH3MgBr adds to acetaldehyde to give isopropanol a secondary alcohol and CH3MgBr adds to acetone to give tertbutanol a tertiary alcohol CH3MgBr adds to carbon dioxide to give acetic acid With the exception of phosphorus ylides all carbonnucleophiles we discuss will behave in an analogous fashion 0 The Wittig Reaction Phosphorus ylides eg Ph3PCH2 can be represented as a zwitterionic species in which the carbon bears a negative charge and the phosphorus bears a positive charge Ylides will add to the carbonyl carbon of an aldehyde or ketone The resulting alkoxide will bite back onto phosphorus to generate the famous oxaphosphetane intermediate a 4membered ring containing oxygen and phosphorus This strained ring will collapse to give an alkene and triphenylphosphine oxide The Wittig reaction can be thought of as the reverse of an ozonolysis Aromatics 3 Lecture 13 Jeff Strahan 22808 Chemistry 318N Y H 5 6 E E Y H Y Electrophiic aromatic substitutions include Nitration Sulfonation Halo genation FriedelCrafts Alkylation FriedelCrafts Acylation Chemistry 318N I Effects of substitution on further eleclmphilic aromatic substitution Sunngly 41H N39mt 4111 R531 Fast activating 0 0 39 ii i Ii t Motltnttely NHCR NHCAr QR Pretty fast activating a t a n Weakly R A g mung Klnda slow v 2 Wettkly C ijn 1 C deactivating pretty 510W 0 Moderately i 9 i ii I 5 dencliva ng CH CR COH COR CNHz 0H CEN 310W 5 v 5 Strongly 0 23 denclivming N01 Nlif Clt 3 CC3 Real Slow ammy 318N Y Can you make these ammy 318N Y Diazonium Salts Chemistry 318N Y Diazonium Salts o The N2 group of an arenediazonium salt can be replaced in a regioselective manner by these groups Schiemann reaction Sandmeyer I reaction Chemistry 318N I Reactions of Diazonium Salts CH O OH AZO cumpnund theme 4131 Y ArN H2 with HNo2 Anilines can be converted to phenols NH2 0H Br1NaNZHZSqH20 Br Q mg CH3 H 3 ZBrommzlimethylaniline ZBromOAL methylphenol Itemixtiy 31m T a Problem What reagents and experimental conditions will bring about this conversion CH3 0 41gt coz H CH3 2 N02 co2 H EJJELgtE 44gt E NO2 NH2 OH co2 H U NH2 0 gt Chemistry 318N Y Another one CH3 Cl CH3 CH3 CH3 EN CHZNHZ gt CH3 Cl CH3 gt 0 Cl Cl Chemistry 318N I More Practice Chemistry 318N Y Experiment 1 Chemistry 318N I The Mechanism SnAr m Chemistry 318N Y Experiment 2 Chemistry 318N I Benzyne Chemistry Chemistry 318N Y Regioselectivity with Benzyne Negative charge by CF3 is more stable via induction Chemistry 318N I Lecture 2 Mass Spectroscopy mum 3 1qu 3mmmmmmwmmmm x elemml hermiunim MEN mekhrmn pk quot m Wm snnwk f I g magnmicmidseparmespanwlx m m km on quotNirsvuharge mm 6 MM mm WWW mum January 17 2007 Chende 318W Mass Spectrum of 1Butene Base Peak um 30 Cu cucuzcnJ MW 5r CHCH 4 lCH Relali e Abund39mce 40 M 5quot Molecular ion 20 0 I 7739 1 r I39 r 1 v v39 1 10 20 an do so so 70 so Chende 318W Mass spectrum of octane aural HITCHTCHZICHZICHTCH 5 43 57 739 29 4 100 3113CH26C113 43 g 80 MW114 E l a so 3 V 40 32 57 I71 I I I l I I I l 60 70 80 l 29 BS 20 I I I II M014 0 quot I r r39 IE I i r r39quot i quot x 10 20 so 40 so 90 100 110 120 mI Chemixtry 318W The Nitrogen Rule 0 Nitrogen rule ifa compound has 7 zero or an even number of nitrogen atoms its molecular ion will have an even mZ value 7 an odd number of nitrogen atoms the molecular ion will have an odd mZ value Chemixtry 318W Resolution C3H60 and C3H30 have nominal masses of 58 and 60 respectively and can be readily distinguished by lowresolution MS C2H402 and C3H30 both have a nominal mass of 60 However we can still distinguish between them by high resolution MS Molecular Nominal Precise Formula Mass Mass C3 H8 0 60 6005754 C2 H4 02 60 6002112 ll Chemixtry 318W Mass spectrum of octane P Rcluliw Ah Citron2 CHTCHZCHZICHZIClIrcn x5 43 57 7 29 100 C13CH25CHJ 43 so MW 114 so 40 29 57 85 20 l 71 I I M 114 39 i r i39 I r fli I I r 39 r i 39 39 I rquot 1l39l l f39 T i 10 20 30 40 so 60 70 so 90 100 110 120 m z Chemixtry 318W Octane M11141 Chemixtry 318W Isotopes 16 1397 0 159949 100 0 169991 004 180 179992 020 sulfur 32066 32S 319721 100 8 329715 078 8 339679 440 chlorine 35453 35C 349689 100 C1 369659 325 Br 789183 100 Br 809163 980 oxygen 15999 bromine 79904 Chemixtry 318W Calculating M1 o M1 Z abundance of heavier isotope X number of atoms in the empirical formula 0 Thus for octane Cng8 M 1 Z111gtlt80016gtlt18 8880288 917 ofM Chemistry 318N Calculated Spectrum Scheffield ChemPuter htt9wwwchemshefacukWebEIementscgiisot Formula CgH18 0 115 88 116 03 117 00 Chemistry 318N M2 Peaks The most common elements that give rise to M 2 peaks are chlorine and bromine o Chlorine in nature is 7577 35Cl and 2423 37Cl 7 a ratio of M to M 2 of approximately 31 indicates the presence of a single chlorine in a compound Bromine in nature is 507 79Br and 493 81Br 7 a ratio of M to M 2 of approximately ll indicates the presence of a single bromine in a compound Chemistry 318N M2 Peaks 0 Sulfur is the only other element common to organic compounds that gives a significant M 2 peak and it is small 328 9502 and 34S 421 Result of isotope pattern calculation Formula ClH4Sl mass 48 1000 49 19 7 50 45 7 Chemistry 318N M2 and StatisticsCI2 0 Possible ways of combining two Chlorines 7 35 35 70 35 37 72 and 37 37 74 7 Three peaks of what relative intensity 7 assume that the probability of 35 is 075 and of 37 is 025 close to true First Cl 35 35 35 37 From the table Relative Probabi x Mass 70 9 916 0 5625 05625 100 Mass 72 6 616 0375 05625 666 Mass 74 1 116 00625 05625 111 Total 16 Chemistry 318N Another way To look at this Probability permutations Product 3535 75X75 1 05625 0562505625X100 100 Ii l 3537 or 75X25 2 03750 0375005625X100 3735 666 IN 3737 25X25 1 00625 0062505625X100 111 unclluauj U V What is Wrong with these things 0 Using more exact isotope masses 3535 7577X7577 1 05741 100 3537or 7577x2423 2 03671 96310574DX100 3735 3737 2423X2423 1 005871 039058710395741X100 102 Chemistry 318N Interpreting MS 1 Check the M2 region of the spectrum The only elements to give significant M 2 peaks are Cl and Br If there is no large M 2 peak then there is no C1 or Br remember S it is small 2 Is the mass of the molecular ion odd or even Apply the Nitrogen Rule a if a compound has zero or an even number of nitrogen atoms its molecular ion will appear as a even mz value b If it has an odd number of nitrogen atoms its molecular ion will appear as an odd mz value Chemistry 318N Fragmentation of M a To attain high efficiency of molecular ion formation and give reproducible mass spectra it is common to use electrons with energies of approximately 70 eV 1600 kcalmol o This energy is sufficient not only to dislodge one or more electrons from a molecule but also to cause extensive fragmentation 0 These fragments may be unstable as well and in turn break apart to even smaller fragments Chemistry 318N Fragmentation of M o Fragmentation of a molecular ion M produces a radical and a cation Only the cation is detected by MS gt A B Radical Cation AB 39 Molecular ion a radical cation D A 39 B Cation Radical Chemistry 318N Fragmentation of M o The chemistry of ion fragmentation can be understood in terms of the formation and relative stabilities of carbocations in solution 0 When fragmentation occurs to form new cations the mode that gives the most stable cation is favored Chemistry 318N Fragmentation of M o The probability of fragmentation to form new carbocations increases in the order CH3 lt 10 lt 2 lt 3 2 3 3 lt 10 lt 1 allylic lt 2 allylic lt 10 benzylic 2 benzylic Increasing carbocation stability gt Chemistry 318N 3 allylic 3 benzylic Alkanes o Fragmentation tends to occur in the middle of unbranched chains rather than at the ends 0 The difference in energy between allylic benzylic 3 2 1 and methyl cations is much greater than the difference among comparable radicals where alternative modes of fragmentation are possible the more stable carbocation tends to form in preference to the more stable radical Chemistry 318N Mass Spectrometry 0 When the weakened bond breaks one fragment retains the single electron becoming neutral and the other must therefore accept the positive charge CHscHZCHZ CHscHZCHZCHSff Detectable by CH3 Mass Spec Bond break CH3CHZCHZCH31T o How the molecule actually fragments will depend on the stabilities of the indiVidual pieces formed Chemistry 318N Mass Spectrometry o The pentane molecular ion can split in several ways 7 cugcuz H2 onion2 The carbon I39ll243 C2C3 bond J CH3CH2CHZCH2CH3P gt CHacHzCHg CHSCH1 Is broken molecular ion mz 29 m 72 z CH3CH3CHEEHZ CH The carbon 257 C1C2 bond is broken CH3CH1CH36HZ CH mz 15 o In each bond breaking case above the positive charge may reside on either of the fragments 7 The mz values for each positive fragment can be determined 7 A line representing that fragment is usually found on the mass spectrum and its abundance can be observed Chemistry 318N Mass Spectrometry 0 Will one of these bonds break more easily 0 The relative abundances indicate higher amounts of the fragments mz 29 and 43 and lesser amounts of the fragments mZ 15 and 57 7 This indicates that the C2C3 bond is more likely to break In this case the increased stability of the resulting C2C3 radicals cations drives the fragmentation at this carbon bond Relative abundance 12 Vlas spectrum ofoclanc cur CH1 CH2 CHZICHZICHZICHFCHJ 57 7 3 s 43 29 100 g cngcnzy cng 43 g 30 MW114 E 601 2 39 4 29 s ll l Iquot 393 Man 0 I I I I lllllllllllllllll lll 10 20 30 40 so 60 70 so 90 100 110 120 711 Chemixny318N Muss spectrum of 2244rimclhylpvnlanc yum CIHJ 57 CH 1 H 3 if sovcnjclfinz gcm CHJ inn 3 3 H i MWU4 CH Cch1 40 E Icnscnzr 41 on 20 A 3 w 3 Mll4l z rrl39il Ji39w u 7 gt 39 rilr iliri39l 10 20 30 40 50 100 l 10 120 Chemixny318N Mass spectrum of Inclhylcyclnpcntanc y 100 5quot g 80 m3 64mm g 56 5 so 69 41 lt1 MW 34 40 C H E 69 I 5 9 5 201 I I I I M 34 0 if 1A n l Liitu KI I rll iilgli iii 10 20 30 40 50 0 70 100 quot1 Chzmlxlty3131V AI ke n es 0 Alkenes characteristically show a strong molecular ion peak 0 They cleave readily to form resonance stabilized allylic cations CH 2CHCH ZCHZCH310 gtCH2CHCH 2 CHZCHa Cilsz 3191v Mass spectrum of llmlcnc 4 CH2 HCHZCH CHZClCl12 MW 56 Rclulhe Abundance 0 l M 56 Chemixtry 318W Alkynes o Alkynes typically show a strong molecular ion peak 0 They cleave readily to form the resonance stabilized propargyl cation or a substituted propargyl cation 1 HcEBZCHZ lt gt HCCCH 2 resonancestabilized propargyl cation Chemixtry 318W Mass spectrum of ipcmyne Reimivc Abundance 100 67 n i HC 2 ccnzcnzcnJ HCE may 8 39 MW 68 39 so 27 40 CI13012 I 9 20 M 68 0 i i 7 I 1141 1 10 20 so 70 Chzmzs t39 Iy 313A Alcohols o A common fragmentation gives M 18 loss of water 0 The other fragmentation produces the alkyl radical ion from the carbon bearing the OH group Chzmixny 31317 Alcohols R QM amp R39C 9H gt R R39C 939H lt gt R39C QH Rquot A radical Rquot Rquot Molecular ion A resonance stabilized a radical cation oxonium ion Most stable radical is lost Please analyze for primary secondary and tertiary alcohols Chemistry 318N 1butanol s OH gt CH3CH2 CH2O c0H HH C OH H MZ31 H2CH3C Ezj Chemistry 318N Mass spectrum of lliutanol E 100 31 5 80 HOCH2CH2CH2CH3 56 E quot MW 74 CH1 0H 5 60 43 C i H J C H a 4039 ICH2CH21 3 7 l 4 x E 20 H10F 28 l M 74 18 quot gigl ggl 1 39 I I 17 I lquotl i 10 20 30 40 SO 60 70 80 quot1 Chemistry 318N 100 M 3 j HOCHZCHchzcl ls CH7OH 56 E 50 MW 4 39 I 39U 5 60 0 CHZCHZ C3H7 C4Hs 40 E v 28 392 20 39 H20 I M04 0 quot i39 39iii39i i 10 20 50 70 70 80 ml ems Emaksicuie Tuuman Elimination of water Elimination of propyl Chemistry 318N I lyou needto know 0 How mass Spectrometry measures mz 0 Basic Function of the Spectrometer Base Peaks molecular ions 0 Application of unit mass resolution Calculating Ml and M2 S Cl Br 0 Application of High resolution How to use isotope tables relative abundance Allows differentiation between molecules with identical Mw at umt mass Chemistry 318N you needto know The nitrogen rule Structures can be differentiated by fragmentation pattern analysis Fragmentation follows carbocation stability trends Alcohols fragment to lose most stable radical We need to know a bit about fragmengtation of Alkanes alkenes alkynes and alcohols Chemistry 318N Molecular Spectroscopy 0 Molecular spectroscopy the study of the frequencies of electromagnetic radiation that are absorbed or emitted by substances and the correlation between these frequencies and aspects of molecular structure Iranian 318N The electromagnetic spectrum In lovlnves IIIquot Iquot quotllquot ll I 19 10quot 19quot NIH 1 0I 19quot 393 191 19quotvCHz Mknr Lang mun wan um 1 nys x rays UV 111 u t l I I l I 10 10quot 10 10m 041 102 10 102 10 106 10quot Mm le speck n quot1 400 500 600 700 E w A Energy per photon 4 Frequency Wave liven WP 20 mnguuuwW aunumnum 1 n mm m auumumnuw 77 mung ammuunum iuu Fomml sm v mm auMagnemliu Hz 77mm mun y um 5mm JGgmaultugHz 771m xmu cm Ggnem nu ma7 u Mlhmeers nu 3 ml mm mu y nu Gghem nua H1177 mmedeuon mum nu ZHz iiyuu mum y 3mm nuiz m if u Mumm nuam nuuuuum nDYa ha39u nu hm 3 them nu 5 H1177 m LivMole Rumnon virus y am pm nut5 H1177 u N HHHH ew nu an M y mm numuxi x rVS an mun nuiE H1177 u umm nuizmx nu Ema nu Hz 77 emu ms 3 x 102 H177 uu mm mews y JDX1D2 H1771DFemmmasrsll l ml 3m x 102 H177 i 3 x lumuii mu mx u2 H177 uumms nu um max to H177 1 Chemixtty 318N Electromagnetic Radiation o Electromagnetic radiation light and other forms of radiant energy 0 Wavelength O the distance between consecutive identical points on a wave 0 Frequency V the number of full cycles of a wave that pass a point in one second 0 Hertz Hz the frequency unit s1 read per secon Chemixtty 318N 21 Radio Frequency and Microwave summm min 39 39 39 39 NM 30mm MMHI moMHz m 50H quotmquot 3mm m 3quot 30m 3cm in m um 5m Chemistry 318N Electromagnetic Radiation llt k Dl o Wavelength Relation Unit to Meter meter m millimeter mm 1 mm 10 3 m microwaves micrometer um I p m 10 6 m infrared nanometer nm 1 nm 10 9 m soft x rays Angstrom A 1A 10 10 m Hard x or Trays Chemistry 318N 22 Electromagnetic Radiation Important relationships M 0 Where C 300 X108ms he E I ZV Where h 9537 X 1039 kcal secmol it See examples of calculations on pages 471 through 473 Carefully follow section 121 Chemistry 318N Absorption of electromagnetic radiation E2 0 Energy in t form of electromagnetic Absorption of ra in ion radiation Energy E1 4 Atom or molecule Atom or molecule l in energy state E1 in energy state E2 Absorbance promotes atom or molecule to higher energy state Chemistry 318N 23 Molecular Spectroscopy c We study three types of molecular spectroscopy Region of the Absorption of Radiation Results Spectrum in Transition Between radio frequency gt nuclear spin energy levels infrared gt vibrational energy levels ultraviolet visible electronic energy levels Chemistry 318N Absorption of electromagnetic radiation 0 Described by quantum mechanical theories 0 Only discrete unique energy states are allowed accessible 0 Therefore only discrete unique amounts of radiation can be absorbed or emitted How many potential energy states are available to the ball Chemistry 318N 24 Summary 0 Molecular Spectroscopy Concept Discrete transitions in energy levels Transitions with varying energy areas of spectrum Nmr nuclear spin radio frequency region IR vibration infrared region UVVis electronic transitions UV to visible Please know relationships between frequency wave length and energy Know length scale conversions micron millimeter nanometer angstrom Chemistry 318N 25 Lecture 12 More Aromatic Chemistry Jeff Strahan 2 26 08 Chemistry 318N Y H 5 6 E E Y H Y Electrophiic aromatic substitutions include Nitration Sulfonation Halogenation Friedeerrafts Alkylation Friedeerrafts Acylation Chemistry 318N I Relative rates of Nitration Goa OH Om Om 1000 10 0033 6x108 lt REaCtivity i Chemistry 318N Y Effects of substitution on further electrophilit aromatic substitution suaa y 4in iiHii an 91 RealFaSl activating 0 0 0 0 39 i Ii l i Madcratdy NHCR NHCAr QR 9tk QCAr Prettyfast activating a i 3 Weakly R E g muting Q Klnda slow 4 0 V t Weakly E l lr c deactivating Pretty slow a Moderately i ii i i i g deactivating CH cn COH COR CNH 0H CEN 310W w u E Straagiy 0 a deactivating N01 NH CF3 CCi3 RealSIDW Chemistry 318N Y Di and Polysubstitution Some observations 0 Alkyl groups phenyl groups all groups in which the atom bonded to the ring has an unshared pair of electrons are orthorpara directing All other groups are meta directing o All orthorpara directing groups except the halogens are activating toward further substitution The halogens are weakly deactivating Chemistry 318N Y Effect on Regioselectivity Orthorpara directors direct an incoming electrophile to positions ortho andor para to themselves 0 Meta directors direct an incoming electrophile to positions meta to themselves 0 A11 n1eta directors are deactivating 0 A11 orthoepara directors are activating except halogen Chemistry318N Y Theory of Directing Effects 50 What s going on here The rate of EAS is limited by the slowest step in the mechanism duh For EAS the rateilimiting step is attack of E on the aromatic ring to form a resonanceistabilized cation intermediate 0 The more stable this cation intermediate the faster the rate limiting step and the faster the overall reaction Chetuistry318N Y Adding a Second Substiuent meta allutk 0c ocr I3 ocn OCH3 ocn3 Gm mow at SUW 39 N02 N02 NOI Inquot N01 para ullack u u H OCHJ OCH3 20cquot OCH 10CH3 ocnJ Ge sbsg a sh hm HNO2 HNOz HNU2 HNO2 No2 Thcmosl Methoxy is is therefore an quotop directorquot Chetuistry318N Y Adding a Second Substiuent melu attack N01 N01 N01 N01 Noz NOE I p QHH GEE p H sow N01 N02 last NO NO para ullack N02 Nol No2 NO2 Noz Gran 5 0 sluw I39as M H NO H N01 N02 The most disfnvnred contributing Cull Nitro is therefore a quotmeta directorquot Chemistry 318N 39 Di and Polysubstitution CH3 COZH quot03 D K2 or2 o7 H2504 sto CH3 N02 N02 pyNitrobenzoic acid 0 2 myNitrobenzoic acid Chemistry 318N I ortho Nitration of Toluene CH3 NO2 H H H Chemistry318N Y ortho Nitration of Toluene CH3 CH3 N02 N02 H b H H H H H H Chemistry 318N I ortho Nitration of Toluene CH3 H3 CH3 N02 N02 N02 H H H H H H H H H H H H H this resonance form is a tertiary carbocation Chemistry 318N Y H H ortho Nitration of Toluene CH3 CH3 CH3 N02 N02 N02 H H H H H H H H H H H H H the raterdetermining intermediate in the ortho nitration of toluene has tertiary carbocation Character Chemistry 318N I meta Nitration of Toluene CH3 H H NO H 2 Chemistry318N Y meta Nitration of Toluene CH3 CH3 H H H a H H H NO NO H 2 H 2 Chemistry 318N E meta Nitration of Toluene CH3 CH3 CH3 H H H H H H H H H a H H H NO NO NO H 2 H 2 H 2 all the resonance forms of the raterdetermining intermediate in the meta nitration of toluene have their positive charge on a secondary carbon Chemistry 318N Y Nitration of Toluene Interpretation 0 The raterdetermining intermediates for ortho and para nitration each have a resonance form that is a tertiary carbocation All of the resonance forms for the raterdetermining intermediate in meta nitration are secondary carbocations Tertiary carbocations being more stable are formed faster than secondary ones Therefore the intermediates for attack at the ortho and para positions are formed faster than the intermediate for attack at the meta position This explains Why the major products are 07 and penitrotoluene Chemistry 318N I Nitration of Toluene Partial Rate Factors 0 The experimentally determined reaction rate can be combined with the orthometapara distribution to give partial rate factors for substitution at the various ring positions Expressed as a numerical value a partial rate factor tells you by how much the rate of substitution at a particular position is faster or slower than at a single position of benzene Chemistry 318N Y Nitration of Toluene Partial Rate Factors CH3 1 1 25 25 1 58 o All ring positions in toluene are more reactive than any position of benzene o A methyl group activates all of the ring positions but the effect is greatest at the ortho and para positons o Steric hindrance by the methyl group makes each ortho position slightly less reactive than para Chemistry 318N I Synthesis of m Bromoacetophenone Br CH3 0 CH3 Br 0 Q Which substituent should be introduced first Chemistry 318N Y Multiple Substituent Effects Chemistry 318N I The Simplest Case all possible EAS sites may be equivalent CH3 CH3 0 O H H AICI3 CCHs CHscOCCHs CH3 CH3 99 Chemistry 318N Y Another Straightforward Case CH3 CH3 Brz Br Fe N02 N02 8690 directing effects of substituents reinforce each other substitution takes place ortho to the methyl group and meta to the nitro group Chemistry 318N I Generalization regioselectivity is controlled by the most activating substituent Chemistry318N Y The Best Man Wins Strong39y NHCH3 NHCH3 activating Br2 Br acetic acid CI CI 87 Chemistry 318N I When activating effects are similar CH3 CH3 HNo3 N02 st04 CCH33 CCHss 88 substitution occurs ortho to the smaller group Chemistry 318N Y Steric effects control regioseectivity when electronic effects are similar CH3 CH3 HNo3 HSO CH3 2 4 CH3 N02 98 position between two substituents is last position to be substituted Chemistry 318N I Factors to Consider order of introduction of substituents to ensure correct orientation Friedeerrafts reactions alkylation acylation cannot be carried out on strongly deactivated aromatics Chemistry 318N Y Substitution in Naphthalene Chemistry 318N I Naphthalene H H H 1 H 0C H H H H two sites possible for electrophilic aromatic substitution all other sites at which substitution can occur are equivalent to l and 2 Chemistry m Y EAS in Naphthalene 0 CCH3 is faster at C71 than at C2 90 Chemistry 318N I EAS in Naphthalene when attack is at C 1 carbocation is stabilized by allylic resonance benzenoid character of other ring is maintained Chemistry 318N H EAS in Naphthalene EH when attack is at C2 E in order for carbocation to be stabilized by allylic resonance the benzenoid character of the other ring is sacri ced Chemistry 318N I 318N Krische Lecture 15 Tu 031009 Electrophilic Aromatic Substitution We begin by reviewing the EAS reactions covered last lecture H D exchange Sulfonation Nitration and Halogenation We considered the general mechanism of EAS and noted that for each of the reactions that we ve covered all we ve done is simply vary the electrophilic partner Friedel Crafts Alkylation of Benzene Isopropyl bromide does not react with benzene However we may activate isopropyl bromide as an electrophile by adding a Lewis acid such as aluminum tribromide AlBr3 Aluminum tribromide complexes isopropyl bromide and promotes the formation of isopropyl cation This secondary carbocation represents an activated electrophile of suf cient reactivity to participate in EAS with benzene The product of EAS is isopropylbenzene aka cumene For the Friedel Crafts alkylation of benzene THE SAME EAS MECHANISM is in operation Tertiary halides also work well in the Friedel Crafts alkylation Thus exposure of benzene to a mixture of tert butyl chloride and aluminum chloride gives tert butyl cation a tertiary carbocation This tertiary carbocation represents an activated electrophile of suf cient reactivity to participate in EAS with benzene The product of EAS is tert butyl benzene Primary alkyl halides are problematic For example exposure of benzene to a mixture of n propyl bromide and aluminum tribromide gives a 11 mixture of two products n propylbenzene and isopropylbenzene In order to explain this result we considered the mechanism of this process n Propyl bromide and aluminum tribromide should produce a primary carbocation Since the primary carbocation is relatively unstable it will undergo a 12 hydride shift to furnish iso propyl cation a more stable secondary carbocation The rate of hydride shift and EAS with benzene are similar so mixtures of n propylbenzene and isopropylbenzene result To conclude our discussion on the Friedel Crafts alkylation of benzene we note that the reaction DOES NOT WORK FOR ELECTRON DEFICIENT BENZENE DERIVATIVES If the benzene ring contains an electron withdrawing group the nucleophilicity of benzene is diminished and EAS is slow Elimination E1 of the electrophile becomes competitive and results in dramatically reduced yields We note that the active electrophilic partner in Friedel Crafts Alkylation is a secondary or tertiary carbocation In the speci c case of tert butyl chloride tert butyl cation is generated We can generate the very same active electrophilic partner tert butyl cation by two other methods 1 Exposure of tert butyl alcohol to acid H3PO4 and 2 exposure of isobutylene aka 2 methylpropene to acid again H3PO4 Thus we have a total of 3 different methods available for preparing branched alkylated aromatics We are still left with the challenge of preparing linear alkylated benzenes Linear alkylated benzenes cannot be prepared via Friedel Crafts Alkylation or other methods involving carbocationic intermediates due to 12 hydride shifts Recall that exposure of benzene to a mixture of n propyl bromide and aluminum tribromide gives a 11 mixture of two products n propylbenzene and isopropylbenzene Friedel Crafts Acylation comes to the rescue Friedel Crafts Acylation involves exposure of benzene to an acid chloride and AlCl3 Under these conditions an acylium ion is formed The acylium ion is the active electrophilic partner in this EAS reaction The product is an acylated benzene Know the mechanism for acylium ion formation as well as the EAS reaction itself To prepare linear alkylated benzenes we 1 perform Friedel Crafts Acylation and then subject the resulting ketone to 2 Wolff Kishner reduction or Clemmensen Reduction We discussed the preparation of disubstituted benzenes SEE SECOND ONLINE HANDOUT ON EAS Just as an alkene will protonate to yield the more stable carbocation benzene will react with electrophiles to afford the most stable carbocationic intermediate in an EAS reaction In lecture we considered para versus meta attack of electrophiles in the EAS reactions of toluene and anisole methoxy benzene We conclude that para attack yields the more stable carbocationic intermediate because the resulting carbocation can be placed directly adjacent to an electron stabilizing group We conclude that electron donating groups EDG s are equivalent to cation stabilizing groups and hence EDG s are orthopara directing groups Lecture 14 mil h ui t y 0 3 H ltx gt C C March 042008 Chemistry 318N Y The Strahan Lectures EAS Chemistry Diazonium Salt Chemistry Order of introduction of substituents to ensure correct orientation in synthesis Multiple substituent effects NAS Benzyne Chemistry Flash Cards 3994 WN Chemistry 318N I Reactions of Diazonium Salts NNOH AZO cumpnund theme 4131 Y Resonance Description of Carbonyl Group 5 5 C II C nucleophiles attack carbon electrophiles attack oxygen Utemixt39y 31m T NomenclatureAldehydes o IUPAC names select as the parent alkane the longest chain of carbon atoms that contains the carbonyl groupsubtract e and add al 7 because the carbonyl group of the aldehyde must be on carbon 1 there is no need to give it a number 0 For unsaturated aldehydes show the presence of the 00 by changing an to en 7 the location of the suf x determines the numbering pattern Chemistry 318N Y NomenclatureAldehydes ll Methane gt Methanal HCH 0 CH3 0 5 4 3 2 1H 4 3J 2 11g CH3CH2CH2CH2CH CH3 HCH2 H Pentane Pentana 3 Methylbutanal o O 3 2 1 7 5 3 1 CH CHdH 2 8 6 4 2 H 2 Pr0penal 2E 37 Dimethyl 26 0ctadienal Acrolein Geranial Chemistry 318N I NomenclatureKetones o IUPAC names select asthe parent alkane the longest chain that contains the carbonyl group numberto give CO the smaller number and then subtract e and add one 7 0 0 CH3 6 o 1 2 3ll4 5 6 CH3CCH3 CH3CH2CCH2CHCH3 5 4 32 Propanone 5 Methyl 3 hexan0ne Bicyclo221 2 Acetone heptanone Chemistry 318N Y IUPAC Nomenclature of Ketones CHscHZCCHZCHZCHs CH3C3HCH200H3 3hexanone CH3 4 methyI2pentanone H30 ltgtO 4methylcyclohexanone Chemistry 318N I IUPAC Nomenclature of Ketones 0 II M CH3C3HCH2CCH3 CH CH CCH CH CH 3 2 2 2 3 CH3 3hexanone 4methyI2pentanone O O CH3CH2CCH2CH2CH3 O ethyl propyl ketone 4oxohexanal Chemistry318N Y Order of Precedence Pecking order 0 For compounds that contain more than one functional group indicated by a suffix Functional Suf x iingher Pre x if Lower Group in Precedence in Precedence CO 2 H 0ic acid 2 CH0 al 0x0 CO 0ne 0X0 E OH 0 hydroxy 39NH 2 amine amino SH thiol mercapto Chemistry 318N I Trivial Nomenclature of Ketones o o CH300H20H3 CH200H20H3 Methyl ethyl ketone benzyl ethyl ketone divinyl ketone Chemistry 318N Y HZCCHCCHCH2 Many aldehydes and ketones occur naturally O 0 MA 2 heptanone trans2 hexenal component of alarm alarm pheromone pheromone of bees of myrmicine ant OH i Testosterone I Synthesis of Aldehydes and Ketones A numberof 0 from alkenes reactions already b 0201101 sis 236 studied provide y y p efficient synthetic from alkynes routes to aldehydes and by hydratlon V1a enol ketones from arenes 0 Via FnedelCrafts acylation Chemistry 318N Y Reaction Theme 0 The most common reaction of a carbonyl group is addition of a nucleophile to form a tetrahedral addition compound R 02 39 A NUZ39COZ gt Nu C so I R l R R Tetrahedral carbonyl addition compound Chemistry 318N Y Reaction Theme 0 A second common reaction is with a proton or Lewis acid to form a resonancestablllzed catlon R coH B39 R Here it is a base or Nucleophile E 7 protonation increases the electron de ciency of the carbonyl carbon and makes it more reactive toward nucleophiles Chemistry 318N Y Carbon Nucleophiles Addition of carbon nucleophiles is one ofthe most important types of nucleophilic additions to a 00 group a new carboncarbon bond is formed in the process RMgX RLi RCacg39 39gCENg A Grignard An organolithium An anion of a Cyanide reagent eagent terminal alkyne ion We will study the addition ofthese carbon nucleophiles Chemistry 318N I Victor Grignard Shara l Nnhd mi1mquot nf Prize with Phipr 2 Barbie Szhz er in 1912 WM 315 Y Grignard Reagents 0 Given the diiference in electronegativity etween carbon and magnesium the CMg bond is polar covalent with c 5 and Mg 7 Grignard reagean behave like a carbanions Carbanion an anion in which carbon has an unshared pair ofelectrons and bears a negative eha e e a rarhaninns are guudnudeuphiles and add ef cientlyth the rarhnnyi gnup ufaldehydes and ketnnes amen 31m 1 Grignard Reagents 0 Addition of a Grignard reagent to formaldehyde followed by H3O gives a 1 alcohol CH3CH239 MgBr H H l V Q 4r CH3CH2C70 MgBrJr amp CHECHf iOH Jng2 THF dil H 39 H O o This sequence mechanism is general and important Chemistry 318N Y Grignard Reagents 0 Addition to any other RCHO gives 3 2 alcohol l 7 CH30H2 c 3 4 CH20H2 O M8133 41130 CH3CHzr C OH MgZ m an H H H You may change decorations at will read pages 568580 7 but be careful of acidic functions like OH Chemistry 318N E Grignard Reagents 0 Addition to CO2 gives a carboxylic acid CH3CHZ39 Q I CH3CH2 C O MgBr LO CH3CHZecioH MgZ dil H H O 39 O o This is a great way to add a carbon Chemistry 318N i Grignard Reagents 0 Addition to a ketone gives a 3 alcohol it is 11 sz Hz sz CHKCHZ39MSBS 70 TE CchHz jio MgBr H29 CHZCHZOH Mg CH3 CH3 0 11 CH3 0 Please try this with other Grignard reagents and other ketones Chemistry 318N I Grignard Reactions 1 t I r 2 CHKCHZ39MgBF Cg gt CHzCHzf O MsBr CH3CHZ C OH Mg H IHF H dil 1I i 7 mfg MgBr H30 CHKCHrcioH M Z r a CHKCHrCiO CHKCHZ M T H H sz EH3 IIH 39sz Hz 39sz CH2 CH2 CH2 I Z CHKCHZ39MSB IQ gt CchHz C O MgBr CH3CH23 0H Mg CH3 CH3 0 11 CH3 Chemistry 318N Y Grignard Reagents Problem 2 phenyI 2 butanol can be synthesized by three different combinations of a Grignard reagent and a ketone Show each combination OH i39 CH3 Chemistry 318N Y Grignard Reactions CH3CHZ39 Q TE CchchiO MgBrJr CH3CH27C70H MgZ dil H H O O MgBr a 01 I B H 0 0H 0 gt 3 THF Dilute These are valuable and important reactions Please add to your card stock Chemistry 318N Y Grignard reagents react with esters R39 5 90H3 dIethyI u 8 ll ether R CIZ QCH3 ng o o ng but species formed is unstable and dissociates under the reaction conditions to form a ketone Chemistry 318N E Grignard reagents react with esters R39 5 90H3 dIethyI I H 8 T ether R CII QCHs ng o O ng this ketone then goes CH3OMgX on to react with a second mole of the R R39 Grlgnard reagent to C give a tertiary alcohol quot Chemistry 318N Y Example 0 ZCHsMgBr CH32CHCOCH3 1 diethyl ether 2 H30 Two of the groups IDH attached to the tertiary carbon CH CHCCH 32 l 3 come from the CH3 Grignard reagent Chemistry 318N Y Grignard reagents react with formaldehyde to give primary alcohols aldehydes to give secondary alcohols ketones to give tertiary alcohols esters to give tertiary alcohols CO2 to give acids epoxides give primary alcohols Chemistry 318N Y Coupling Reactions 7 CH3CH2MgBr CH3I CH3CH2 CH3 0 Copper catalyzes this coupling reaction 0 But there is a better way Chemistry 318N I Gilman Reagent Lithium diorganocopper Reagents Preparation of Gilman Reagents M01 2Li Li LiCl 1 Chlor0butane Butyllithium 2IH73H21H2CHLi 2111 F cnnjugcngtHggctr Li Lil Butyliithium Copper Lithium dibutylcoppcr iodide 21 Gilman reagent Ch emistry 31 8N 39 Coupling Reactions CoreyHouse coupling Gilman reagent R CuLi R X R R RCu LiX R This works well with certain limitations Ch emistry 31 8N I ALKYLATION WITH R2CuLi CoreyHouse Reaction EXAMPLES CH3ZCuLi CH3CH24l gt CH3CH24CH3 C8H17 C8H17 CH3CH2CH2CH22CuLi gt H Br H C4H9 Chemixtry 318N I Lithium dialkylcopper Gilman reagents mz dxzc uh CH3CH2SCHZI E53 CH3CH2BCH2C IL Lil c pu Lithium 1Iododecane Undecane 90 dimethxlco aer quot39C7Hls H nC7HL5 H 00 71 1 1 J1VULI gt 00 uy llw39u L11 H I H C Hhn 39ranslIodolnonene transSTridecene 71 I CH g ICI39LAgCuLj gt 0 139LCu Lil Iodobenzene Toluene 91 17 Gilman Reagents coupling with a Vinylic halide is stereospecific the configuration of the carboncarbon double bond is retained transl Iodo l nonene lithium dibutylcopper W dieth ether vtcu Y 2 orTHF 0C bond transS Tridecen e Chemistry 318N Y Substrates for Gilman Reagents o The most common substrate for an organocuparate is a primary alkyl halide usually an iodide 0 Secondary and tertiary halides undergo elimination Via the famous E2 reaction that you studied CH3CuLi ICH2CH28CH3 gt CH3CH2CH28CH3 6H52Licu ICH2CH24CH3 gt C HSCH2CH24CH3 Chankny31ampV I Salts of Terminal Alkynes o Addition of an acetylide anion followed by H30 gives an oc acetylenic alcohol 1 11 12 IHZ IHZ EH2 CHZ CH2 CHZ r m 7 l r H 0 l RCEC Na go Igt RCC4CO Na 34gt RCEC OH Na l THF l d l CH3 CH3 CH3 Chemistry 318N Y Salts of Terminal Alkynes 0 H20 HO ECH3 lgt H 2 S O 4 H g 504 6 H 0 CE C H i an a hydroxyketone O X HO CH zl H 2 H202 NaOH 3 B hydroxyaldehyde See pages 274279 Chemistry 318N 39 318N Krische Lecture 1 Tu 012009 Course Introduction amp Aldehydes and Ketones Today we go over the course syllabus with attention to exam dates course policies and other administrative items Please note that 1H 13C NMR and IR spectroscopy were covered in Professor Krische s section of 318M last semester If you were not in Professor Krische s section of 318M last semester or have not been exposed to these topics you should reconsider enrollment in this course We now begin the chapters covering aldehydes and ketones Structure begets reactivity CO double bond is polarized such that the oxygen bears a partial negative charge and the carbon bears a partial positive charge This naturally follows from the electronegativities of carbon and oxygen the latter being more electronegative The polaritydipole of the CO double bond is re ected by a zwitterionic resonance structure In accordance with the polarization of the CO double bond electrophiles react at oxygen and nucleophiles react at carbon From the standpoint of mechanism it is important to recognize that in reactions with electrophiles Bronsted acids or Lewis acids oxygen reacts using its lone pairs not the CO pibond Based on our understanding of the structure of the carbonyl group we began to explore its reactivity with oxygen nucleophiles Speci cally acid catalyzed hydration was discussed and a comparison was made with the reactivity of alkenes under similar conditions It was shown that protonation activates the carbonyl group as an electrophile rendering it highly susceptible to nucleophilic addition This activation is manifested by an increase in the C0 bond length of the carbonyl group upon protonation ie 120 angstroms vs 127 angstroms This is substantial considering a normal CO single bond has a length of 143 angstroms This lengthening re ects the contribution of the nonoctet resonance structure of the protonated carbonyl We observed that formaldehyde hydrates more readily than acetaldehyde and that acetaldehyde hydrates more readily than acetone These effects were rationalized on the basis of steric and Lecture 23 The Aldol Condensation 11 H O O O OH39 A 4 H 39 H H OH ril 10 2008 Chemistry 315w Y The Aldol Reaction 0 The product of an aldol reaction is a Bhydroxyaldehyde nucleophilic acyl substitution is not possibe here why 0 H O OH 0 I M NaOH Bl a H CH3 CH CH2 CH CH3 CHCH 2 CH Ethanal Ethanal 3Hydr0xybutanal Acetaldehyde Acetaldehyde a 3hydr0xya1dehyde Aldol Aldehyde Alcohol Chemistry 318N Y Loss of water Aldol products are ver easily dehydrated so the major product is an LBunsaturated aldehyde or ketone 39OH H H O H O I l gt CH C d C CH C C C 3 3 K H I H H H H H 39OH H OH An 13 aldehyde Chemistry 318N Y From what H3Cmn H ch H 0 Chemistry 318N E Crossed Aldol Reactions 0 In a crossed aldol reaction one kind of molecule provides the enolate anion and another kind provides the carbonyl group 0 ii CH 3CHZCH CH3CHCH2CH HO39 CH3 In most cases this makes a big fat mess Ch emixtry 31 81V The Crossed Aldol Reaction EH r 0 A CH3CH2CH IHCH n CH3 0 Ho 5 l u CH3CHCHZCHCHCH quot20 I H3 H3 CH3 CH CHgCHzCH CH3 IHCHZCH on c A B CH3 Ho CH3CH2CH7C HCH quot2 J A C HCH3 CHgCHgHCH CH3 33 a l u CHgflmHgCHi iHCII CH3 CHCH3 CH3 Crossed Aldol Reactions 0 Crossed aldol reactions only work if 7 one of the reactants has no Xhydrogen and therefore cannot form an enolate anion and 7 the other reactant has a very reactive carbonyl group namely an aldehyde 0 O o o 39 l H H O SH 0L 3H CH 33 CCH F dziyge Benzaldehyde Furfural 22Dimethyl propanal Look no othydrogens so no enolate anions Chemistry 318N Y From What Chemistry 318N I Let s Discuss a Plan for actually Running a Crossed Aldol Reaction Does the addition sequence matter What goes into the pot first second and third Chemistry 318N Y Directed Aldol Reactions 0 Kinetic vs thermodynamic control when alkali metal hydroxides or alkoxides are used as bases the position of equilibrium for formation of enolate anions favors reactants o II 393 Na CH3 CCH3 NaOH Ke 5 x10 5 1 CH CCH H o pKa 20 weaker 2 3 2 weaker base stronger pKSI 157 acid base stgiigfr Chemistry 318N I Directed Aldol Reactions 0 With a super strong base however the formation of enolate anion can be driven to the right 0 lithium diisopropylamide LDA a very strong base but because of crowding around nitrogen is a poor nucleophile H3C CH CH3 n N CH3 CH CH3 Chemistry 318N Y Directed Aldol Reactions 0 LDA is prepared by treatment of diisopropylamine with butyllithium K 1010 CH 3ZCH 2NH CH3CH23Li m gt Diisopropylamine Butyllithium p stronger base stronger acid CH 3ZCH 2 N39 Ll CH3CH 2ZCH3 Lithium diisopropyl Butane amide LDA pKa 50 weaker base weaker acid Chemistry 318N E Using LDA to Form an Enolate O 0 HU H20 pKa17 lto1 pKa157 O Oquot b LDA a 6 DIA pKa17 400 pKa35 Ch emistiy 31 8N I Directed Aldol Reactions 0 With 1 mol of LDA an aldehyde ketone 0r ester can be converted completely to its enolate anion 039 Li Ke 1020 A Hach5 CH 3ZCH2N39Li gtCH2 CH3 CH 3ZCH2NH pKz 20 LDA A lithium enolate stronger acid stronger base weaker base weaker acid Ch emistiy 31 8N l Enolate Anions a When a ketone has two different ochydrogens is formation of the enolate anion regioselective o The answer depends on experimental conditions when a slight excess of LDA a ketone is converted to its lithium enolate anion which consists almost entirely of the less substituted enolate anion this reaction is said to be under kinetic control Chemistry 318N Y Kinetic Control with slight excess of LDA o slight eltcess 0 Li 0 Li j LEA L 6 6 iPr 2 NH 2Methyl 99 1 cyclohexanone I fastest but least stable Chemistry 318N I Thermodynamic Control With slight excess of ketone o lght excess 0 Li 0 Li i ET Cr 10 90 Slow but I1 ost Stable Chemistry 318N Y Kinetic Control 0 When a reaction is under kinetic control the composition of the product mixture is determined by the relative rates of formation of each product Thermodynamic Control 0 When a reaction is under thermodynamic control the composition of the product mixture is determined by the relative stabilities of each product Chemistry 318N Y a Deprotonation of Carbonyl Compounds by Lithium Dialkylamides Chemistry 318N Y Deprotonation of Simple Esters oEthyl acetoacetate pKa 11 and diethyl malonate pKa 13 are completely deprotonated by alkoxide bases oSimple esters such as ethyl acetate are not completely deprotonated the enolate reacts with the original ester and Claisen condensation occurs oAre there bases strong enough to completely deprotonate simple esters giving ester enolates quantitatively ChemimymN Y Lithium diisopropylamide LDA oLithium diisopropylamide converts simple esters to the corresponding enolate o CHscHZCHZCOCHs LiNCHCH322 pKa22 o CHscHzEDHCOCHs HNCHCH322 Li pKa 36 Chemistry318N Y Lithium diisopropylamide LDA oEnolates generated from esters and LDA can be alkylated CHscHZCHCIIOCHs lech3 O CHSCH2I 92 CHscHz HgOCHs Chemistry 318N I Practice Exercises show how the following compounds could be synthesized by a path that Includes an aldol or mixed aldol condensation Chemistry 318N Y From what HHHHCHS CH3 0 H3O H H3O CH3 Chemistry 318N E Make starting with ethyl acetate or diethyl malonate and anything else Help 5 Chemistry 318N Y Nucleophiic Addition to a Unsaturated Aldehydes and Ketones 012addition direct addition nucleophile attacks carbon of CO 014addition conjugate addition nucleophile attacks Bcarbon Chemistry 318N I Kinetic versus Thermodynamic Control 0 attack is faster at CO Kinetic Product 0 attack at 3carbon gives the more stable product Therniodynamic Product Chemistry 318N Y formed faster H O 0 major product under C Y conditions of kinetic control ie when C C addition is not readily reversible Chemistry 318N I 14addition o enol H O 0 goes to keto form c under reaction YC conditions C Chemistry 318N Y O C 14addition o keto form is isolated 0 product of 14addition C o is more stable than 12 addition product Y C C H Chemistry 318N I Chemgttry 318N Y Nucleophiic Addition to a Unsaturated Aldehydes and Ketones 012addition direct addition nucleophile attacks carbon of CO 014addition conjugate addition nucleophile attacks Bcarbon Chemistry 318N I 1 2 A ddition 0 observed with strongly basic nucleophiles Grignard reagents LiA1H4 NaBH4 Sodium acetylide a strongly basic nucleophiles add 12 amp irreversibly Chemistry 318N Y Example 0 CHSCHCHCH HCECMgBr 1 THF 2 H30 OH CH30HCHCHCECH Chemistry 318N I 14Addiz ion or quotconjugate Addition 0 observed with Laid basic nucleophiles cyar1ide ion CN thiolate ions RS ammonia and amines azide ion N 3 a weakly basic nucleophiles add 14 amp reversibly Chemistry 318N Y Example C6HSCHCHCC6H5 KCN ethanol acetic acid H C6H5C3HCHzCC6H5 CN Chemistry 318N Y Example C6HSCHCHCC6H5 KCN ethanol acetic acid H C6H5C3HCH2006H5 CN Chemistry 318N Example CH3 CBH5CHZSH HO H20 0 CH3 SCHzC6H5


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