William H. Brown & Christopher S. Foote Organic Chemistry William H. Brown & Christopher S. Foote

Nucleophilic Substitution and -Elimination Chapter 8 Chapter 8

Nucleophilic Substitution Nucleophilic substitution: any reaction in which one nucleophile is substituted for another at a tetravalent carbon Nucleophile: a molecule or ion that donates a pair of electrons to another molecule or ion to form a new covalent bond; a Lewis base

Nucleophilic Substitution An important reaction of alkyl halides

Solvents Protic solvent: a solvent that is a hydrogen bond donor the most common protic solvents contain -OH groups Aprotic solvent: a solvent that cannot serve as a hydrogen bond donor nowhere in the molecule is there a hydrogen bonded to an atom of high electronegativity

Dielectric Constant Solvents are classified as polar and nonpolar the most common measure of solvent polarity is dielectric constant Dielectric constant: a measure of a solvent’s 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 solvent: dielectric constant < 15

Protic Solvents

Aprotic Solvents

Mechanisms Chemists propose two limiting mechanisms for nucleophilic displacement a fundamental difference between them is the timing of bond breaking and bond forming steps At 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)

Mechanism - SN2 both reactants are involved in the transition state of the rate-determining step

Mechanism - SN2

Mechanism - SN1 Bond breaking between carbon and the leaving group is entirely completed before bond forming with the nucleophile begins This 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 intermediate

Mechanism - SN1 Step 2: reaction of the carbocation with methanol gives an oxonium ion. Attack occurs with equal probability from either face of the planar carbocation Step 3: proton transfer completes the reaction

Mechanism - SN1

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?

Kinetics For an SN1 reaction, the rate of reaction is first order in haloalkane and zero order in nucleophile

Kinetics For an SN2 reaction, the rate is first order in haloalkane and first order in nucleophile

Nucleophilicity Nucleophilicity: a kinetic property measured by the rate at which a Nu causes a nucleophilic substitution under a standardized set of experimental conditions Basicity: a equilibrium property measured by the position of equilibrium in an acid-base reaction Because all nucleophiles are also bases, we study correlations between nucleophilicity and basicity

Nucleophilicity

Nucleophilicity Relative nucleophilicities of halide ions in polar aprotic solvents are quite different from those in polar protic solvents How do we account for these differences?

Nucleophilicity A guiding principle is the freer the nucleophile, the greater its nucleophilicity Polar 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, and nucleophilicity parallels basicity: F- > Cl- > Br- > I-

Nucleophilicity Polar 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 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-

Nucleophilicity Generalizations within a period, nucleophilicity increases from left to right; that is, it increases with basicity

Nucleophilicity Generalizations in a series of reagents with the same nucleophilic atom, anionic reagents are stronger nucleophiles than neutral reagents

Nucleophilicity when comparing groups of reagents in which the nucleophilic atom is the same, the stronger the base, the greater the nucleophilicity

Stereochemistry For an SN1 reaction at a stereocenter, the product is almost completely racemized

Stereochemistry For SN1 reactions at a stereocenter examples of complete racemization have been observed, but partial racemization with a slight excess of inversion is more common

Stereochemistry For SN2 reactions at a stereocenter, there is inversion of configuration at the stereocenter Experiment of Hughes and Ingold

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

Structure of RX SN1 reactions governed by electronic factors; the relative stabilities of carbocation intermediates SN2 reactions governed by steric factors; the relative ease of approach of the nucleophile to the site of reaction

Effect of -Branching

Effect of -Branching

Allylic Halides Allylic cations are stabilized by resonance delocalization of the positive charge a 1° allylic cation is about as stable as a 2° alkyl cation

Allylic Cations 2° & 3° allylic cations are even more stable As also are benzylic cations

The Leaving Group The more stable the anion, the better the leaving ability the most stable anions are the conjugate bases of strong acids

The Solvent - SN2 The 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

The Solvent - SN2

The Solvent - SN1 SN1 reactions involve creation and separation of unlike charge in the transition state of the rate-determining step Rate depends on the ability of the solvent to keep these charges separated and to solvate both the anion and the cation Polar protic solvents (formic acid, water, methanol) are the most effective solvents for SN1 reactions

The Solvent - SN1

Rearrangements in SN1 Rearrangements are common in SN1 reactions if the initial carbocation can rearrange to a more stable one

Rearrangements in SN1 Mechanism of a carbocation rearrangement

Summary of SN1 & SN2

Neighboring Groups In an SN1 reaction, departure of the leaving group is not assisted by Nu In an SN2 reaction, departure of the leaving group is assisted by Nu These two types are distinguished by their order of reaction; SN2 reactions are 2nd order, and SN1 reactions are 1st order But some reactions are 1st order and yet involve two successive SN2 reactions

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

Mustard Gases the reason is neighboring group participation by the adjacent heteroatom proton transfer to solvent completes the reaction

SN1/SN2 Problems Problem 1: predict the mechanism for this reaction, and the stereochemistry of each product Problem 2: predict the mechanism of this reaction

SN1/SN2 Problems Problem 3: predict the mechanism of this reaction and the configuration of product Problem 4: predict the mechanism of this reaction

SN1/SN2 Problems Problem 5: predict the mechanism of this reaction

Phase-Transfer Catalysis A substance that transfers ions from an aqueous phase to an organic phase An 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 it The following salt is an effective phase-transfer catalysts for the transport of anions

Phase-Transfer Catalysis

-Elimination -Elimination: a reaction in which a small molecule, such as HCl, HI, or HOH, is split out or eliminated from a larger molecule

-Elimination Zaitsev rule: the major product of a -elimination is the more stable (the more highly substituted) alkene

-Elimination There are two limiting mechanisms for -elimination reactions E1 mechanism: at one extreme, breaking of the R-X bond is complete before reaction with base to break the C-H bond only R-X is involved in the rate-determining step E2 mechanism: at the other extreme, breaking of the R-X and C-H bonds is concerted both R-X and base are involved in the rate-determining step

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

E1 Mechanism

E2 Mechanism

Kinetics of E1 and E2 E1 is a 1st order reaction; 1st order in RX and zero order is base E2 is a 2nd order reaction; 1st order in base and 1st order in RX

Regioselectivity of E1/E2 E1: major product is the more stable alkene E2: with strong base, the major product is the more stable 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) alkene

Stereoselectivity of E2 E2 is most favorable (lowest activation energy) when H and X are oriented anti and coplanar

Stereochemistry of E2 Consider E2 of these stereoisomers

Stereochemistry of E2 in the more stable chair of the cis isomer, the larger isopropyl is equatorial and chlorine is axial

Stereochemistry of E2 in 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

Stereochemistry of E2 it is only the less stable chair conformation of this isomer that can undergo an E2 reaction

Stereochemistry of E2 Problem: account for the fact that E2 reaction of the meso-dibromide gives only the E-alkene

Summary of E2 vs E1

SN vs E Many nucleophiles are also strong bases (OH- and RO-) and SN and E reactions often compete The ratio of SN/E products depends on the relative rates of the two reactions

SN vs E

SN vs E (cont’d)

Prob 8.9 Draw a structural formula for the most stable carbocation of each molecular formula.

Prob 8.11 From each pair, select the stronger nucleophile.

Prob 8.12 Draw a structural formula for the product of each SN2 reaction.

Prob 8.12 (cont’d)

Prob 8.14 Account for the fact that the rate of this reaction is 1000 times faster in DMSO than it is in ethanol.

Prob 8.15 The following reaction involves two successive SN2 reactions. Propose a structural formula for the product.

Prob 8.16 Which member of each pair shows the greater rate of SN2 reaction with KI in acetone?

Prob 8.17 Which member of each pair gives the greater rate of SN2 reaction with KN3 in acetone?

Prob 8.19 Limiting yourself to a single 1,2-shift, suggest a structural formula for a more stable carbocation.

Prob 8.21 Draw a structural formula for the product of each SN1 reaction.

Prob 8.24 From each pair, select the compound that undergoes SN1 solvolysis in ethanol more rapidly.

Prob 8.25 Account for the following relative rates on solvolysis under SN1 conditions.

Prob 8.26 Explain why the following compound is very unreactive under SN1 conditions.

Prob 8.27 Propose a synthesis for each compound from a haloalkane and a nucleophile.

Prob 8.29 Propose a mechanism for the formation of each product.

Prob 8.30 Propose a mechanism for the formation of this product. If the configuration of the starting material is S, what is the configuration of the product?

Prob 8.31 Propose a mechanism for the formation of the products of this solvolysis reaction.

Prob 8.32 Propose a mechanism for the formation of each product.

Prob 8.33 Which compound in each set undergoes more rapid solvolysis when refluxed in ethanol?

Prob 8.34 Account for these relative rates of solvolysis in acetic acid.

Prob 8.35 On 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.

Prob 8.36 Draw structural formulas for the alkene(s) formed on treatment of each compound with sodium ethoxide in ethanol. Assume reaction by an E2 mechanism.

Prob 8.37 Draw structural for all chloroalkanes that undergo dehydrohalogenation when treated with KOH to give each alkene as the major product.

Prob 8.38 On 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?

Prob 8.39 On treatment with sodium ethoxide in ethanol, this compound gives a single stereoisomer. Predict whether the alkene has the E or Z configuration.

Prob 8.40 Elimination of HBr from 2-bromonorbornane gives only 2-norbornene. Account for the regiospecificity of this elimination reaction.

Prob 8.43 Arrange these haloalkanes in order of increasing ratio of E2 to SN2 products on reaction of each with sodium ethoxide in ethanol.

Prob 8.44 Draw a structural formula for the major product of each reaction and specify the most likely mechanism for its formation.

Prob 8.44 (cont’d)

Prob 8.45 Propose a mechanism for the formation of each product.

Prob 8.46 Show how to bring about each conversion.

Prob 8.46 (cont’d) Show how to bring about each conversion.

Prob 8.47 Which reaction gives the tert-butyl ether in good yield? What is the product of the other reaction?

Prob 8.48 Each ether can, in principle, by synthesized by a Williamson ether synthesis forming bond (1) or bond (2). Which combination gives the better yield?

Prob 8.49 Propose a mechanism for this reaction.

Prob 8.50 Each compound can be synthesized by an SN2 reaction. Propose a combination of haloalkane and nucleophile that will give each product.

Prob 8.50 (cont’d)

Nucleophilic Substitution and -Elimination End Chapter 8