ORGANIC CHEMISTRY I
ORGANIC CHEMISTRY I CHEM 333
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chapter 8 Alkyl Halides amp Radical Rx s Structure Nomenclature Physical Properties Halogenation of Alkanes Mechanism of Halogenation Q Allylic Halogenation Note the Chapter Summary and Key Rx s 81 Structure of RX haloalkane RX H3CCl haloalkene sp3 C haloarene alkyl halide X sp2 aryl halide a vinyl halide 81 Structure of RX Haloalkane alkyl halide sp3 R X 3 halide R R i H3CCl methyl chloride H l 2 halide R tf R39 x 39i 1 halide R 2 H X 82 Nomenclature IUPAC halides X are substituents Substituent names halo fluoro chloro bromo iodo haloalkane Br haocycloalkane Cl R4bromo1choro4fuoro1cyclopentene structure Common Names alkyl halide or special names isopropyl bromide vs 2bromopropane r H3C 39 CH3 H chloroform vs trichloromethane 83 Physical Properties polar covalent bond dipole mismatch of electronegativity 84 Halogenation of Alkanes u a 0 o C i H c C u 5 H3C 3 39 H3C H hv H3C 39 substitution of X for H hv ultraviolet light A heat seldom F2 too reactive exothermic or 2 endothermic unreactive Substitution productsand byproducts H A quot H H other RX s gt0r quot7 M quot6 hv Generally halogenation not useful mixtures separate A few rx s are useful eg A Q Br2 gt Br HBr other Br39s Others allylic amp benzylic Substitution products and byproducts monobromination h H3C CH3 Br2 v gt H3C CHZBr HBr diBr etc 9H3 9H3 9 9H2 Br2 gt BrC H Hl3H HBr diBr 33 CHzBr 92 8 9H3 39 CICH3 HBr d1Br H Br bromination favors 30 gt 20 gt 1 initiation 39 propagation H3C Br Br H30 H H o V39gr H 0 Br termlnatlons 3 C39 quot 3 clt H3C H H3C H andor m n 0 gBur andor C H3 H H o 3 HsCC39 H gt C CH3 C CH3 H3C CI CH3 J H CH3 H 8E A Ahmv i i lt wol 0 oo 6 0 nzw EmeEo hm I m1 Lm wIl I mI hmuzw 26 0 as A3 EA o a A ON A om 5 2386863 520 ES m Em 5 35 5 20 Selectivity 30 gt 20 gt 1 but Cl and Br are different CH3 CH3 H20 A quot392C HX other R X I X2 gt I C H3C E CH3 H3CI CH3 major monoX product 30 20 1 Br2 1600 80 1 cr2 5 4 1 Cl39 more reactive less selective than Br39 Hammond s Postulate Cl vs Br Hammond s Postulate the structure of the transition state for an exothermic reaction looks more like the reactants of that step for an endothermic reaction looks more like the products of that step Hammond s Postulate In halogenation of an alkane the ratelimiting step is hydrogen abstraction this step is endothermic for bromination and exothermic for Chlorination AHO Ugcalnmol CH3 CH239H Br gt OHS CH2 HBr 98 88 10 CHE CH2H 0 gt CH3 CH2 93 103 5 Hammond s Postulate For chlorination hydrogen abstraction is exothermic transition state resembles the alkane and chlorine atom little radical character on carbon in ts regioselectivity only slightly influenced by radical stability early tS like SII H CI R C H site of collision important SM prog rX PrOd R late tS H Br T R l H stability of R important Halogenation free radical substitution H Br 6 HBr Allyl Radical resonance H Br H B H2C Cc r2 H2C CC H l H A l H H H Hzc gEQSHz H2CC CH2 NBS for Br2 H H initially O with progress rx NBr g 0 NBS for Br2 O A 33 N 3 Bl o O O H H C H C H H Free Radical Stability H H H vgH CH CH CH D 4 lt gtC lt gt Free Radical Stability allylic X benzyhc I I H I 39 v 39 39 H i Ii 4 H y CHz f Radical ADDITION note rx conditions Add HX in the presence of peroxides w H X reverses normal addition Roo X H antiMarkovnikov Markovnikov m normal m3 Radies ADDHTIQN Here rx eerrdirierrs Add HX in the presence of perexides w HX reverses normal additien Roo X H antiMarkevnikev X C Br I RQJ Q lq R0 OR m RO39 HEX quotquot quot39gt RO H 39X Chapter 15 Organometallic Compounds RM Organomagnesium amp Organolithium compds 151 H H H C39H quotE IC HHHH B M Lithium Diorganocopper Gilman Reagents 152 Not covered Organopalladium reagents Heck reaction carbenes carbenoids amp alkene metathesis Synthesis Concepts and the Final Prep of Organometallic Compounds Grignard organomagnesium compound th I39I3Cc r Mg0 e E H3CCJV939Br H2 H2 H3C r ether C gt M covalent H2 pzMg and free radical like ionic View Prep of Organometallic Compounds Grignard H3C Br Mgo 12 H3ccMgBr 2 H2 Alkyllithium ether H3CCH2CH2Br2LI gt H3CCH2CH2Li LiBr HOW does one make the anion 0f butane H H H xi C CKBr HRH H H H Use baseE2 or Nu 8N2 M H 6 LI HOU gt HRTKLIEEH H H H B Rxs protic compounds acids 7 6fr HO CH3 c gt H C H H H3C MgBr H 3 5H3 CH3 6 6 H IMgCHZCH3 c 4 gt 39 6 MgI H C 839 3 H 39 u H H3C IC Li N gt H3Cc Ll N Hsc H H3C H Prep 0f R M Nu M alkyl halide sp3 metal But also vinyl halide spz metal aryl halide spz metal eg Grignard 0r organomagnesium reagent x 6 6 M90 ether IVIQX metal Lithium Diorganocopper Reagents Prep and use in Synthesis RLi Cu R2CuLi Lil 39ether39 Clquot gt similar Grignard reagent can be made 39ether39 2CH3Mgl Cul CH32CuMgl Mgl2 Use substitution rx replace halides Grignards and alkyllithiums can be nucleophiles TH F HH20 neut m cuprates are better Use Substitution replace leaving group OCH3 LICU Br OCH3 HH2O ether new CuMgBr Jyj 39ether39 HH2O add 2 neut elrmmate R39 RI CuLi l th H add MM 6 61 neut eliminate not really 8N2 ignore mechanism 2nd semester ltgt THF HH20 gt gt neut Primary site inverted secondary unchanged Organometallic Compounds 15 Better Do 4 1 ether 2 HH2O Jr neut WECuMgX earlier RMgX 0r RLi 1 ether 2 HH20 neuD Nucleophilic RXS 6 MgX 1ether xf a gt OH 2 HH20 neut SYNTHESIS Propose how to convert starting material m to a target rules Use any number of steps For each step show necessary reagents necessary conditions expected product or products SYNTHESIS Cornpare functional groups and carbon skeleton starting material y N c 6 Need 1 carbon CN and ketone nitrile from ole n SYNTHESIS retroanalysis SYNTHESIS retroanalysis OH O 13r 2 J PCC BE A N 0 SM H20 6 RCO3H H PCC target synthesi How 39 thoughts join expected byproduct H20 p i O O O skeleton nal groups convert 2 bromopropene to 2 hexanone co skeleton misnal groups Chapter 6 61 Alkenes ll 1 Types of Rxn elimination addition substitution 2 Mechanisms How rxn s of molecules occur 3 Electrophilic Markovnikov addition ddition oft X iegioselective inductive effects most stable R R30 gt RQHC gt RHQC gt H30 B Hydration H HQO C Reariangeinents D Biomoniurn ions anti addition E Halonydiin formation anti F H39nydiation Hg lnydiation 7 anti 4 Hydroboration syn addition 5 Oxidation syn 6 Reduction syn ole n and diene stability 7 Reactions relative to stereocenters Addition Reaction What is a rx starting material products H conditions Reaction Agt B Reaction Mechanism how Reaction mechanism describes hOW a reaction occurs which bonds brokenformed Three Classes of Reaction 1 Addition increase in atoms bonded at 2 adjacent carbons 2 Elimination decrease in atoms bonded at 2 adjacent atoms 3 Substitution replace 1 groupatom by another Rxn s of Alkenes additions to the CC break 111 form 20 bonds Table 61 Electrophilic Additions Hydrohalogenation Hydration Halogenation Halohydrination Oxymercu ration Hydroboration Diol formation oxidation Hydrogenation etc 61 E Dlagams graph showing the changes in energy during a reaction potential energy reaction coordinate progress of reaction starting products materials activation energy Ea heat of reaction energy given off reaction coordinate A XY AX Y starting materials products 6 transition state t an energy maximum believed to be formed unstable species of maximum energy transition state cz x 4 activation energy heat of reaction energy absorbed products CZ X reaction coordinate PE diagrams intermediates energy minima between intermediate tl an me m gt gattaem 112 m ame t m C6 I o C 1 prod ucts reaction coordinate PE diagrams large Ea few collisions slow reactions small Ea fast rx 6 I o c heat of reaction p rod ucts reaction coordinate A Addition of HCI HBr H H H H 39 CI HlC H HCI gt Hq CH CH3 CH3 MAJOR Markovnikov s rule H electrophile to carbon with most H s less substituted carbon regioselective explain next Electrophilic Additions Ft any alkyl group ie methyl ethyl etc primary 1 secondary H 20 tertiary 30 61 Mechanism of Electrophilic Addition Base is CC functional group H E electrophile is acids base J39ISSYStem H H f gt H I H lie carbocatlon H3C C H H3c H R E others later Carbocation trigonal1200sp2 Lewis base Lewis acid H w 6 I E gt 169 H3C Cl39 H3C H Carbocation Lewis base Lewis acid H j I E gt quotlt9 H3C CH H3C How Regioselective 61 Which intermediate carbocation is easier to form Why Regioselective 61 Which intermediate carbocation is easier to form ts1 Products Alkyl groups slightly electron donating stabilize charge H H ILltH H G ClH no alkylgps C H I H 1 alkyl gp 1o B Addition of H20 AcidCatalyzed Hydration of Alkenes H H H I H HO H H ll H20 H2804 CH3 CH3 1 Catalyst HZSO4 or H3PO4 2 H adds to least substituted end of alkene 3 39OH adds to more substituted end regioselective Hydration Addition of H20 HX addition H H H Rx H H HO H ll H20 H2504 H3 CH3 CH3 9 H H O H Mechanism H Q Qg aCId base H H O H H o H transfer H I H H GD IH H gt HE IcH u product I CH3 Why regioselective H H Pkgl 1 H Jl 3 v H 47 H H H H 339 Slow or rate determining highest Ea s Selective for 20 R over 10 R R30 gt R2CH gt RCH2 gt CH3 halogenation hallohydration hydration rearrangements mercury hydration hydrolboration other additions 61 number of regioisomersstereoisomers examples 10 OltOH 10 H proton from H2804 H3PO4 HClO4 etc or H3O 14 OH HO Dom 6 284 each C carbocation characteristic rearrangements oo H 39 H H3C c H major normal and rearranged product I l I o I l H H 20 R mechanism C carbocation characteristic rearrangements o o H 39 Imp H H Hs y H H 5 H H3C 9 9 Groups H alkyl etc adjacent to Ccan migrate with 93 if forms a more stable carbocation R normal rearranged H c39 H H c I 392 H 3 C C H3C H Ce 939 H mech H migration H3CCC H C H H3CC9c H H3C H H H3C Hydration Rearrangements can occur R mechanism E Rearrangements problems in the book and a web worksheet 0 Hydration Rearrangements can occur R 61 H3C H H so quot39 II3C IC C H 2 4 Hscl CLH H0H3C VlI C o Hsc CC H3C CC I HC 3 H H H H3c I4OH H3C ILI H D Bromination amp Chlorination F2 too reactive I2 poor to OK Br o o Br Br gt hi anti addition Antiaddition H H H3CCC H3C C H H mechanism then stereochemistry BrBI has very weak bond Nu BrCBr gt Nu Br Antiaddition 61 H H H gt C H B H C CBr H Notice 1 No stereochemistry Anti Addition Stereoohemistry O I O I Br0 39 Br Br gt 39 H O I v H H X Bro H 1 o C Es 396 3r394H H transdiaxial addition stereospecific bromonium ion controls anti addition halohydration mercury hydration hydm bomugn other additions Issues Why selective for 20 alcohol vs 10 me 7 ll E a ON EB wg gi A BE doN E Chapter 4 Acid Base Chemistry439 Br nstedLowry and Lewis AcidsBases Acid Dissociation Constants pKa the Relative strength of Acids and Bases electron pushing arrows electronic view rxs Equilibrium in AcidBase Reactions H c03i H Molecular structure and acidity H30 periodicity electronegativity amp size of atom Q H H c8 0 hybridization Inductive effects resonance Hsc See the Chapter Summary H 3 H CH H T GIVEH 0amp3 H3O 14 t t H Chapter 4 strut QCI HEQQCTH cal QZ ch mm tr 4 quotCH3 6 H I EH3 Q0 9 acidbase strength general Bronsted Lowry Lewis AcidBase structure effects on acidity b6b7 4 gtjl road trip started 0 Br NucAnionic OH R th d t H 1 0 er pro uc HO 2 other product gt structure effects on acidity Arrhenius Acids and Bases acid substance that produces H3O ions aqueous solution Haq H20l gt H3Oaq hydronium ion base substance that produces OH39 ions in aqueous solution KOH E K 39OHaq BronstedLowry Definitions Acid a proton donor Base a proton acceptor 0 O O H IDSH o H Conjugate Acids amp Bases BryanstedLowry does not require water only H transfer conjugate acidbase pair conjugate acidbase pair I W o O O CH3 C NH3 CH3C 39 H NH3 o H 39 Pi Electrons As Basic Sites pi electrons base donate a pair of e39s H3C H c 0 6 Q33quot l quotI Br c H3C H Result formation of a carbocation C has 6e39s 1charge Lewis Acids and Bases Lewis acid moleculeion that accepts a pair of electrons Lewis base moleculeion that donates a pair of electrons e e AOB gt A B forms a new covalent bond Lewis Acids and Bases H c H examples 3 cLH e I 39Br 0 H3CH carbocations very strong Lewis acid gmgrag Bmms gd LQWw ng g Agmdmag acidbase strength Sirwmwe ag s m a d y Acids amp Base Strengths How is acid base strength expressedcompared By equilibrium constant eg dissociation ionization of acetic acid 0Q quotO Hlt IH 1939 H I H3C 3 l H3c c 093 H3OA HAHHZO H30A39 Ka KeqHZO HA pKa log Ka Weaker acid Acid Ethane Ethylene Ammonia Hydrogen Acetylene Ethanol Water Methylammonium ion Bicarbonate ion Phenol Ammonium ion Hydrogen sul de Carbonic acid Acetic acid Benzoic acid Formula CH3CH3 CH2CH2 NH3 H2 HCECH CH3CH20H H20 CH3NH3 HCO3 C5H5OH NH4 H25 H2C03 CH3COOH C5H5COOH Conjugate Base CH3CH239 Stronger CH2CH39 conjugate base NH2 H HCEC CH3CH20 HO CH3NH2 C032 C5H5O NH3 HS HC03 CH3COO C5H5 COO Phosphoric acid Eg mn nmmm H2P04 u 9 AcidBase Equilibria What favors the direction of acid base reactions Strong acid completely to products Weak incomplete gives an Equilibrium direction favors reaction of stronger acidbase pair 0 9 H O H CH3 C N H 39 H NTH CH3 c H e acetate ion ammonium pKa 924 AcidBase Equilibria acetic acid sodium bicarbonate omit Na MN M g xxquot structure effects on acidity AcidBase Theories BronstedLowry acidproton donor baseproton acceptor H3Cc H H3CcH HEB gt I H c HscCBH Lewis acidaccept pair electrons basedonate pair electrons H3C H lt H gt H3Cc1 I r How does Structure effect Acidity relative acidities the more A39l stable greater the acidity of HA 000 H O o G H CH3 c Dir H T o HN H AH B A39 HBquot39 Ways to stabilize A39 the negative charge ON a more electronegative atom ON larger atom RESONANCE delocalized STABILIZED by inductive effect lN an orbital with more 3 character electronegativity within a period the greater the electronegativity of A39 the more A39 is stablized the stronger the acid incerasing acidity Acid Conjugate base H3C39OH CH3 09 CH3 N H H H pKa 51 chcgH CH3 2 H H H3CNH H pKa 38 1ncreasm ac1o 1t Size Of A39 Within a column the larger the atom bearing the the greater its stability H3CSH alts g ms 39339 H3c 6 H PKa 70 pKa 16 inductive effect electronwithdrawing covalent bonds transmit electronegativity polarizing effects push or pull shared el39ls of adjacent atoms pKa 159 124 146 154 H I I F Ii 390 F H III 0 F H H III on H c c g F c c gi F c c c d F C C C CQ H H I H l I l H H H lt F H F H H F H H H if B 8 decreases w distance H H F H l 39 quot H CC OCTgt F QtsQ O n quot H H F H inductive effect butanoic and chlorobutanoic acids 0 0 CI 0 pKa 482 pKa 452 pKa 398 Hybridization greater the 8 character with the more stable the anion Weak Eonjugate Acid Base pKa sCharacter 9 HCECH HCC 25 50 U H H H 9 a 99 CC 39 44 33 g0 H H H H a HH C C39HH HH C 6 g 39 7 quott 39 7 25 0 U H H H H 51 7 E HOH water HOquot 157 Conjugate Acids amp Bases curved arrows show the flow of electrons in an acidbase reaction H 0 CH3 39NilH CHs Q o 0 H 00 acetate ion ammonium recall resonance also uses curved arrows n Resonance delocalized of charge on Al Compare alcohol and carboxylic acid acidity resonance stabilization ofAi39 Use of resonance theory molecules may have 2 or more sites that can accept a H eg carboxylic acids esters and amides protonation favored where the charge is more delocalized which oxygen is protonated 390 H 39 Hsc C lacsosHgtH3c c OR H3C C 0quot 0 H 0 C a Use of resonance theory resonance O H 39 octets greater quot3C Co contribution even 39 H with plus charge on O I Q H Use of resonance theory OH H on the hydroxyl To 3 quot39 H on the ea 9 quot39 carbonyl 0 gquot H 39 Hsc C H2304 gt Hsc C o39 o 39 H H can write contributing structures create amp separate charge I Chapter 10 Alcohols amp Thiols Sources Structure Nomenclature Properties Acidity and Basicity Rx with active metals Conversion to RX inorganic acid halides Rxs with HX SN1ISN2 sulfonates Dehydration of alcohols Oxidation of 10 and 2 alcohols Oxidation of glycols Pinacol amp ThioIsSulfur chemistry skip 6 31 5534 Preparation of alcohols review 1 HgOAc2HZO 2 NaBH4 4113 gt HHZO OH 1 BH3 2 H202 39OH gt H039 or i H20 H2 Met cat e g Pt 1 OsO4HZO OR 2 KMnO439OHcold Structure Alcohols Alcohol functional group OH group bonded to an sp3 bond angles 1095 hybridized NomenclatureAlcohols IUPAC names Longest chain that contains the OH root Give OH group lowest number Change suffix e to o S2methy1butano HC H OH oH H3C CH3 H Nomenclature of Alcohols Unsaturated alcohols The double bond becomes infix en The hydroxyl group is the suffix o numbering give OH the lower number H HQ H I s H3C 9C C i R CH3 HHH SE4hexen2o Physical Properties Hydrogen bonding H bonded to an electronegative atom F O or N etc HI Hydrogen bond weak 5 kcalmol But have significant effects on properties and reactions 7 Physical Properties ethanol amp dimethyl ether constitutional isomers but weak hydrogen bonds amp dipoledipole interactions have dramatic effects CH3CH20H CH30CH3 bp 78 C bp 24 C hydrogen bonds no hydrogen bonds Acidity of Alcohols alcohols weak acids CH3 conjugate bases strong r Acidity of Alcohols Compound Formula pKa hydrogen chloride H CI 7 Strof dger acI acetic acid C H3 C02 H 48 RSH 85 methanol CH3 OH 155 water H2 0 1 57 ethanol CH3 CHZOH 159 2 ro anol CH CHOH 1 7 p p 3 2 Weaker 2 methyI 2 propanol CH3 3COH 1 8 aCid Acidity of Alcohols Acidity oc on stabilization and solvation R H o C 39 39 m 1 8x J H R electron donation destabiize alkoxides lt1 H m Hue 63 C 9 H 0 I 3r 1 O H R R U c decreases solvation r 7 Basicity of Alcohols H39 0 H X H3CC 39 HquotCH3 H O H HstQ 6 H CH3 like water Lewis base Reaction with Metals Alcohols Li Na K active metals form metal alkoxides 2CH30H 2N3 gt 2CH30 Na H2 metal alkoxide sodium methoxide Reaction with Metals H3CH2C O H MgO gt H3CHzc Q Mg H2 2 H C 3C H Ko gt H3C K H2 H3C HBC CH3 quot0 Na gt HH sodium cyCohexoxide Conversion to RX with HX 3 alcohols react very rapidly with HCI HBr HI OH 0 C Cl 0 HCI T O H20 CH3 e H CH3 Lowmolecularweight 1 alcohols are unreactive under these conditions good leaving group 1o RX with HX 5N2 X diSplace 0H2 Reaction with SOCI2 1 and 2 alcohols OH gt IIIIICI pyridine o g 0 HC Write mech With amine stereoselective Reaction with PBr3 PBI39Z Good leaving group sulfonic acid a very strong acid a very weak base reactions acid base active metal sources nomenclature properties substitution oxidation alkyl sulfonates CHZCH3 CO Q R HCl gt pyridine H O sulfonyl H3C chloride 8 good leaving group for Sn2 rx CH2CH3 9 NEC N5 H2CH3 I CC wC 0 H u H H3C 9 63 CH3 8 R I O 4 I 3 3 x lt 1 I x u amp hwy News mIo o I o quotOn 000 m 39239 U000 oI W 4 I0 m 5 I 4 0 I mIo m mz 0 I wm mcoussm gtvm alkyl sulfonates NEt3 Q R p 8 b Dehydration of ROH 1 ROH sto4 or H3PO4 H 30 CH3CH20H g CH2CH2 H20 2 alcohols OH H 80 0 24 0 140 C 3 alcohols CH3 CH I H so 3 CH3l3OH AHsc39Q 20 50 C C H CH3 2 ROH dehydration often CH3 H C CH H3C CH3 H2504 3 3 I II CH C I H C I o 3 0 140170C H3C CH3 H3C Cl H E1 for 2 and 3 ROH R formed in the rate limiting step Dehydration of ROH Mechanism same forward or reverse Dehydration and alkene hydration compete H H20 H H20 Pinacol Rearrangement This section out rearrangement under dehydration conditions Chapter 10 4 c Hac f 0 x H c H2 quot1 G H 1 cm HC CHJ I39lg reactions acid base active metal sources nomenclature properties substitution oxidation Oxidation CF03 ChromiumVI oxide H20HZSO4gt H2CFO4 Chromic acid H20 K2CF207 H2304b HZCrZO7 Potassium dichromate Oxidation 1 ROH Pyridinium chlorochromate PCC pyridine Cr03 CrV HCI 39Cl l C ilr OH PCC converts 1 alcohols to aldehydes and 2 alcohols to ketones Oxidation 0 0 W H E aldehyde H H H 39 acid WH K2Cr207 H OH gH H gm go k 2 4 O or K2CI 2O7 0 PCC x H or H2Cr64 NR no reaction or K2Cr207 RH o R C O Cro2 HOH Oxidation 1 ROH PCC oxidation of a 1 alcohol gt aldehyde H2Cr04 also K2Cr07 Oxidation 1 and 2 ROH K2Cr207 and many other reagents Oxidation of Glycols with H5io6 or HIO42H20 OOH OO 0504 HIO4 equivalent to O3lred source of diols 0504 Q OH ROOH I 0 00 O Oxidation of Glycols with H5IO6 0r HO42H201o 0OH O mechanism L14 O L 0 H Oxidation of Glycols with H5io6 or HIO42H20 Oxidation of Glycols with H5io6 or HIO42H20 How does one make butanal from 1bromobutane What else can be made using the chemistry of chapters 3 5 6 7 8 9 1O amp 11 1 f L sources nomenclature properties reactions Chapter 10 4113 1 C 0 Q Hacl H 63912 H hquot 1quot H 1 CH3 CH HC 1 H35 H 7 l ch K f H30 H 3 acid base 2 I Q a aCtive metal HBO1 1 R HSC substitution Chapter 1115 7 54 oxidation 1 O HacK I 51 H74 i H 6 4s Hquotquot CH chapter 11 Ethers Sulfides and Epoxides Structure nomenclature properties Ether synthesis Williamson synthesis 8N2 HROH addition to olefins chapt 6 Reactions acid catalyzed cleavage of ethers SNZSNlEl oxidation out Ethers as Protecting Groups Gps Epoxides oxirane nomenclature Preparation epoxidation halohydrin Reactions nucleophilic cleavage SNZSNlEl sulfides out Synthesis continued 512 blue repeat of earlier chemistry 19 Ethers Sulfides and Epoxides 11 Structure tetrahedral sp3 oxygen amp carbon diethyl ether mwg39 109 V 3 Z 3 tetrahydrofuran or THF 9 dihydropyran lt 39 Ethers Sulfides and Epoxides 11 Nomenclature ether group is a substituent HO AO 2cyclopentenol 4ethoxy2cyclopentenol 1S4R4ethoxy2cyclopenten1o 11 Ethers Sulfides and Epoxides 11 6 Properties polar CO covalent bonds But low dielectric constant Hydrogen bond acceptor Lewis base Ethers Sulfides and Epoxides 11 Two ways to prep benzyl ethyl ether t 7 oJ 2H kx 9 OJ Williamson ether synthesis 8N2 substitution recall similar problems in chapter 9 M 948 and M Ethers Sulfides and Epoxides 11 Two ways benzyl ethyl ether can be prepared 7 it Specifically how would each be done Nucleophic form of the alcohol alkoxide Solvent polar aprotic Which way should be best benleIiC SUbStrate Others 8N1 some cases HOJ Ethers Sulfides and Epoxides 11 HROH addition to olefins hydrationlike 0 1 AoO Familiar I H H I 0 H A Recallreview addition problems 629 634a Ethers Sulfides and Epoxides 11 Reactions acid catalyzed cleavage of ethers jr V X E gtlt H20 0 Br gt 3N2 SN1IE1 Ethers Sulfides and Epoxides 11 Ethers Protecting Groups ref problems 633 want Br O quotI O O I Br I I H H H v K4 I O H Problem 633 alcohol interferes with Br2 addition Ethers Sulfides and Epoxides 11 Ether Protecting Groups ref problems 633 P9 Problem 633 alcohol interferes with Br2 addition protecting group Pg blocking group Ethers Sulfides and Epoxides 11 TMS ethers H CH3 Pyridine l H3CSi C CH3 Brz gt Crown Ethers not covered Cyclic polyeihei s o The parent name is crown preceded by 0 0 a number describing the size of the E 1 ring followed by the number of oxygen atoms in ihe ring eg bod QrCl39OWIllS Ethers and Epoxides 11 Nomenclature epoxy substituent or oxirane H ether 45epoxycycloheptene 4S5R45epoxycycloheptene H 11 Ethers Sulfides and Epoxides 11 Prep of epoxidesloxiranes m H R gtVltOHJJ o R Ethers Sulfides and Epoxides 11 Prep of epoxides better mechanistic view 0 o M HOOLR gtlt HJ O R O 39Wz39q gi k 39039 in stereospecific like bromine addition 11 other epoxide sources halohydrinslbase H RC Brz Rx o B gt ICH H20xs rC H gt C H b39 H H 5 mechanism intramolecular 8N2 See problem 950 same reaction Other sources of epoxides halohydrinsbase 11 H Et 1 B gt CH CH H20 Br C H I J v H H quotV l H quoti t W OH H r f H H Chapter 6 Reactions of epoxides H or LA Opening B or LB Opening 0 H OH 4 H20 6H 0 HO39 OH 4 gt H20 H Stereochemistry H H20 12 transdiol OH Recall oso 4gt OH ROOH 12 Cisdiol 11 1 r 1 ess hindered O Regioselectivity 3 more hindered 3N2 like Regioselectivity gt HOCH3 39 539 CH3 o H HESH H 39 CH3 prong go H 5 3N1 like Regioselectivity CH3 39 e p 39 1 Q39CHs 39 H20 gt gt x 39939 DMF 69 9 HoCH3 1039 CH3 0 0 H OH R 39Squot O H RH alkyl example epoxyresin Application of Epoxy Chemistry Application of Epoxy Chemistry Z0m N Ing N from 3 m ozo I I I mo I I0 u 1 NI NIIMR IOlOZO m I z wmo ouF I0 I NIInu NI I I z I Ea I0 I NIIm E2820 aaqm v5 co oamplt lithium aluminum hydride like sodium borohydride 1 LAH H5 2 H20 chapter 5 Alkenes Bonding Nomenclature Properties Structure Hydrogen Deficiency R E Nomenclature Physical Properties Naturally Occurring AlkenesTerpenes but first stereochem practice A L quotB 63 C626 w FF 1 m y cistrans EZ structure nomenclature hydrogen deficiency properties Unsaturated Hydrocarbons 1 Alkene contains a carboncarbon double bond H H HCCH ethene 2 Alkyne contains a carboncarbon triple bond Ch 7 H CEC H ethyne acetylene 3 Arene benzene and its derivatives Ch 2122 H H HQH H H H H RQH pheny Ph H H Structure of Alkenes Double Bond 1 o bond formed by overlap of 2 sp2 hybrid orbitals 1 rcbond formed by overlap of 2 parallel 2p orbitals 7 bond o bonded atoms 3 39bond 3 in a plane gt t gonalbond angles 120 Bh3lpU9dJ9d to the plane A Structure of Alkenes No rotation about a CC bond why Overlap a Rotation requires breaking a bond 63 kcallmol b 5 Nomenclature IUPAC Root name longest continuous chain containing the olefin Number chain olefin lowest number 39 339 kene Number of C s in CC indicates CC Chain in chain H3 6 C H2 9H3 591 H2C9 CH 4 2 H 3 2 ethyI4methyI1pentene B 2 hexene A 5 Nomenclature IUPAC Root name longest continuous chain containing the olefin Number chain olefin lowest number 39alkene Number of C s in chain indicateSCC with an CC In Chaln Nomenclature IUPAC Root name longest continuous chain containing the olefin Number chain olefin cycloalkene lowest number g i Number of C s in chain with iNdiCateS CC an CC Cyclic Olefin functional group positions 12 Number around the ring to w accommodate substituents IUPAC names 7S7bromo42iodoethyl6methyI3octene H F H3CHZC quot Hsc H36 S6ethy1fuoro55dimethyl1cycooctene A The Cis Trans System recall cistrans isomers cis12dichloroethene trans12dichloroethene trans generally more stable than cis dipoles and 12 interactions The Cis Trans System Configuration is determined by the orientation of atoms of the main chain C H H3C o s CH3 trans3hexene cis34dimethyIZpentene A Cycloalkenes 3 to 7 cis olefins H H H H H lt H mg OCH E L EH rings not large enough to accommodate trans double bonds C8 limited stability as trans QEH EZ Configuration uses priority rules Chapter 3 higher priority groups same side 2 higher priority opposite sides E hi er higher higher lower lower lower lower higher E EIZ priorities of groups on ends of CC 1Atom assigned a priority higher atomic number higher prlo 2 Isotopes higher atomic mass higher priority 1Hlt2Hlt3H Hlt DltT 3 If priority the same go to the next set of atoms CH2H lt OH lt CH2C 4 double triple bonds replaced by single bonds The El System Example name each alkene and specify its configuration by the El system lt f a b IUPAC names H3C H CC Hc CH20I Stereochemistry H l acER Fl Br transIongest chain 3Z7S7bromo42chloroethyl6methyl3octene If same atoms priority goes to the next point of difference Br E 9 bromo 5 2 methylpropyI 4 nonene I 4E j Nomenclature more than 1 unsaturated group Diene or diyne enyne longest chain ring with both groups alkadiene alkadiyne akenyne if the same ene gt yne number so enes enyne ynes have the lowest possible number 14cycloheptadiene Dienes Trienes and Polyenes alkenes with n double bonds which can be cistrans 2n stereoisomers are possible example 24heptadiene 1 4 2 39 4 5 2242 6 7 2E4E24hepta diene 2 L4 4 2E4Z QZAE k A Dienes E or Z per olefin with number 22 43 6E16dichlor024dimethyl26decadiene b to 63m Physical Properties Alkenes are nonpolar compounds attractive forces between molecules are dispersion forces The physical properties of alkenes are similar to those of alkanes Common Names used lab amp lecture not on tests Alkenyl Group Common Name Example IUPAC Name H CH2CH Vinyl H O 4ethenylcyclopentene ethenyl 39139 H CH2CHCH2 ally HC CIJClt 12propenylcyclopentene 2propenyl 39 H H CH2 methylidene H methylene Cltl 3methylidenecyclopentene H A Index of Hydrogen De ciency Index of hydrogen deficiency IHD IHD 2 number of rings number of n bonds Compare Hs of alkane with H5 in a compound CnH2n2 Con eg C6H10 1 1 C6H262 IHD Hreferencszf IFillulecula 14 101 2 Index of Hydrogen Deficiency Other elements present F Cl Br I add one H Group 7 O No correction to unknown formula N P subtract one H Group 5 99 CGHQCI 9 1 7 1 8 1 1 Index of Hydrogen De ciency Problem calculate the IHD for niacin molecular formula CsHsNzO reference hydrocarbon CsH14 IHD 14 62I2 5 Chapter 3 Stereochemistry 1 Stereoisomen39sm 2 Chirality 3 Naming stereocenters RS configuration 4 Acyclic Molecules with 2 or more stereocenters 5 Cyclic Molecules with 2 or more stereocenters 6 Properties of Stereocenters 7 Optical activity 8 Separation of Enantiomers Resolution 9 Signi cance ofChirality in the biological world U uiwf ij ste reois um quot di je r conformational isomers chairboat diastereomers H H z Br CI cis enantiomers eg Prozac one isomer H S is significantly more H K H st active J H Chirality right and lefthanded substances 2 spatial arrangements of atoms analyze re ections mirrors same achiral different chiral chiral n0nsuperp0sable different arrangements in space Elements of Symmetry Plane of symmetry an imaginary passing through an object dividing it such that one half is the mirror image of the other half Elements of Symmetry Conformations of 23butanediol syn plane of symmetry anti point of symmetry TH3 x 9quot Ho 3 H O qu H3 quotHOquot quotquot H If symmetry element is present substance is aehiral meso or RS later Elements of Symmetry Tl Q i Center of symmetry a point situated so identical components of the object are located equidistant on opposite sides willllllll 39 ll ll Chirality rotgge 180 E U l L x U superposable mirror images same compound a plane of symmetry achiral Chiralitysp3 or tetrahedral center with 4 different groups chiral molecule see if images are superposable eg rotate eg 180 Different nonsuperposable mirror images enantiomers Tetrahedral 4 different substituents sp3 enantiomers Cl Cl F Bryn F Stereocenter Stereogenic center an atom that interchange of 2 groups gives a stereoisomer Enantiomers awequot quot02 H0 H HCV 0H H3C CH3 Lactic acid How do we distinguish chiral molecules R S RS Convention Priority rules 1 Assign priority to each atom bonded to stereocenter higher atomic number higher priority RS Convention 2 If same atoms bonded to the stereocenter look to next set of atoms Priority to the first point of difference H 1 Z stereocenter 4 gps HUH W w Hoc 39Z C CH3 O gt N gt C gt H 8 gt 7gtESgt 1 H 9 NH2 H 7 RIS absolute configuration of chiral compounds Rules 1 Identify stereogenic center C 4 different gps 2 Assign priority to groups C 1 2 3 4 3 View C with 4 back 1 2 3 FRONT 4 If 1gt2gt3 clockwise R counterclockwise S 3 I 4 C quot 1 R amp S configuration enantiomers nH Hmquot Cl Cl 0 R S m2 RS Convention fe1L 3 Atoms in double triple bond H viewed as equivalent number of single bonds C l3 a Siel eegenie Center priorities and assigning RS i H c H HlH Mm C H C H c C H I C H H H C H VS 139 c VS H H 1 Z N 4 I C Q C S l WWPNQ T H H c OvH Assign RS t0 the stereogenic center of the ester m Assign R or S to carvone o R Spearmint S carawaydill R con139ine poison hemlock Golden pitcher plant Enantiomers amp Diastereomers For a molecule with Q stereocenters a maximum of 2n stereoisomers might be possible For a molecule with 1 stereocenter 21 2 stereoisomers are possible For a molecule with 2 stereocenters a MAXIMUM of 22 4 stereoisomers might exist sugarO3 256 ignore sugar earlier Br Molecules With more than 1 stereocenter 22 4 trans 1br0m02chlor0cyclopr0pane relative stereochemistry both are trans Cl absolute stereochemistry each is unique enantiomers CI H CI R 7 11 s 47 s H Br H H H 1 R2R1bromo2chorocycopropaqjle 1 S21 bromo2chlorocyclopropane Molecules With more than 1 stereocenter r lt 22 CI 13L E b ma Em 223 4 Bis 1 bromO 2 chlorocyclopropane 182R 1 br m 2 chlorocyclopropane 1 R2 1 br m 2 chIorocyclopropane Cl Br Br CI H r r H jl were au 2 CI lt17I R H R H S H Br Br H 1 R2R 1 br m 2 chIorocyclopropane 1 S2 1 br m 2 chIorocyclopropane Mallewles with more than Til stereocenter HS2R 1bromo2chIorocycloprolpane R28 1bromo2chIorocyclolprolpane Cl Br Br Cl R 7 s R s H H H H H H Cl H H Cl R quot7 R S S H Br Br H H H 1R2lR1 bromo2chlomcyclloprepane 1 S21 bromo2chIorocyclopropane Molecules With more than 1 stereocenter 1S2R 1bromo2chlorocyclopropane 1 RZS1 bromo2chorocyclopropane R H s R w vquotHs ClVquot HBr Brvc39 RH BrR S Br H S CIVH HVCI 1 R2R 1bromo2chlorocyclopropane 1 S21 bromo2chIorocyclopropane 2 or more stereocenters with symmetry leads to a meso isomer superposable mirror images Consider 23dibromobutane Br H 2 or more stereocenters with symmetry leads to a meso isomer superposable mirror images Consider 23dibromobutane Br H H Br 7 H3C I l SCH3 S k Hl Br Brl H Br Br maesqe smeer is diastereomeric to H3c CH3 enantlomers I only 3 realized H H part 2 Looking for a change in the polarized plane gt D ch39rzll gt 11 no change in the plane Looking for a Change in the polarized plane 0C gt f a 3 g rotates the plane H3CH2C CHZOH CHZCH3 HOH2 C 3quot H H3C CH3 R2methyl 1butanol S2methyl 1butanol 20 575 M20 575 D D 5050 mixture of S and R 50 S5750 with 50 R5750 0i net rotation 0 RACEMIC MIXTURE Speci c Rotation 0L Observed on dependent on c0nc cell length temp Speci c Rotation 0L degrees 1 dm c gmL on t temperature 9 wavelength l path length dm c concentration gmL Speci c Rotation 0 C OLE 1 Example A sample of 2 g in 10 mL of solution measured in a 25 cm long cell gives an observed on of 1340 The speci c rotation is 1340 25 02 2680 actually degcczg391 Optical purity Absolutely pure 100 cholesterol has a speci c rotation of 390 Q pf synthetic sample may contain the enantiomer all or lt 39 or a diastereomer all or lt 39 or other junk all or lt 39 Optical purity Absolutely pure Cholesterol has a speci c rotation of 390 0C observe t 391 ldm 1g pure 1 390 0t Tdm gcrap 39L on less than 39 386 39t l 1dm099g001g o 386 351 1dm 09g01g 312 1dm 08g02g OL 3510 p39y 391t on 3120 Pure S 2 bromobutane CH3 speci c rotation 2310 H 3 Br But What if observe optical rotation 92 CHZCH3 Not pure possibly a miX of R and S 231 gt 92o lt 0 Mix is between100 S and 5050 SR optical purity Pure 8 9H2bmm huf ane eCH3 Speci c mm wm 2310 H 39V Br Bimini whet if e bsewe p ee ragtime 92 CHZCH3 Net pure pese b y 41 mix of R and S 0bserved0c 100 92100 optical purity 0c of pure enantiomer 231 40 40 optical purity Le 40 excess of S isomer 40 excess 408 608R mixture 30S30R The sample has 708 and 30R enantiomeric excess or 99 optical purity moles 1 isomer moles of other ee 0 moles of both enantiomers X 100 e 70 30 e 39 m X 100 ee 40 S2br0m0butane on 575 or a measured physical property not predictable These similar S compounds rotate light in the opposite direction Kw if Ho H NaOH OfH Slactic acid sodium Slactate Resolution separation Convert mixture of enantiomers same properties TO diastereomers different physical properties can be separated RESOIUtiOH new compounds enantiomeric mixture dlasterelomerlc mixture 2 equivalents I S 1 R R R l l nonseparable dl erent R1 compound separate remove R1 R I R1 remove R1 b Resolution by acidbase reactions remove amine H o H CH I Hg 39 H30quotgtC C N 0 If H F3C O I 1 I C CC CF8 gt resolved 3quot 0 0 CF39 39 3 l O H I39aCCl IIIC 3 o H ml I H 39m 3 C 69 C H 3 89 P remove amlne j b Resolution 9 Examples of enantiomerically pure bases cinchonine RH quinidine R OCH3 quinine b ocD 1270 HCCl3 from Strycnos seeds S nuxvomica enantiomeric mixture pure enantiomer FH on s s O F H S WOH H 1g582 H O Ea of OI UNI OUR I 0c IR 1amp8 cmam Ilo xo o I 333A no of fo oNI No xof 5 f A 5050 enantiomeric mixture of esters forms Racid and REnzyme recover S ester CHEMICAL amp ENGINEERING NEWS Oct 23 2000 pg 55 Chiral Drugs Sales top 100 Billion CampE NEWS Oct 1 2001 pg 79 40 of all dosage form drug sales in 2000 were single enantiomers NOW gtgt50 single enantiomer b a Some drugs are racemic mixtures eg antidepressants Wellbutrin bupropion Effexor venlafaxine hydrochloride Remeron mirtazapine H3C2N OH HCl H3CO Ibuprofen is moi H3C 39H H39 CH3 S isomer particularly active but R slowly converted to S Naproxen S isomer CH3 H OCH3 R enantiomer liver toxin A a R ketamine hallucinogenic Sketamine anaesthetic analgesic DarvoN I NovraD antitussive 283R pr0p0xyphen 2R3Spr0p0xyphen H3C FH3 Q Q H2 H3 3 H3C C H3 0f3CH2CH3 H3CH2C Thalidomide R sedative antiinflammatory Crohn s disease S teratogenic O but thalidomide racemized in the body U