CHAPTER s 8 81 attacks electrophile loves No pair of Nucleophile donates contain µ f His Pi bonds iii B H charge hence its name e j HI É can t R E H nitin E it H i H H also be nucleophilic centers Ex RE LÉÉÉ Identify all Nu centers N.tt 2 Electrophile eg poor in e density attacked by Nu 1st Me induction causes e shift towards Cl Cl is R more electro to induction be neg resonance H I nucleophile electrophile F 8.3 Nucleophilicity Basicity measure for an ran possible for a will rates of the position acid base ran leg strong Nu a Elt an not matter how does It is of measure B I of how quickly measure attack a Cl fast Nu of equilibrium concentrations ran to be occurs a weak base I weak base large atom charge spread across so highly stabilized conj base of strong Nu HI strong acid greater area large atom polarizable e density shift easily can He base strong small atom dense charge weak nucleophile not very unstable large and polarizable H2O weak base weak nucleophile HE strong base strong Hydroxide nucleophile Ho can function as a base or a Nu Nucleophile O O RITO R OH atop attacks the electrophile Base RIGHT 11 RT removes a o proton 8.4 Nucleophilic Attack I B nucleophile electrophile nucleophile attacks electrophile Transfer Proton R É base H HII p acid base removes proton from Edd acid to base THE pi bonds take can act o t as and base a proton a Loss of Leaving Group a Na Ho t Ci leaving group leaving group leaves good leaving groups I weak base HO strong base are weak bases excelling leaving group poor leaving group Rearrangement carbocation of rearrangement change the SNI Ct ans 1 2 3 SNL occur in location comprise of proton transfer loss of leaving group nucleophilic attack rxns at can once have multiple steps Identify the sequence OH of steps lot µ in following mechanism I I y proton transfer pi bond functions as proton transfer resonance a d base and takes proton from water functions base and takes proton Hot 81 Carbocations short lived intermediates B.r Br carbocation Protonated to gain a proton as Ht a a carbocation tease oxonium qq.gq.am is Each hump in nrg diagram Hump w highest formation Factors that step rate determing step nrg is of carbocation in speed Each valley a this mechanism up ratedet step will affect the entire process in nrg carbocation diagram is oxonium in an nrg intermediate be has octet but carbocation does not Carbocation stability H H H H methyl Ct least stable R 10 Ct so R R 20 Ct unstable R H H oxonium R R 30 Ct most stable stability due to more substituted hyperconjugation stable more groups orT é s R e travel from to delocalize y are so R R neighboring empty p orbital charge for a e donating they reduce charge and increase groups of p can Ct and moment stability Carbocations are h stabilized y s g Tertiary allylic stable more by positive Carbocations more A 20 Ct two stable than tertiary Ct of resonance will stable over locations be also Ct charge spread Us Benzylic resonance stable rearrange methyl shift be resonance to become H 30 Ct hydride shift A H H H 81 substitution rxn group X X stereochemistry of SNI mechanism SN2 mechanism replaced y s substitution inversion y rains racemic 50 group mixture R 50 5 of config by elimination rxn proton Ht LG leaving group La removed to form I H and double bond stereochemistry Br of elimination NaOEt y rxns t minor major product product cis trans regiochemistry NaOEt major minor product constitutional isomers formed is removed based product on which proton addition rxn X pi bond is destroyed y and two new groups are added stereochemistry of addition rxns R MR 1 Bits THF H 1111 H 2 11202 NaOH anim 2 chiral centers formed 4 stereoisomer products BUT only syn addition so groups must either both wedge or both dash must be hydroboration SYN mechanisms addition on SAME oxidation justify regiochemical products the of side rains are stereochemical and a ran CHAPTER 9 SUBSTITUTION RANS 91 attacks Nucleophile SN2 electrophile an ran rate dependent on concentration of both nucleophile and electrophile be it happens order second No Leaving group attached La Configuration ran no withdraws e C atom is step one 40 LG st in density from makes C atom electrophilic inverted SNI ran 2 steps 1 La leaves 2 No attacks G Lo forms Ct Ct a No No racemic racemic mixture be Ct is be attacked from can so sp either side can be either R or S 50 50 rate dependent either Nu or step be the that on Elt 1 chemical entity based other isn't step first order ran on which needed at to consider Need beta SNI factors 4 and for choosing SN2 electrophile nucleophile leaving group solvent TI Electrophile R alkyl groups Alkyl rxn Estate groups groups crowd electrophilic center in steric hindrance Nv for SN2 10 substrate better an SN2 can't attack In SNI out into trigonal BUT Ct stability is R no steric intermediate an of and plane 20 7 hindrance step so 30 better for substrate groups go matters Ct 10 30 leaves ca reins SNI EX Era 10 substrate so This 20 substrate stabilizes the can smart undergo Snl be Ct i.fm a resonance Recognize LG in Benzylic position Mx X Allylic position xx be these compounds resonance 93 generate structures NUCLEOPHILE SN2 of can reins a dependent are on the strength nucleophile SNI doesn't need rate of SNI No dependent in only step 1 on ratesepdet substrate conc Nu strong favors strong Nu weak Nu slows Weak Nu Nucleophile up rate of speeds favors strength more down ran SN2 rate of SN2 by many factors neg charge OH eg polarizability H2O ability to distribute e unevenly as size eg I sulfur 7 polarizability Br F a very polarizable eg Common ran SNI def is SN2 Hs Has nucleophiles stet HS HO 9 density so Br Has RO CI RSH NIC halides except sulfurs HS oxides F Has RSA OH cyanide OR CIN Wead H2O F so ROH F water H2O alcohol R OH 9 LEAVING SN't ans SN2 rate determining step the leaving must be acids strong I H strong so group more sensitive to runs the is be loss of the leaving group stable Good leaving H generally are groups than leaving the GROUP groups conj bases of are weak bases Q I Iot E conj acid weak base neg charge of I area I large so good can is is leaving be stable on spread over very stable group its own a weak bases so they LG are at donating weak keep e w them e they as leave th H LG COMMON LEAVING GROUPS Goody's I EY's Br Cl H so O HzC H 8 mesylate halides except F water OF OO oof EE 00 triflate Bogie do no N H H oxides so Nitz OH is a bad possible to convert LG and bad La base strong into good LG NEETA nÉ bad LG OH good LG H2O 9 SOLVENT favor Polar aprotic solvents SNI need ans carbocation SNZ to dissolve polar need reins stabilize to polar SN2 nucleophile Protic of hydrogen capable at least contains attached atom can be be Ht Apotc cannot to an leg OH a can source be hydrogen bonding I be hydrogen electronegative NH of protons removed bond Common polar apron I acetone i dimethylsulfoxide s O solvents DMSO o dimethoxyethane DME dimethyl formamide y DME needs protic be solvent Ct and shield to stabilize SNI forms delocalize H it H Q's H in H SN2 needs aprotic it from Q µ protic forms Nv and attacking substrate solvent shield it H be arond solvent shield prevents charge no H Review SNL Nns 2 steps 1st order ran rate def step is only dependent racemic SNZ loss on of La LG rate det step mixture Ans I step 2nd order ran dependent on be all in inversion of both one Nu step config and Elt Substrate 10 Electrophile favors SNZ carbocation is 30 favors formed so stability matters SNI too much steric hindrance for SN2 Nucleophile SNI dependent not strong No weak Nu SNZ SN I S strength based polarizability size nu strong Nu on on charge and nu OH OR Has As OEt RSA OME Cl Br I NEC no weak F H2O ROH Leaving Group SNI Good more LG dependent stable strong bases donate é weak are their on don't donate to stabilize Good LG It Ots Br Cr H2O e on LG bases own take w them Bad LG OR OH Nitz solvent polar aprotic SN 2 protie would block polar protic SNI protic stabilizes 10 sub SW2 20 sub SNI 30 sub SNI Nu SNL Ct strongnvist weak Nv Weak LG SNI neither SN2 aprotic Ex F i sub strong No good La SN2 SN2 undet Es SNZ SNI be Ct Ch 10 Ct have can is rearrangements but not formed Elimination SN2 Reactions Y't Br substitution a p B elimination sub runs In elim runs In La is replaced Lat B Ht Two types of elim El EZ ans are B w No replaced w a double bond EZ 101 Mechanism P Base pg X C is carbon attached B C are 1 I B a t to LG carbon away B It are attached to B C Base takes one B It and LG leaves step involves both base In an SN2 ran attacks electrophile 30 so In p an and substrate reagent acts as that substrates EZ ran proton which is 30 simultaneously substrates can don't a and by R groups Nu be guarded work reagent acts as a base and takes not guarded by alkyl groups can work 30 substrates actually than 10 substrates so react faster C Regiochemistry EZ 101 Br EE t l 2possib Doublebondsubstitutons at H H H mono sub more substituted It H H R tri sub di sub product less sub product is usually zaitsev is I is II tetra sub zaitsev product hoffman product major product HOWEVEL Br o I I Minor major Zaitsev hoffman be bulky base so the center in common bulky Potassium easier It to attack the side get B bases Kt T hard to N IN O Lit tertbutoxide t BOOK Lithium diisopropylamide LDA 103 Stereochemistry EZ it N EE major Br minor no regiochem be identical B and trans be both cis two be available trans If there is can is I positions produced protons stereoselective major only it B It then only one product LG must be antiperiplanar and Ht stereospecific SO FOR EZ of LG If to be B ttt has ca dash is wedge to opposite Itt has Draw the Ex MI product major EE CI major product I B Itt so draw I H a Et stereospecitic newman Me f zaitsev H projection slept it make E H f 11 Itt and La so This Et La double bond in formed Mein double bond z in beta H 12 n 2 m Me or Not Me Et ran removed Me y Ez occur can At and conform the that the it Me slept is anti are MyE Hit mmr tips y 9 minor at hoffman di sub 4 3 É Br 11 zaitsev III hoffman product e s et cha Br Ift Utz c 2413 c E O C Both methyls dash Et It and HI 3C are both wedge Ph a i Ap both so so both Itsy É cH3 Br same on same CFC p H 34 H to Utz H b glitz ph Ph H CE isomer H Ph Edm É PI H side Ph E isomer city side Ph g City z isomer Clt mmmm 10 2 Mechanism El steps LG step 1 La t y leaves to to form Ct Base F step 2 base takes Step 1 loss of LG is beta proton rate def step Step I is SNI usually get a 30 and identical and mix El and you El compete of products 20 the substrate then you need it and Snl alkyl halides undergo El for Ct 10 too unstable be If for a an bad LG to protanate good Lh OH Olt 42504 neat using L to make it acid an t Azo I El Regiochemistry Two possibilities OH 42504 t heat hoffman least be not major minor Ct is NOT conform sub matter about El Does hoffman most sub zaitsev Does zaitsev formed bulky base first stereochemistry need to be anti and Cis there are trans possible B two 9h IE hydrogen M Sub Xp 30 substrate strong base weak NVC Us É SNI minor less stable Elim A El Ez El EZ SNI t major trans is usually major be steric hindrance so more 1 if El EZ E fastest option is EZ Kath 30 sub protic Snl strong nuc spy I Fx Det Sub Elim When I El SNI Ome SNI EZ El ez of Reagent nucleophile reagent ran reagent ren comparing atoms in basicity and each H nucleophilicity other base same row parallel When comparing and basicity parallel more atoms column nucleophilicity do not each in same other neg atoms can stabilize weak base better electro charge eg Ho us Han since N O and are same row i nucleophilicity follows basicisity basicity electroneg larger atoms can weak so eg stabilize charge better base HO Hs us O and S on same column size so no parallel basicity a nut large atoms a halides eg nucleophile common No be Br I HS RS Azs as polarizability only C fx usually only sub rxns RSA weak bases so no elim Common small III H Base only shown as O I 00 strong No 1 Nait J only dim reins tert butoxide Strong Base Ed SNz be steric hindrance SW2 HOO yay ELL Meo Et O Weak No H2O Meon Et OH Weak Base É 101 Nv SNI only 10 sub SN 2 20 sub SNZ 30 sub Base Ez O Ez EZ SW2 EZ EZ so Strong Base be EZ 30 sub or H Q 30 sub EZ Has RSA Ez 10 sub 20 sub Cl Rs usually strong base 10sub Br Hs El 20 sub SNZ It SNI only Strong No or SN2 not sensitive SNZ unless bulky to steric conditions too much steric for SN2 or EZ one Oro y Weak Base Weak Nv 10 sub 20 sub SNI It 30 sub not practical be reins too slow EZ SN2 Swat El tE2 SNI t heat El heat favors elim Ex Pr 20 sub strong no strong base SM SNZ El Nuott Ez Ez saz 10 sub SN2 Ez Predicting the Alcohols 42504 will undergo El major minor products H2o MeOH Eton Regiochemistry No attacks a SN2 where La attached Nu attacks Ct SNI usually where Ct Lh rearrangement Zaitsev Ez position own Hoffman Zaitsev of inversion configuration d racemic mixture trans alkene untess bulky base El NV replaces 26 NV replaces LG was can stereochemistry hoffman Hoffman when only one B Itt must be trans cis alkene p Itt La and ANTI conform cis alkene EI NY 20 sub strong base strong Naome EZ SNZ nu major pome minor Problex 10.27 NaOH Oy 10 sub SN Ez strong b spy n major I on minor N 10.28 1 4 10 SB major Lome Ome SN IF minor 10 29 If FE Ez It Sm IM major minor 10.30 NI 20 SB Br SW It major m E Br EH e it 14 3 H CALCHzCHz H Utz H 3 check µ Clt3 7 H Utz minor NEO 10.31 AH not 30 SNI El 12504 t alcohol t heat El major NO SNI AA Minor N 10.32 I É weak B WN SNI or El 30 No major Uh minor h 10.33 NÉE 20 SW2 puke say SN majoring 10.34 Et sÉ major EZ E ez in minor 10.35 major É K h minor FBI 30 J Ez sur EZ only t 10.36 If Ft SB s IM Ez To 5 MI É major minor ISH 10 SNZ EZ SN SNO 10.38 xp 10 SN SNZ Asme REVIED Ne do Bro I ASO RSO Bye It O Base strength Koccats 00 Me OOH O OR DEE f IN Has Rst t Buoy to Isn É t 00 Fo ROH Hao Meolt Etony 19 mmmm Nuc Snl 10 SNZ 20 SN 30 SN2 or strong No 2 weak Nu SNI EZ SB SB SN SNZ or 10 SNZ 7 20 Ez EZ EZ SW2 30 EZ IF 1 EZ t 20 EZ 30 El SNZ SNZ t El SNI SNI heat favors El SN2 SNI mmmm hoffman Zaitsev unless bulky base Ct rearrangements of inversion racemic can SW El SNI mix FOREL in saz config trans alkene one occur cis alkene anti conform when only B Ht mmmmmmmm Goodloe Br I Ots CI I I 8 H2O FzC É 00 HzC 11 s o 8 BEE Nii Yoo 18 ammunition stability nothmmm P S CI se g BI Nu Base size v TP n my LG Mmmmm AW 6 3 chloro z methyl propyl methyl ether O i azide ion 10 IN JIN 3 azido z methylpropyl methyl N No ether No Eri FN O H N SN2r H H H CHzona Mto Nta Cy CH OH Br Hz a better ca than RS better Nu than RO I NO F P S Cl se Nu Br I v Base size u th v 12 inversion B O L NulBase LG No strength aprotic n F 4 Br I 180 1 TOH a t HCl 7 HCl or Hcl Me OH which faster in H2o H2O be it MeOH oh Snl is more Eton polar t BuOH than Meon transition state SN2 NC O NICE of ran betw and bromoethane TBR HIIIII
