案例有机化学11chapter reactions of alkyl halides nucleophilic substitu48

1、Chapter 11Reactions of Alkyl Halides: Nucleophilic Substitutions and EliminationsAlkyl halides are polarized at the carbon-halide bond, making the carbon electrophilicNucleophiles will replace the halide in C-X bonds of many alkyl halides (reaction as Lewis base)Nucleophiles that are Brnsted bases p

2、roduce eliminationAlkyl Halides React with Nucleophiles and BasesNucleophilic substitution, base induced elimination are among most widely occurring and versatile reaction types in organic chemistryReactions will be examined closely to see:How they occurWhat their characteristics areHow they can be

3、usedWhy this Chapter?In 1896, Walden showed that (-)-malic acid could be converted to (+)-malic acid by a series of chemical steps with achiral reagentsThis established that optical rotation was directly related to chirality and that it changes with chemical alterationReaction of (-)-malic acid with

4、 PCl5 gives (+)-chlorosuccinic acidFurther reaction with wet silver oxide gives (+)-malic acidThe reaction series starting with (+) malic acid gives (-) acid11.1 The Discovery of Nucleophilic Substitution ReactionsReactions of the Walden InversionThe reactions alter the array at the chirality center

5、The reactions involve substitution at that centerTherefore, nucleophilic substitution can invert the configuration at a chirality centerThe presence of carboxyl groups in malic acid led to some dispute as to the nature of the reactions in Waldens cycleSignificance of the Walden InversionReaction is

6、with inversion at reacting centerFollows second order reaction kineticsIngold nomenclature to describe characteristic step:S=substitutionN (subscript) = nucleophilic 2 = both nucleophile and substrate in characteristic step (bimolecular)11.2 The SN2 ReactionRate (V) is change in concentration with t

7、imeDepends on concentration(s), temperature, inherent nature of reaction (barrier on energy surface)A rate law describes relationship between the concentration of reactants and conversion to productsA rate constant (k) is the proportionality factor between concentration and rateExample: for S conver

8、ting to PV = dS/dt = k SKinetics of Nucleophilic SubstitutionThe study of rates of reactions is called kineticsRates decrease as concentrations decrease but the rate constant does notRate units: concentration/time such as mol/(L x s)The rate law is a result of the mechanismThe order of a reaction is

9、 sum of the exponents of the concentrations in the rate law the example is second orderReaction KineticsThe reaction involves a transition state in which both reactants are togetherSN2 ProcessThe transition state of an SN2 reaction has a roughly planar arrangement of the carbon atom and the remainin

10、g three groups SN2 Transition StateSensitive to steric effectsMethyl halides are most reactivePrimary are next most reactiveSecondary might reactTertiary are unreactive by this pathNo reaction at C=C (vinyl halides)11.3 Characteristics of the SN2 ReactionHigher reactant energy level (red curve) = fa

11、ster reaction (smaller G).Higher transition state energy level (red curve) = slower reaction (larger G).Reactant and Transition State Energy Levels Affect RateThe carbon atom in (a) bromomethane is readily accessibleresulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane (primary), (c)

12、 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower SN2 reactions. Steric Effects on SN2 ReactionsThe more alkyl groups connected to the reacting carbon, the slower the reactionOrder of Reactivity in SN2Neutral or n

13、egatively charged Lewis baseReaction increases coordination at nucleophileNeutral nucleophile acquires positive chargeAnionic nucleophile es neutralSee Table 11-1 for an illustrative listThe NucleophileDepends on reaction and conditions More basic nucleophiles react faster Better nucleophiles are lo

14、wer in a column of the periodic tableAnions are usually more reactive than neutralsRelative Reactivity of NucleophilesA good leaving group reduces the barrier to a reactionStable anions that are weak bases are usually excellent leaving groups and can delocalize chargeThe Leaving GroupIf a group is v

15、ery basic or very small, it prevents reactionAlkyl fluorides, alcohols, ethers, and amines do not typically undergo SN2 reactions.Poor Leaving GroupsSolvents that can donate hydrogen bonds (-OH or NH) slow SN2 reactions by associating with reactantsEnergy is required to break interactions between re

16、actant and solventPolar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reactionThe SolventTertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to addition of the nucleophileCalled an SN1

17、reaction occurs in two distinct steps while SN2 occurs with both events in same stepIf nucleophile is present in reasonable concentration (or it is the solvent), then ionization is the slowest step 11.4 The SN1 ReactionRate-determining step is formation of carbocationV = kRXSN1 Energy DiagramThe ove

18、rall rate of a reaction is controlled by the rate of the slowest stepThe rate depends on the concentration of the species and the rate constant of the stepThe highest energy transition state point on the diagram is that for the rate determining step (which is not always the highest barrier)Rate-Limi

19、ting StepThe planar intermediate leads to loss of chiralityA free carbocation is achiralProduct is racemic or has some inversionStereochemistry of SN1 ReactionCarbocation is biased to react on side opposite leaving groupSuggests reaction occurs with carbocation loosely associated with leaving group

20、during nucleophilic additionAlternative that SN2 is also occurring is unlikelySN1 in RealityIf leaving group remains associated, then product has more inversion than retentionProduct is only partially racemic with more inversion than retentionAssociated carbocation and leaving group is an ion pairEf

21、fects of Ion Pair FormationSubstrateTertiary alkyl halide is most reactive by this mechanismControlled by stability of carbocationRemember Hammond postulate,”Any factor that stabilizes a high-energy intermediate stabilizes transition state leading to that intermediate”11.5 Characteristics of the SN1

22、 ReactionAllylic and benzylic intermediates stabilized by delocalization of chargePrimary allylic and benzylic are also more reactive in the SN2 mechanismAllylic and Benzylic HalidesCritically dependent on leaving groupReactivity: the larger halides ions are better leaving groupsIn acid, OH of an al

23、cohol is protonated and leaving group is H2O, which is still less reactive than halidep-Toluenesulfonate (TosO-) is excellent leaving groupEffect of Leaving Group on SN1Since nucleophilic addition occurs after formation of carbocation, reaction rate is not normally affected by nature or concentratio

24、n of nucleophileNucleophiles in SN1Stabilizing carbocation also stabilizes associated transition state and controls rateSolvent effects in the SN1 reaction are due largely to stabilization or destabilization of the transition stateSolvent in SN1Polar, protic and unreactive Lewis base solvents facili

25、tate formation of R+ Solvent polarity is measured as dielectric polarization (P) Nonpolar solvents have low PPolar solvents have high P valuesPolar Solvents Promote IonizationSN1 and SN2 reactions are well known in biological chemistryUnlike what happens in the laboratory, substrate in biological su

26、bstitutions is often organodiphosphate rather than an alkyl halide11.6 Biological Substitution ReactionsElimination is an alternative pathway to substitutionOpposite of additionGenerates an alkeneCan compete with substitution and decrease yield, especially for SN1 processes11.7 Elimination Reactions

27、 of Alkyl Halides: Zaitsevs RuleIn the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates Zaitsevs Rule for Elimination Reactions Ingold nomenclature: E “elimination”E1: X- leaves first to generate a carbocation a base abstracts a proton from the carbocat

28、ionE2: Concerted transfer of a proton to a base and departure of leaving groupMechanisms of Elimination ReactionsA proton is transferred to base as leaving group begins to departTransition state combines leaving of X and transfer of HProduct alkene forms stereospecifically11.8 The E2 Reaction and th

29、e Deuterium Isotope Effectallows orbital overlap and minimizes steric interactionsGeometry of Elimination E2Overlap of the developing orbital in the transition state requires periplanar geometry, anti arrangementE2 Stereochemistry E2 is stereospecificMeso-1,2-dibromo-1,2-diphenylethane with base giv

30、es cis 1,2-diphenylRR or SS 1,2-dibromo-1,2-diphenylethane gives trans 1,2-diphenylPredicting ProductAbstracted proton and leaving group should align trans-diaxial to be anti periplanar (app) in approaching transition state Equatorial groups are not in proper alignment11.9 The E2 Reaction and Cyclohexene FormationCompe