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1 William H. Brown & Christopher S. Foote Organic ChemistryWilliam H. Brown & Christopher S. Foote
2 Nucleophilic Substitution and -Elimination Chapter 8Chapter 8
3 Nucleophilic Substitution Nucleophilic substitution: any reaction in which one nucleophile is substituted for another at a tetravalent carbonNucleophile: a molecule or ion that donates a pair of electrons to another molecule or ion to form a new covalent bond; a Lewis base
4 Nucleophilic Substitution An important reaction of alkyl halides
5 Solvents Protic solvent: a solvent that is a hydrogen bond donor the most common protic solvents contain -OH groupsAprotic solvent: a solvent that cannot serve as a hydrogen bond donornowhere in the molecule is there a hydrogen bonded to an atom of high electronegativity
6 Dielectric Constant Solvents are classified as polar and nonpolar the most common measure of solvent polarity is dielectric constantDielectric constant: a measure of a solvent’s ability to insulate opposite charges from one anotherthe greater the value of the dielectric constant of a solvent, the smaller the interaction between ions of opposite charge dissolved in that solventpolar solvent: dielectric constant > 15nonpolar solvent: dielectric constant < 15
9 MechanismsChemists propose two limiting mechanisms for nucleophilic displacementa fundamental difference between them is the timing of bond breaking and bond forming stepsAt one extreme, the two processes take place simultaneously; designated SN2S = substitutionN = nucleophilic2 = bimolecular (two species are involved in the rate-determining step)
10 Mechanism - SN2both reactants are involved in the transition state of the rate-determining step
12 Mechanism - SN1Bond breaking between carbon and the leaving group is entirely completed before bond forming with the nucleophile beginsThis mechanism is designated SN1 whereS = substitutionN = nucleophilic1 = unimolecular (only one species is involved in the rate-determining step)
13 Mechanism - SN1Step 1: ionization of the C-X bond gives a carbocation intermediate
14 Mechanism - SN1Step 2: reaction of the carbocation with methanol gives an oxonium ion. Attack occurs with equal probability from either face of the planar carbocationStep 3: proton transfer completes the reaction
16 Evidence of SN reactions 1. What is the rate of an SN reaction affected by:the structure of Nu?the structure of RX?the structure of the leaving group?the solvent?2. What is the stereochemistry of the product if the Nu attacks at a stereocenter?3. When and how does rearrangement occur?
17 KineticsFor an SN1 reaction, the rate of reaction is first order in haloalkane and zero order in nucleophile
18 KineticsFor an SN2 reaction, the rate is first order in haloalkane and first order in nucleophile
19 NucleophilicityNucleophilicity: a kinetic property measured by the rate at which a Nu causes a nucleophilic substitution under a standardized set of experimental conditionsBasicity: a equilibrium property measured by the position of equilibrium in an acid-base reactionBecause all nucleophiles are also bases, we study correlations between nucleophilicity and basicity
21 NucleophilicityRelative nucleophilicities of halide ions in polar aprotic solvents are quite different from those in polar protic solventsHow do we account for these differences?
22 NucleophilicityA guiding principle is the freer the nucleophile, the greater its nucleophilicityPolar aprotic solvents (e.g., DMSO, acetone, acetonitrile, DMF)are very effective in solvating cations, but not nearly so effective in solvating anions.because anions are only poorly solvated, they participate readily in SN reactions, andnucleophilicity parallels basicity: F- > Cl- > Br- > I-
23 Nucleophilicity Polar protic solvents (e.g., water, methanol) anions are highly solvated by hydrogen bonding with the solventthe more concentrated the negative charge of the anion, the more tightly it is held in a solvent shellthe nucleophile must be at least partially removed from its solvent shell to participate in SN reactionsbecause F- is most tightly solvated and I- the least, nucleophilicity is I- > Br- > Cl- > F-
24 Nucleophilicity Generalizations within a period, nucleophilicity increases from left to right; that is, it increases with basicity
25 Nucleophilicity Generalizations in a series of reagents with the same nucleophilic atom, anionic reagents are stronger nucleophiles than neutral reagents
26 Nucleophilicitywhen comparing groups of reagents in which the nucleophilic atom is the same, the stronger the base, the greater the nucleophilicity
27 StereochemistryFor an SN1 reaction at a stereocenter, the product is almost completely racemized
28 Stereochemistry For SN1 reactions at a stereocenter examples of complete racemization have been observed, butpartial racemization with a slight excess of inversion is more common
29 StereochemistryFor SN2 reactions at a stereocenter, there is inversion of configuration at the stereocenterExperiment of Hughes and Ingold
30 Hughes-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-131
31 Structure of RX SN1 reactions governed by electronic factors; the relative stabilities of carbocation intermediatesSN2 reactions governed by steric factors;the relative ease of approach of the nucleophile to the site of reaction
34 Allylic HalidesAllylic cations are stabilized by resonance delocalization of the positive chargea 1° allylic cation is about as stable as a 2° alkyl cation
35 Allylic Cations 2° & 3° allylic cations are even more stable As also are benzylic cations
36 The Leaving GroupThe more stable the anion, the better the leaving abilitythe most stable anions are the conjugate bases of strong acids
37 The Solvent - SN2The most common type of SN2 reaction involves a negative Nu and a negative leaving groupthe weaker the solvation of Nu, the less the energy required to remove it from its solvation shell and the greater the rate of SN2
39 The Solvent - SN1SN1 reactions involve creation and separation of unlike charge in the transition state of the rate-determining stepRate depends on the ability of the solvent to keep these charges separated and to solvate both the anion and the cationPolar protic solvents (formic acid, water, methanol) are the most effective solvents for SN1 reactions
44 Neighboring GroupsIn an SN1 reaction, departure of the leaving group is not assisted by NuIn an SN2 reaction, departure of the leaving group is assisted by NuThese two types are distinguished by their order of reaction; SN2 reactions are 2nd order, and SN1 reactions are 1st orderBut some reactions are 1st order and yet involve two successive SN2 reactions
45 Mustard Gases Mustard 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 nucleophile
46 Mustard Gasesthe reason is neighboring group participation by the adjacent heteroatomproton transfer to solvent completes the reaction
47 SN1/SN2 ProblemsProblem 1: predict the mechanism for this reaction, and the stereochemistry of each productProblem 2: predict the mechanism of this reaction
48 SN1/SN2 ProblemsProblem 3: predict the mechanism of this reaction and the configuration of productProblem 4: predict the mechanism of this reaction
49 SN1/SN2 ProblemsProblem 5: predict the mechanism of this reaction
50 Phase-Transfer Catalysis A substance that transfers ions from an aqueous phase to an organic phaseAn effective phase-transfer catalyst must have sufficienthydrophilic character to dissolve in water and form an ion pair with the ion to be transportedhydrophobic character to dissolve in the organic phase and transport the ion into itThe following salt is an effective phase-transfer catalysts for the transport of anions
52 -Elimination-Elimination: a reaction in which a small molecule, such as HCl, HI, or HOH, is split out or eliminated from a larger molecule
53 -EliminationZaitsev rule: the major product of a -elimination is the more stable (the more highly substituted) alkene
54 -EliminationThere are two limiting mechanisms for -elimination reactionsE1 mechanism: at one extreme, breaking of the R-X bond is complete before reaction with base to break the C-H bondonly R-X is involved in the rate-determining stepE2 mechanism: at the other extreme, breaking of the R-X and C-H bonds is concertedboth R-X and base are involved in the rate-determining step
55 E1 Mechanism ionization of C-X gives a carbocation intermediate proton transfer from the carbocation intermediate to the base (in this case, the solvent) gives the alkene
58 Kinetics of E1 and E2E1 is a 1st order reaction; 1st order in RX and zero order is baseE2 is a 2nd order reaction; 1st order in base and 1st order in RX
59 Regioselectivity of E1/E2 E1: major product is the more stable alkeneE2: with strong base, the major product is the more stable alkenedouble bond character is highly developed in the transition statethus, the transition state of lowest energy is that leading to the most stable (the most highly substituted) alkene
60 Stereoselectivity of E2 E2 is most favorable (lowest activation energy) when H and X are oriented anti and coplanar
61 Stereochemistry of E2Consider E2 of these stereoisomers
62 Stereochemistry of E2in the more stable chair of the cis isomer, the larger isopropyl is equatorial and chlorine is axial
63 Stereochemistry of E2in the more stable chair of the trans isomer, there is no H anti and coplanar with X, but there is one in the less stable chair
64 Stereochemistry of E2it is only the less stable chair conformation of this isomer that can undergo an E2 reaction
65 Stereochemistry of E2Problem: account for the fact that E2 reaction of the meso-dibromide gives only the E-alkene
74 Prob 8.14Account for the fact that the rate of this reaction is 1000 times faster in DMSO than it is in ethanol.
75 Prob 8.15The following reaction involves two successive SN2 reactions. Propose a structural formula for the product.
76 Prob 8.16Which member of each pair shows the greater rate of SN2 reaction with KI in acetone?
77 Prob 8.17Which member of each pair gives the greater rate of SN2 reaction with KN3 in acetone?
78 Prob 8.19Limiting yourself to a single 1,2-shift, suggest a structural formula for a more stable carbocation.
79 Prob 8.21Draw a structural formula for the product of each SN1 reaction.
80 Prob 8.24From each pair, select the compound that undergoes SN1 solvolysis in ethanol more rapidly.
81 Prob 8.25Account for the following relative rates on solvolysis under SN1 conditions.
82 Prob 8.26Explain why the following compound is very unreactive under SN1 conditions.
83 Prob 8.27Propose a synthesis for each compound from a haloalkane and a nucleophile.
84 Prob 8.29Propose a mechanism for the formation of each product.
85 Prob 8.30Propose a mechanism for the formation of this product. If the configuration of the starting material is S, what is the configuration of the product?
86 Prob 8.31Propose a mechanism for the formation of the products of this solvolysis reaction.
87 Prob 8.32Propose a mechanism for the formation of each product.
88 Prob 8.33Which compound in each set undergoes more rapid solvolysis when refluxed in ethanol?
89 Prob 8.34Account for these relative rates of solvolysis in acetic acid.
90 Prob 8.35On SN1 solvolysis in acetic acid, (1) reacts 1011 times faster than (2). Furthermore, solvolysis of (1) occurs with complete retention of configuration. Draw structural formulas for the products of each solvolysis and account for the difference in rates.
91 Prob 8.36Draw structural formulas for the alkene(s) formed on treatment of each compound with sodium ethoxide in ethanol. Assume reaction by an E2 mechanism.
92 Prob 8.37Draw structural for all chloroalkanes that undergo dehydrohalogenation when treated with KOH to give each alkene as the major product.
93 Prob 8.38On treatment with sodium ethoxide in ethanol, each compound gives 3,4-dimethyl-3-hexene. One compound gives an E alkene, the other gives a Z alkene. Which compound gives which alkene?
94 Prob 8.39On treatment with sodium ethoxide in ethanol, this compound gives a single stereoisomer. Predict whether the alkene has the E or Z configuration.
95 Prob 8.40Elimination of HBr from 2-bromonorbornane gives only 2-norbornene. Account for the regiospecificity of this elimination reaction.
96 Prob 8.43Arrange these haloalkanes in order of increasing ratio of E2 to SN2 products on reaction of each with sodium ethoxide in ethanol.
97 Prob 8.44Draw a structural formula for the major product of each reaction and specify the most likely mechanism for its formation.