1、 uChapter 8 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 baseMaci nt osh PI CTi mage f ormati s not support eduSome nucleophilic substitution rea
2、ctions Macintosh PICTimage formatis not supported a solvent that is a hydrogen bond donor 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 electronegativityuSolvents are classi
3、fied as polar and nonpolar the most common measure of solvent polarity 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 dissol
4、ved in that solvent polar solvent:dielectric constant 15 nonpolar solvent:dielectric constant 15Macintosh PICTim age form atis not supportedMacintosh PICTimage formatis not supporteduChemists propose two limiting mechanisms for nucleophilic substitution a fundamental difference between them is the t
5、iming 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-determining step)both reactants are involved in the transition state of the rate-determining stepMa
6、ci nt osh PI CTi mage f or mati s not suppor t eduBond breaking between carbon and the leaving group is entirely completed before bond forming with the nucleophile beginsuThis mechanism is designated SN1 where S=substitution N=nucleophilic 1=unimolecular(only one species is involved in the rate-dete
7、rmining step)Step 1:ionization of the C-X bond gives a carbocation intermediateMa c i n t o s h PI CTi ma g e f o r ma ti s n o t s u p p o r t e d Step 2:reaction of the carbocation(an electrophile)with methanol(a nucleophile)gives an oxonium ion Step 3:proton transfer completes the reactionMaci nt
8、osh PI CTi mage formati s not supportedMacintosh PICTimage formatis not supported1.What is relationship between the rate of an SN reaction and:the structure of Nu?the structure of RLv?the structure of the leaving group?the solvent?2.What is the stereochemical outcome if the leaving group is displace
9、d from a chiral center?3.Under what conditions are skeletal rearrangements observed?uFor an SN1 reaction reaction occurs in two steps the reaction leading to formation transition state for the carbocation intermediate involves only the haloalkane and not the nucleophile the result is a first-order r
10、eactionM a c in t o s h P IC Tim a g e f o r m a tis n o t s u p p o r t e duFor an SN2 reaction,reaction occurs in one step the reaction leading to the transition state involves the haloalkane and the nucleophile the result is a second-order reaction;first order in haloalkane and first order in nuc
11、leophileMaci nt osh PI CTi mage f ormati s not support ed 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 n
12、ucleophiles are also bases,we study correlations between nucleophilicity and basicityMacintosh PICTimage formatis not supporteduRelative nucleophilicities of halide ions in polar aprotic solvents are quite different from those in polar protic solventsuHow do we account for these differences?Increasi
13、ng NucleophilicitySolventPolar aproticPolar proticF-Cl-Br-I-I-Br-Cl-Cl-Br-I-uPolar protic solvents(e.g.,water,methanol)anions are highly solvated by hydrogen 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
14、 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,nucleophilicity is I-Br-Cl-F-uGeneralization within a row of the Periodic Table,nucleophilicity increases from left to right;that is,it increases with basicity
15、Increasing NucleophilicityPeriodPeriod 2Period 3F-OH-NH2-CH3-Cl-SH-PH2-uGeneralization 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 NucleophilicityROH RO-H2O OH-
16、NH3 NH2-RSH RS-uGeneralization when comparing groups of reagents in which the nucleophilic atom is the same,the stronger the base,the greater the nucleophilicity M a c in t o s h P IC Tim a g e f o r m a tis n o t s u p p o r t e duFor an SN1 reaction at a chiral center,the R and S enantiomers are f
17、ormed in equal amounts,and the product is a racemic mixtureCHClCl-Cl-C+HClCH3OH-H+CH3OCHClClCOCH3HR EnantiomerS Enantiomer+R EnantiomerA racemic mixturePlanar carbocation (achiral)uFor SN1 reactions at a chiral center examples of complete racemization have been observed,but partial racemization with
18、 a slight excess of inversion is more commonMaci nt osh PI CTi mage f or mati s not suppor t eduFor SN2 reactions at a chiral center,there is inversion of configuration at the chiral centeruExperiment of Hughes and IngoldMacintosh PICTimage formatis not supported the reaction is 2nd order,therefore,
19、SN2 the rate of racemization of enantiomerically pure 2-iodooctane is twice the rate of incorporation of I-131Maci nt osh PI CTi mage f or mati s not suppor t eduSN1 reactions:governed by electronic factors the relative stabilities of carbocation intermediatesuSN2 reactions:governed by steric factor
20、s the relative ease of approach of a nucleophile to the reaction siteGoverned byelectronic factorsGoverned bysteric factorsSN1SN2R3CXR2CHXRCH2XCH3XAccess to the site of reaction(3)(methyl)(2)(1)Carbocation stability1.2 x 10-51.2 x 10-3Relative RateAlkyl Bromideb b-Branches01231.04.1 x 10-1BrBrBrBrb
21、bb bb bb bMacintosh PICTimage formatis not supportedMacintosh PICTimage formatis not supportedMacintosh PICTimage formatis not supportedM a c in to s h P IC Tim a g e fo rm a tis n o t s u p p o rte dBromoethane(Ethyl bromide)Macintosh PICTimage formatis not supportedMacintosh PICTimage formatis not
22、 supportedMacintosh PICTimage formatis not supported1-Bromo-2,2-dimethylpropane(Neopentyl bromide)M a c in t o s h P IC Tim a g e f o r m a tis n o t s u p p o r t e duAllylic cations are stabilized by resonance delocalization of the positive charge a 1 allylic cation is about as stable as a 2 alkyl
23、 cation+Allyl cation(a hybrid of two equivalent contributing structures)CH2=CH-CH2CH2-CH=CH2 2&3 allylic cations are even more stable as also are benzylic cations adding these carbocations to those from Section 6.3Maci ntosh PI CTi mage formati s not supportedMaci ntosh PI CTi mage formati s not sup
24、portedMaci ntosh PI CTi mage formati s not supporteduThe more stable the anion,the better the leaving ability the most stable anions are the conjugate bases of strong acidsMaci nt osh PI CTi mage f or mati s not suppor t eduThe most common type of SN2 reaction involves a negative Nu and a negative l
25、eaving 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 SN2Maci nt osh PI CTi mage f or mati s not suppor t edBrN3-CH3CNCH3OHH2O(CH3)2S=O(CH3)2NCHON3Br-SolventTypepolar aproticpolar protic50002800130071k(methanol)k(so
26、lvent)Solvent+solventSN2+uSN1 reactions 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,wate
27、r,methanol)are the most effective solvents for SN1 reactionsMacintosh PICTimage formatis not supporteduRearrangements are common in SN1 reactions if the initial carbocation can rearrange to a more stable oneMacintosh PICTimage formatis not supporteduMechanism of a carbocation rearrangementMacintosh
28、PICTimage formatis not supportedMacintosh PICTimage formatis not supported predict the mechanism for this reaction,and the stereochemistry of each product predict the mechanism of this reactionMacintosh PICTimage formatis not supportedMacintosh PICTimage formatis not supported predict the mechanism
29、of this reaction and the configuration of product predict the mechanism of this reaction and the configuration of the productMacintosh PICTimage formatis not supportedMaci ntosh PI CTi mage formati s not supported predict the mechanism of this reactionMacintosh PICTimage formatis not supported a rea
30、ction in which a molecule,such as HCl,HBr,HI,or HOH,is split out or eliminated from adjacent carbonsMa c i n t o s h PI CTi ma g e f o r ma ti s n o t s u p p o r t e d the major product of a b b-elimination is the more stable(the more highly substituted)alkene2-Methyl-2-butene (major product)CH3CH2
31、O-Na+CH3CH2OH 2-Bromo-2-methylbutane2-Methyl-1-buteneBr+1-Methyl-cyclopentene(major product)CH3O-Na+CH3OH1-Bromo-1-methyl-cyclopentaneBrMethylene-cyclopentaneuThere are two limiting mechanisms for b b-elimination reactions at one extreme,breaking of the R-Lv bond to give a carbocation is complete be
32、fore reaction with base to break the C-H bond only R-Lv is involved in the rate-determining step at the other extreme,breaking of the R-Lv and C-H bonds is concerted both R-Lv and base are involved in the rate-determining step ionization of C-Lv gives a carbocation intermediate proton transfer from
33、the carbocation intermediate to the base(in this case,the solvent)gives the alkeneMaci nt osh PI CTi mage f or mati s not suppor t edMacintosh PICTimage formatis not supporteduE1 mechanism reaction occurs in two steps the rate-determining step is carbocation formation the reaction is 1st order in RL
34、v and zero order is baseuE2 mechanism reaction occurs in one step reaction is 2nd order;first order in RLv and 1st order in baseMacintosh PICTimage formatis not supportedMacintosh PICTimage formatis not supporteduE1:major product is the more stable alkeneuE2:with strong base,the major product is the
35、 more stable(more substituted)alkene double bond character is highly developed in the transition state thus,the transition state of lowest energy is that leading to the most stable(the most highly substituted)alkeneuE2:with a strong,sterically hindered base such as tert-butoxide,the major product is
36、 often the less stable(less substituted)alkeneuE2 is most favorable(lowest activation energy)when H and Lv are oriented anti and coplanarM a c i n t o s h P I C Ti m a g e f o r m a ti s n o t s u p p o r t e duConsider E2 of these stereoisomersMacintosh PICTimage formatis not supported in the more
37、stable chair of the cis isomer,the larger isopropyl is equatorial and chlorine is axialMa c i n t o s h P I C Ti ma g e f o r ma ti s n o t s u p p o r t e d in the more stable chair of the trans isomer,there is no H anti and coplanar with Lv,but there is one in the less stable chairM a c i n t o s
38、h P I C Ti m a g e f o r m a ti s n o t s u p p o r t e d it is only the less stable chair conformation of this isomer that can undergo an E2 reactionMaci nt osh PI CTi mage f or mati s not suppor t ed account for the fact that E2 reaction of the meso-dibromide gives only the E alkeneMaci nt osh PI
39、CTi mage f or mati s not suppor t edM a c in to s h P IC Tim a g e fo r m a tis n o t s u p p o r te duMany nucleophiles are also strong bases(OH-and RO-)and SN and E reactions often competeuThe ratio of SN/E products depends on the relative rates of the two reactionsMaci nt osh PI CTi mage f ormati
40、 s not support edM a c in to s h P IC Tim a g e fo r m a tis n o t s u p p o r te dThe main reaction with bases/nucleophiles where theR3CXpKa of the conjugate acid is 11 or less,as for exampleI-and CH3COO-.R2CHXMain reaction with strong bases such as HO-and RO-.Main reactions with poor nucleophiles/
41、weak bases.The main reaction with bases/nucleophiles whereE2SN2 E2SN2 reactions of tertiary halides are never observedSN1/E1SecondaryTertiarybecause of the extreme crowding around the 3 carbon.SN1/E1Common in reactions with weak nucleophiles in polarprotic solvents,such as water,methanol,and ethanol
42、.pKa of the conjugate acid is 11 or greater,as for exampleOH-and CH3CH2O-.uIn an SN2 reaction,departure of the leaving group is assisted by Nu;in an SN1 reaction,it is notuThese two types of reactions are distinguished by their order of reaction;SN2 reactions are 2nd order,and SN1 reactions are 1st
43、orderuBut some substitution reactions are 1st order and yet involve two successive SN2 reactionsuMustard gases contain either S-C-C-X or N-C-C-X what is unusual about the mustard gases is that they undergo hydrolysis so rapidly in water,a very poor nucleophileMacintosh PICTimage formatis not support
44、edBis(2-chloroethyl)sulfide(a sulfur mustard gas)Bis(2-chloroethyl)methylamine(a nitrogen mustard gas)ClSClClNCl the reason is neighboring group participation by the adjacent heteroatom proton transfer to solvent completes the reactionMa c i n t o s h P I CTi ma g e f o r ma ti s n o t s u p p o r t
45、 e duA substance that transfers ions from an aqueous phase to an organic phaseuAn effective phase-transfer catalyst must have sufficient hydrophilic character to dissolve in water and form an ion pair with the ion to be transported hydrophobic character to dissolve in the organic phase and transport the ion into ituThe following salt is an effective phase-transfer catalysts for the transport of anions(CH3CH2CH2CH2)4N+Cl-Tetrabutylammonium chloride(Bu4N+Cl-)
