Chapter 8Nucleophilic Substitution (in depth)& Competing Elimination8.1Functional Group Transformation By Nucleophilic Substitution

8.1Functional Group Transformation By Nucleophilic Substitution

Nucleophilic Substitutionnucleophile is a Lewis base (electron-pair donor)often negatively charged and used as Na+ or K+ saltsubstrate is usually an alkyl halideRXYR+ +

Nucleophilic SubstitutionSubstrate cannot be an a vinylic halide or anaryl halide, except under certain conditions tobe discussed in Chapter 23.X

Table 8.1 Examples of Nucleophilic Substitution+Alkoxide ion as the nucleophile

Example(CH3)2CHCH2ONa + CH3CH2BrIsobutyl alcohol

Table 8.1 Examples of Nucleophilic Substitution+Carboxylate ion as the nucleophile..O:..R'C

ExampleOK+CH3(CH2)16CCH3CH2Iacetone, water

Table 8.1 Examples of Nucleophilic Substitution+Hydrogen sulfide ion as the nucleophile

ExampleKSH + CH3CH(CH2)6CH3Brethanol, water

Table 8.1 Examples of Nucleophilic Substitution+Cyanide ion as the nucleophile

ExampleDMSONaCN+

Table 8.1 Examples of Nucleophilic SubstitutionAzide ion as the nucleophile

ExampleNaN3 + CH3CH2CH2CH2CH2I2-Propanol-water

Table 8.1 Examples of Nucleophilic Substitution+Iodide ion as the nucleophile

ExampleNaI is soluble in acetone; NaCl and NaBr are not soluble in acetone.acetone

8.2Relative Reactivity of Halide Leaving Groups

GeneralizationReactivity of halide leaving groups in nucleophilic substitution is the same as for elimination.

Problem 8.2Br is a better leaving group than ClBrCH2CH2CH2Cl + NaCNA single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product?

Problem 8.2BrCH2CH2CH2Cl + NaCNA single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product?

8.12Improved Leaving Groups Alkyl Sulfonates

Leaving GroupsWe have seen numerous examples of nucleophilic substitution in which X in RX is a halogen.Halogen is not the only possible leaving group, though.

Other RX Compoundsundergo same kinds of reactions as alkyl halidesAlkyl methanesulfonate (mesylate)Alkyl p-toluenesulfonate (tosylate)

Preparation(abbreviated as ROTs)pyridineTosylates are prepared by the reaction of alcohols with p-toluenesulfonyl chloride (usually in the presence of pyridine).

Tosylates Undergo Typical Nucleophilic Substitution ReactionsKCNethanol- water

The best leaving groups are weakly basic.

Table 8.8Approximate Relative Reactivity of Leaving GroupsLeaving Relative Conjugate acidpKa of Group Rateof leaving group conj. acid F10-5HF3.5Cl1HCl-7Br10HBr-9I102HI-10H2O101 H3O+-1.7TsO105 TsOH-2.8 CF3SO2O 108 CF3SO2OH -6

Table 8.8Approximate Relative Reactivity of Leaving GroupsLeaving Relative Conjugate acidpKa of Group Rateof leaving group conj. acid F10-5HF3.5Cl1HCl-7Br10HBr-9I102HI-10H2O101 H3O+-1.7TsO105 TsOH-2.8 CF3SO2O 108 CF3SO2OH -6Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.

Tosylates can be Converted to Alkyl HalidesTosylate is a better leaving group than bromide.NaBrDMSO(82%)

Tosylates Allow Control of StereochemistryPreparation of tosylate does not affect any of the bonds to the chirality center, so configuration and optical purity of tosylate is the same as the alcohol from which it was formed.TsClpyridine

Tosylates Allow Control of StereochemistryHaving a tosylate of known optical purity and absolute configuration then allows the preparation of other compounds of known configuration by SN2 processes.

8.3The SN2 Mechanism of Nucleophilic Substitution

KineticsMany nucleophilic substitutions follow a second-order rate law. CH3Br + HO CH3OH + Br rate = k[CH3Br][HO ]inference: rate-determining step is bimolecular

Bimolecular Mechanismone step

StereochemistryNucleophilic substitutions that exhibit second-order kinetic behavior are stereospecific and proceed with inversion of configuration.

Inversion of Configuration

Stereospecific ReactionA stereospecific reaction is one in which stereoisomeric starting materials give stereoisomeric products.The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific.(+)-2-Bromooctane ()-2-Octanol()-2-Bromooctane (+)-2-Octanol

Stereospecific ReactionNaOH(S)-(+)-2-Bromooctane

Problem 8.4The Fischer projection formula for (+)-2-bromooctane is shown. Write the Fischer projection of the ()-2-octanol formed from it by nucleophilic substitution with inversion of configuration.

Problem 8.4The Fischer projection formula for (+)-2-bromooctane is shown. Write the Fischer projection of the ()-2-octanol formed from it by nucleophilic substitution with inversion of configuration.

8.4Steric Effects and SN2 Reaction Rates

Crowding at the Reaction SiteCrowding at the carbon that bears the leaving group slows the rate of bimolecular nucleophilic substitution.The rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects.

Table 8.2 Reactivity Toward Substitution by the SN2 MechanismAlkylClassRelative bromiderateCH3BrMethyl221,000CH3CH2BrPrimary1,350(CH3)2CHBrSecondary1(CH3)3CBrTertiarytoo small to measureRBr + LiI RI + LiBr

Decreasing SN2 ReactivityCH3BrCH3CH2Br(CH3)2CHBr(CH3)3CBr

Decreasing SN2 ReactivityCH3BrCH3CH2Br(CH3)2CHBr(CH3)3CBr

Crowding Adjacent to the Reaction SiteThe rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects.

Crowding at the carbon adjacent to the one that bears the leaving group also slows the rate of bimolecular nucleophilic substitution, but the effect is smaller.

Table 8.3 Effect of Chain Branching on Rate of SN2 SubstitutionAlkylStructureRelative bromiderateEthylCH3CH2Br1.0PropylCH3CH2CH2Br0.8Isobutyl(CH3)2CHCH2Br0.036Neopentyl(CH3)3CCH2Br0.00002RBr + LiI RI + LiBr

8.5Nucleophiles and Nucleophilicity

NucleophilesAll nucleophiles, however, are Lewis bases.

Nucleophiles..for exampleMany of the solvents in which nucleophilic substitutions are carried out are themselves nucleophiles.

SolvolysisThe term solvolysis refers to a nucleophilicsubstitution in which the nucleophile is the solvent.

Solvolysissubstitution by an anionic nucleophileRX + :NuRNu + :X

Solvolysis+substitution by an anionic nucleophileRX + :NuRNu + :XsolvolysisRX + :NuHRNuH + :XRNu + HXproducts of overall reaction

Example: MethanolysisRXMethanolysis is a nucleophilic substitution in which methanol acts as both the solvent and the nucleophile.+

Typical solvents in solvolysissolventproduct from RX water (HOH)ROHmethanol (CH3OH)ROCH3ethanol (CH3CH2OH)ROCH2CH3

formic acid (HCOH)

acetic acid (CH3COH)ROCCH3ROCH

Nucleophilicity is a measure of the reactivity of a nucleophileTable 8.4 compares the relative rates of nucleophilic substitution of a variety of nucleophiles toward methyl iodide as the substrate. The standard of comparison is methanol, which is assigned a relative rate of 1.0.

Table 8.4 NucleophilicityRankNucleophileRelative rate strongI-, HS-, RS->105good Br-, HO-, 104RO-, CN-, N3-fairNH3, Cl-, F-, RCO2-103weakH2O, ROH1very weakRCO2H10-2

Major factors that control nucleophilicitybasicitysolvationsmall negative ions are highly solvated in protic solventslarge negative ions are less solvated

Table 8.4 NucleophilicityRankNucleophileRelative rate good HO, RO104fairRCO2103weakH2O, ROH1When the attacking atom is the same (oxygen in this case), nucleophilicity increases with increasing basicity.

Major factors that control nucleophilicitybasicitysolvationsmall negative ions are highly solvated in protic solventslarge negative ions are less solvated

Figure 8.3Solvation of a chloride ion by ion-dipole attractive forces with water. The negatively charged chloride ion interacts with the positively polarized hydrogens of water.

Table 8.4 NucleophilicityRankNucleophileRelative ratestrongI->105good Br-104fairCl-, F-103A tight solvent shell around an ion makes it less reactive. Larger ions are less solvated than smaller ones and are more nucleophilic.

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