1、Organic ChemistryNucleophilic Substitution and -Elimination uChapter 8Nucleophilic Substitution any reaction in which one nucleophile substitutes for another at a tetravalent carbon a molecule or ion that donates a pair of electrons to another molecule or ion to form a new covalent bond;a Lewis base
2、n nu uc cl le eo op ph hi il li ic cs su ub bs st ti it tu ut ti io on nN N u uc cl le eo op ph hi il le e+C CN Nu uC CL Lv vN Nu u:-L Lv vL Le ea av vi in ng gg gr ro ou up pNucleophilic SubstitutionuSome nucleophilic substitution reactions I I -H HS S -R RO O -H HO O -C CN NH HC CC C -N N u u N NH
3、 H3 3H HO O H HC CH H3 3I IC CH H3 3S SH HC CH H3 3O O H HC CH H3 3O O R RC CH H3 3O O-H HH HC CH H3 3C CN NC CH H3 3B Br rC CH H3 3N N H H3 3+C CH H3 3C CC CH HC CH H3 3N N u uB Br r+a an n a al lc co oh ho ol l (a af ft te er r p pr ro ot to on n t tr ra an ns sf fe er r)a an n a al lk ky yl la am
4、 m m m o on ni iu um m i io on na an n a al lk ky yl l i io od di id de ea a n ni it tr ri il le ea an n a al lk ky yn ne e:a a t th hi io ol l (a a m m e er rc ca ap pt ta an n)a an n e et th he er ra an n a al lc co oh ho ol lR R e ea ac ct ti io on n:+:Solvents a solvent that is a hydrogen bond d
5、onor the most common protic solvents contain-OH groups a solvent that cannot serve as a hydrogen bond donor nowhere in the molecule is there a hydrogen bonded to an atom of high electronegativityDielectric ConstantuSolvents are classified as polar and nonpolar the most common measure of solvent pola
6、rity is dielectric constant a measure of a solvents ability to insulate opposite charges from one another the greater the value of the dielectric constant of a solvent,the smaller the interaction between ions of opposite charge dissolved in that solvent polar solvent:dielectric constant 15 nonpolar
7、solvent:dielectric constant 15Protic SolventsH H2 2O OH HC CO O O O H HC CH H3 3O O H HC CH H3 3C CH H2 2O O H HC CH H3 3C CO O O O H HS So ol lv ve en nt tS St tr ru uc ct tu ur re eD D i ie el le ec ct tr ri ic cC C o on ns st ta an nt t(2 25 5 C C)W W a at t e er rF Fo or rm m i ic c a ac ci id d
8、M M e et t h ha an no ol lE Et th ha an no ol l7 79 95 59 93 33 32 24 4A A c ce et ti ic c a ac ci id d6 6Aprotic SolventsC CH H2 2C Cl l2 2C CH H3 3C CH H2 2O O C CH H2 2C CH H3 3C CH H3 3C CN NC CH H3 3(C CH H2 2)4 4C CH H3 3(C CH H3 3)2 2S S=O O(C CH H3 3)2 2N N C CH H O O(C CH H3 3)2 2C C=O OC C
9、6 6H H5 5C CH H3 32 2.3 3T To ol lu ue en ne e4 4.3 3D D i ie et th hy yl l e et th he er r9 9.1 1D D i ic ch hl lo or ro om m e et th ha an ne eS So ol lv ve en nt tD D i ie el le ec ct tr ri ic cC C o on ns st ta an nt tS St tr ru uc ct tu ur re eD D i im m e et th hy yl l s su ul lf fo ox xi id d
10、e e (D D M M S SO O)A A c ce et to on ni it tr ri il le eA A c ce et to on ne eN N,N N-D D i im m e et th hy yl lf fo or rm m a am m i id de e (D D M M F F)4 48 8.9 93 37 7.5 53 36 6.7 72 20 0.7 7P Po ol la ar rN N o on np po ol la ar rH H e ex xa an ne e1 1.9 9MechanismsuChemists propose two limiti
11、ng mechanisms for nucleophilic substitution a fundamental difference between them is the timing of bond-breaking and bond-forming stepsuAt one extreme,the two processes take place simultaneously;designated SN2 S=substitution N=nucleophilic 2=bimolecular(two species are involved in the rate-determini
12、ng step)Mechanism-SN2 both reactants are involved in the transition state of the rate-determining stepC CB Br rH HH HH HH H O O:-+C CH HH HH HH H O OB B r r Mechanism-SN2Mechanism-SN1uBond breaking between carbon and the leaving group is entirely completed before bond forming with the nucleophile be
13、ginsuThis mechanism is designated SN1 where S=substitution N=nucleophilic 1=unimolecular(only one species is involved in the rate-determining step)Mechanism-SN1 Step 1:ionization of the C-X bond gives a carbocation intermediateC CC C H H3 3C C H H3 3H H3 3C C+C CH H3 3C CH H3 3C CB B r rH H3 3C Cs s
14、l lo ow w,r ra at te ed de et te er rm m i in ni in ng gA A c ca ar rb bo oc ca at ti io on n i in nt te er rm m e ed di ia at te e;i it ts s s sh ha ap pe e i is s t tr ri ig go on na al l p pl l a an na ar r+B Br rMechanism-SN1 Step 2:reaction of the carbocation(an electrophile)with methanol(a nuc
15、leophile)gives an oxonium ion Step 3:proton transfer completes the reactionC CC C H H3 3C C H H3 3H H3 3C CO O C C H H3 3H HC CC CH H3 3C C H H3 3O OH H3 3C CH HC CH H3 3C CH H3 3C CH H3 3C CO OH H3 3C CH HC C H H3 3+E El le ec ct tr ro op ph hi il le eN N u uc cl le eo op ph hi il le ef fa as st tO
16、 O x xo on ni iu um m i io on ns s+:+f fa as st tC CH H3 3C CH H3 3C CO OH H3 3C CO OC CH H3 3H HO OH HO OC CH H3 3C CH H3 3H HH HC CH H3 3H H3 3C CC CH H3 3C CH H3 3C C:Mechanism-SN1Evidence of SN reactions1.What is relationship between the rate of an SN reaction and:the structure of Nu?the structu
17、re of RLv?the structure of the leaving group?the solvent?2.What is the stereochemical outcome if the leaving group is displaced from a chiral center?3.Under what conditions are skeletal rearrangements observed?KineticsuFor an SN1 reaction reaction occurs in two steps the reaction leading to formatio
18、n transition state for the carbocation intermediate involves only the haloalkane and not the nucleophile the result is a first-order reactionC CH H3 3C CB Br rC CH H3 3C CH H3 3C CH H3 3O O H Hd d(C CH H3 3)3 3C CB Br r d dt tR Ra at te e =-=k k(C CH H3 3)3 3C CB Br r C CH H3 3C CO O C CH H3 3C CH H
19、3 3C CH H3 3H HB Br r+2 2-B Br ro om m o o-2 2-m m e et th hy yl lp pr ro op pa an ne eM M e et th ha an no ol l2 2-M M e et th ho ox xy y-2 2-m m e et th hy yl lp pr ro op pa an ne eKineticsuFor an SN2 reaction,reaction occurs in one step the reaction leading to the transition state involves the ha
20、loalkane and the nucleophile the result is a second-order reaction;first order in haloalkane and first order in nucleophiled d C CH H3 3B B r r d dt tr ra at te e =k k C C H H3 3B B r r O O H H-C C H H3 3B B r r+N N a a+O O H H-C C H H3 3O O H H+N N a a+B B r r-B Br ro om m o om m e et th ha an ne e
21、M M e et th ha an no ol lNucleophilicity a kinetic property measured by the rate at which a Nu causes a nucleophilic substitution under a standardized set of experimental conditions a equilibrium property measured by the position of equilibrium in an acid-base reactionuBecause all nucleophiles are a
22、lso bases,we study correlations between nucleophilicity and basicityNucleophilicityG G o oo od dP Po oo or rB Br r-,I I-H HO O-,C CH H3 3O O-,R RO O-C CH H3 3S S-,R RS S-C CH H3 3C CO O O O-,R RC CO O O O-H H2 2O OC CH H3 3O O H H,R RO OH HC CH H3 3C CO O O O H H,R RC CO O O O H HN N H H3 3,R RN N H
23、 H2 2,R R2 2N NH H,R R3 3N NC CH H3 3S SH H,R RS SH H,R R2 2S SN N u uc cl le eo op ph hi il le eM M o od de er ra at te eC CN N-,N N3 3-E Ef ff fe ec ct ti iv ve en ne es ss sC Cl l-,F F-NucleophilicityuRelative nucleophilicities of halide ions in polar aprotic solvents are quite different from tho
24、se in polar protic solventsuHow do we account for these differences?Increasing NucleophilicityIncreasing NucleophilicitySolventSolventPolar aproticPolar aproticPolar proticPolar proticF-Cl-Br-I-I-Br-Cl-Cl-Br-I-NucleophilicityuPolar protic solvents(e.g.,water,methanol)anions are highly solvated by hy
25、drogen bonding with the solvent the more concentrated the negative charge of the anion,the more tightly it is held in a solvent shell the nucleophile must be at least partially removed from its solvent shell to participate in SN reactions because F-is most tightly solvated and I-the least,nucleophil
26、icity is I-Br-Cl-F-NucleophilicityuGeneralization within a row of the Periodic Table,nucleophilicity increases from left to right;that is,it increases with basicityIncreasing NucleophilicityIncreasing NucleophilicityP Pe er ri io od dP Pe er ri io od d 2 2P Pe er ri io od d 3 3F-OH-NH2-CH3-Cl-SH-PH2
27、-NucleophilicityuGeneralization in a series of reagents with the same nucleophilic atom,anionic reagents are stronger nucleophiles than neutral reagents;this trend parallels the basicity of the nucleophileIncreasing NucleophilicityIncreasing NucleophilicityROH RO-H2O OH-NH3 NH2-RSH RS-Nucleophilicit
28、yuGeneralization when comparing groups of reagents in which the nucleophilic atom is the same,the stronger the base,the greater the nucleophilicity N N u uc cl le eo op ph hi il le eR RC CO O O O-H HO O-R RO O-C C o on nj ju ug ga at te e a ac ci id dp pK Ka aR RC CO O O O H H4 4-5 5R RO O H HH HO O
29、 H H1 16 6-1 18 81 15 5.7 7H H y yd dr ro ox xi id de e i io on nA A l lk ko ox xi id de e i io on nC C a ar rb bo ox xy yl la at te e i io on nI In nc cr re ea as si in ng g A A c ci id di it ty yI In nc cr re ea as si in ng g N N u uc cl le eo op ph hi il li i c ci it ty yStereochemistryuFor an SN
30、1 reaction at a chiral center,the R and S enantiomers are formed in equal amounts,and the product is a racemic mixtureCHClCl-Cl-C+HClCH3OH-H+CH3OCHClClCOCH3HR EnantiomerR EnantiomerS EnantiomerS Enantiomer+R EnantiomerR EnantiomerA racemic mixtureA racemic mixturePlanar carbocationPlanar carbocation
31、 (achiral)(achiral)StereochemistryuFor SN1 reactions at a chiral center examples of complete racemization have been observed,but partial racemization with a slight excess of inversion is more commonA A p pp pr ro oa ac ch h o of f t th he e n nu uc cl le eo op ph hi il le e f fr ro om m t th hi is s
32、 s si id de e i is s l le es ss s h hi in nd de er re ed d+R R1 1C CH HR R2 2C Cl l-A A p pp pr ro oa ac ch h o of f t t h he e n nu uc cl le eo op ph hi i l le e f fr ro om mt th hi is s s si id de e i is s p pa ar rt ti ia al ll l y y b bl lo oc ck ke ed d b by y l le ea av vi in ng g g gr ro ou u
33、p p,w w h hi ic ch h r re em m a ai in ns s a as ss so oc ci ia at te ed d w w i it th h t th he e c ca ar rb bo oc ca at ti io on n a as s a an ni io on n p pa ai ir rStereochemistryuFor SN2 reactions at a chiral center,there is inversion of configuration at the chiral centeruExperiment of Hughes a
34、nd IngoldI Ia ac ce et to on ne eS SN N2 2-1 13 31 1+I II I1 13 31 1I I-+2 2-I Io od do oo oc ct ta an ne eHughes-Ingold Expt the reaction is 2nd order,therefore,SN2 the rate of racemization of enantiomerically pure 2-iodooctane is twice the rate of incorporation of I-131I I:-C CH HI IC C6 6H H1 1 3
35、 3H H3 3C CH HC CH H3 3C C6 6H H1 1 3 3I IC CI IS SN N2 2a ac ce et to on ne e+131131+(S)-2-Iodooctane(R)-2-IodooctaneStructure of RXuSN1 reactions:governed by electronic factors the relative stabilities of carbocation intermediatesuSN2 reactions:governed by steric factors the relative ease of appro
36、ach of a nucleophile to the reaction siteGoverned byGoverned byelectronic factorselectronic factorsGoverned byGoverned bysteric factorssteric factorsS SN N1 1S SN N2 2R3CXR2CHXRCH2XCH3XAccess to the site of reactionAccess to the site of reaction(3(3)(methyl)(methyl)(2(2)(1(1)Carbocation stabilityCar
37、bocation stabilityEffect of -Branching1.21.2 x 10 x 10-5-51.2 x 101.2 x 10-3-3Relative RateRelative RateAlkyl BromideAlkyl Bromide-Branches-Branches0 01 12 23 31.01.04.14.1 x 10 x 10-1-1BrBrBrBr Effect of -BranchingC C H H3 3C C H H2 2B B r rf fr re ee ea ac cc ce es ss sBromoethaneBromoethane(Ethyl
38、 bromide)(Ethyl bromide)C C H H3 3C C C C H H2 2B Br rC C H H3 3C C H H3 31-Bromo-2,2-dimethylpropane1-Bromo-2,2-dimethylpropane(Neopentyl bromide)(Neopentyl bromide)b bl lo oc ck ke ed da ac cc ce es ss sAllylic HalidesuAllylic cations are stabilized by resonance delocalization of the positive char
39、ge a 1 allylic cation is about as stable as a 2 alkyl cation+Allyl cationAllyl cation(a hybrid of two equivalent contributing(a hybrid of two equivalent contributing structures)structures)CH2=CH-CH2CH2-CH=CH2Allylic Cations 2&3 allylic cations are even more stable as also are benzylic cations adding
40、 these carbocations to those from Section 6.3C C6 6H H5 5-C C H H2 2+C C H H2 2+B Be en nz zy yl l c ca at ti io on n(a a b be en nz zy yl li ic c c ca ar rb bo oc ca at ti io on n)T Th he e b be en nz zy yl l c ca at ti io on n i is s a al ls so o w wr ri it tt te en ni in n t th hi is s a ab bb br
41、 re ev vi ia at te ed d f fo or rm mC CH H2 2=C CH H-C CH H-C CH H3 3C CH H3 3C CH H2 2=C CH H-C C-C CH H3 3+A A 2 2 a al ll ly yl li ic c c ca ar rb bo oc ca at ti io on nA A 3 3 a al ll ly yl li ic c c ca ar rb bo oc ca at ti io on nI In nc cr re ea as si in ng g s st ta ab bi il li it ty y o of f
42、 c ca ar rb bo oc ca at ti io on ns s2 2 a al lk ky yl l1 1 a al ll ly yl li ic c1 1 b be en nz zy yl li ic cm m e et th hy yl l 1 1 a al lk ky yl l 3 3 a al lk ky yl l2 2 a al ll ly yl li ic c2 2 b be en nz zy yl li ic c B Br r-C Cl l-H H2 2O O F F-C CH H3 3C CO O-H H O O-C CH H3 3O O-N N H H2 2-R
43、Re ea ac ct ti iv vi it ty y a as s a a l le ea av vi in ng g g gr ro ou up pS St ta ab bi il li it ty y o of f a an ni io on n;s st tr re en ng gt th h o of f c co on nj ju ug ga at te e a ac ci id dr ra ar re el ly y f fu un nc ct ti io on n a as s l le ea av vi in ng g g gr ro ou up ps sO OThe So
44、lvent-SN2uThe most common type of SN2 reaction involves a negative Nu and a negative leaving group the weaker the solvation of Nu,the less the energy required to remove it from its solvation shell and the greater the rate of SN2+T Tr ra an ns si it ti io on n s st ta at te en ne eg ga at ti iv ve el
45、 ly y c ch ha ar rg ge ed dn nu uc cl le eo op ph hi il le en ne eg ga at ti i v ve el ly y c ch ha ar rg ge ed dl le ea av vi in ng g g gr ro ou up pn ne eg ga at ti iv ve e c ch ha ar rg ge e d di is sp pe er rs se ed d i i n n t th he e t tr ra an ns si it ti io on n s st ta at te eL Lv vC CL Lv
46、vC CN Nu uC CN N u uN N u u:-The Solvent-SN2BrN3-CH3CNCH3OHH2O(CH3)2S=O(CH3)2NCHON3Br-SolventSolventTypeTypepolar aproticpolar aproticpolar proticpolar protic5000500028002800130013007 71 1k k(methanol)(methanol)k k(solvent)(solvent)SolventSolvent+solventsolventS SN N2 2+The Solvent-SN1uSN1 reactions
47、 involve creation and separation of unlike charge in the transition state of the rate-determining stepuRate depends on the ability of the solvent to keep these charges separated and to solvate both the anion and the cationuPolar protic solvents(formic acid,water,methanol)are the most effective solve
48、nts for SN1 reactionsThe Solvent-SN1waterwater80%water:20%ethanol80%water:20%ethanol40%water:60%ethanol40%water:60%ethanolethanolethanolSolventSolventsolvolysissolvolysis+k k(solvent)(solvent)k k(ethanol)(ethanol)1 110010014,00014,000100,000100,000C C H H3 3C C H H3 3C C H H3 3C C H H3 3C C H H3 3C
49、C C C l lR RO O H HC C H H3 3C C O O R RH H C C l lRearrangements in SN1uRearrangements are common in SN1 reactions if the initial carbocation can rearrange to a more stable one2 2-M M e et th ho ox xy y-2 2-p ph he en ny yl lb bu ut ta an ne e2 2-C C h hl lo or ro o-3 3-p ph he en ny yl lb bu ut ta
50、 an ne e+C C H H3 3O O H H+C C l l -C C H H3 3O O H HC C H H3 3O O H HH HC C l lO O C C H H3 3+Rearrangements in SN1uMechanism of a carbocation rearrangementC Cl lH HO O-C CH H3 3H HH HO OH HC CH H3 3C Cl l+A A 2 2 c ca ar rb bo oc ca at ti io on n+A A 3 3 b be en nz zy yl li ic c c ca ar rb bo oc c
