Chapter 9 Nucleophilic Substitution and ß-Elimination
Nucleophilic Substitution Nucleophile: From the Greek meaning nucleus loving. A molecule or ion that donates a pair of electrons to another atom or ion to form a new covalent bond; a Lewis base. Nucleophilic substitution: Any reaction in which one nucleophile substitutes for another at a tetravalent carbon. 2
Nucleophilic Substitution Electrostatic potential map showing the nucleophile (OH - ) reacting at its negative (red) end with the electrophilic carbon (blue) in the reaction of hydroxide with chloromethane. Electrophile: from the Greek meaning electron loving. A molecule or ion that accepts a pair of electrons from another molecule or anion; A Lewis acid. 3
Nucleophilic Substitution-Haloalkanes Table 9.1 Some nucleophilic substitution reactions 4
Mechanisms Chemists propose two limiting mechanisms for nucleophilic substitution. 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 S N 2. S = substitution N = nucleophilic 2 = bimolecular (two species are involved in the ratedetermining step) 5
Mechanism - S N 2 Make a bond between a nucleophile and an electrophile and simultaneously break a bond to give stable molecules or ions. Both reactants are involved in the transition state of the rate-determining step. 6
Mechanism - S N 2 Figure 9.1 An energy diagram for an S N 2 reaction. One transition state and no reactive intermediate. 7
Mechanism - S N 1 Bond breaking between carbon-leaving group (C-Lv) is entirely completed before bond forming with the nucleophile begins. This mechanism is designated S N 1 where S = substitution N = nucleophilic 1 = unimolecular (only one species is involved in the ratedetermining step) 8
Mechanism - S N 1 Step 1: Beak a bond to give stable molecules and ions. Ionization of the C-Lv bond gives a carbocation intermediate. 9
Mechanism - S N 1 Step 2: Make a bond between a nucleophile and an electrophile. Reaction of the carbocation on either face with methanol gives an oxonium ion. Step 3 Take a proton away. Proton transfer completes the reaction. 10
Mechanism - S N 1 Figure 9.2 Energy diagram for an S N 1 reaction. There are three transition states. Step1 crosses the highest energy barrier and is rate determining. 11
Evidence of S N reactions 1. What is relationship between the rate of an S N reaction and the structure of Nu? the structure of the haloalkane? the structure of the leaving group? the solvent? 2. What is the stereochemical outcome if the leaving group is displaced from a chiral center? 3. Under what conditions are skeletal rearrangements observed? 12
Kinetics For S N 1 Reaction occurs in two steps. The reaction leading to formation of the transition state for the carbocation intermediate involves only the haloalkane and not the nucleophile. The result is a first-order reaction. 13
Kinetics For S N 2 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 nucleophile. 14
Stereochemistry For an S N 1 reaction at a chiral center attack is on a p orbital with two faces. One gives an R enantiomer, the other gives an S enantiomer. The product is a racemic mixture. 15
Stereochemistry For S N 1 reactions at a chiral center Examples of complete racemization have been observed, but Partial racemization with a slight excess of inversion is more common. 16
Stereochemistry For an S N 2 reaction at a chiral center, there is inversion of configuration at the chiral center. Experiment of Hughes and Ingold 17
Stereochemistry The reaction is 2nd order and therefore, S N 2. The rate of racemization of enantiomerically pure 2-iodooctane is twice the rate of incorporation of I-131. 18
Carbocation Stability Allylic cations are stabilized by resonance delocalization of the positive charge. A 1 allylic cation is about as stable as a 2 alkyl cation. 19
Carbocation Stability-Allylic Cations 2 & 3 allylic cations are even more stable. as also are benzylic cations. adding these carbocations to those from Section 6.3A. 20
Effect of -Branching 21
Effect of -Branching 22
Structure of RX S N 1 reactions: governed by electronic factors namely, the relative stabilities of the carbocation intermediates. S N 2 reactions: governed by steric factors namely, the relative ease of approach of a nucleophile to the reaction site. 23
The Leaving Group The more stable the anion, the better the leaving ability. The most stable anions and the best leaving groups are the conjugate bases of strong acids. 24
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. 25
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. 26
Aprotic Solvents 27
Protic Solvents 28
Aprotic solvents 29
The Solvent - S N 2 The most common type of S N 2 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 S N 2. 30
The Solvent - S N 2 31
The Solvent - S N 1 S N 1 reactions involve the creation and separation of unlike charges in the transition state of the ratedetermining 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 S N 1 reactions. 32
The Solvent - S N 1 33
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: An 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. 34
Nucleophilicity 35
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? 36
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 S N 2 reactions, and nucleophilicity parallels basicity: F - > Cl - > Br - > I -. 37
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 S N 2 reactions. Because F - is most tightly solvated and I - the least, nucleophilicity is I - > Br - > Cl - > F -. 38
Nucleophilicity Generalization Within a row of the Periodic Table, nucleophilicity increases from left to right; that is, increases with basicity. 39
Nucleophilicity Generalization 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 nucleophile. 40
Nucleophilicity Generalization When comparing groups of reagents in which the nucleophilic atom is the same, the stronger the base, the greater the nucleophilicity. 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 nucleophile. 41
Rearrangements in S N 1 Rearrangements are common in S N 1 reactions if the initial carbocation can rearrange to a more stable one. 42
Rearrangements in S N 1 Mechanism of a carbocation rearrangement 43
Summary of S N 1 & S N 2 44
S N 1/S N 2 Problems Problem 1: Predict the mechanism for this reaction, and the stereochemistry of each product. Problem 2: Predict the mechanism of this reaction. 45
S N 1/S N 2 Problems Problem 3: Predict the mechanism of this reaction and the configuration of product. Problem 4: Predict the mechanism of this reaction and the configuration of the product. 46
S N 1/S N 2 Problems Problem 5: Predict the mechanism of this reaction. 47
-Elimination -Elimination: A reaction in which a small molecule, such as HCl, HBr, HI, or HOH, is split out or eliminated from adjacent carbons. 48
-Elimination Zaitsev rule: The major product of a -elimination is the more stable (the more highly substituted) alkene. 49
-Elimination There are two limiting mechanisms for -elimination reactions. E1 mechanism: At one extreme, breaking of the R-Lv bond to give a carbocation is complete before reaction with base to break the C-H bond. Only R-Lv is involved in the rate-determining step. E2 mechanism: 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. 50
E1 Mechanism Step 1: Break a bond to give stable molecules or ions. Rate-determining ionization of the C-Lv bond gives a carbocation intermediate. Step 2: Take a proton away. Proton transfer from the carbocation intermediate to the base (in this case, the solvent) gives the alkene. 51
E1 Mechanism Figure 9.6 Energy diagram for an E1 reaction. Two transition states and one carbocation intermediate. 52
E2 Mechanism Figure 9.7 Energy diagram for an E2 reaction. There is considerable double bond character in the transition state. 53
Kinetics of E1 and E2 E1 mechanism Reaction occurs in two steps. The rate-determining step is carbocation formation. Reaction is 1st order in R-Lv and zero order is base. E2 mechanism Reaction occurs in one step. Reaction is 2nd order; first order in R-Lv and 1st order in base. 54
Regioselectivity of E1/E2 E1: major product is the more stable alkene. E2: with strong base, the major product is the 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) alkene. E2: with a strong, sterically hindered base such as tertbutoxide, the major product is often the less stable (less substituted) alkene. 55
Stereoselectivity of E2 E2 is most favorable (lowest activation energy) when H and Lv are oriented anti and coplanar. 56
Stereoselectivity of E2 There is an orbital-based reason for the anti and coplanar arrangement of -H and -Lv involved in E2 reactions. 57
Stereochemistry of E2 Consider E2 of this haloalkane. 58
Stereochemistry of E2 In the more stable chair form of the trans isomer, there is no H anti and coplanar with Lv, but there is one in the less stable chair. 59
Stereochemistry of E2 It is only the less stable chair conformation of the trans isomer that can undergo an E2 reaction. 60
Stereochemistry of E2 Problem: Account for the fact that the E2 reaction of the mesodibromide gives only the E alkene. 61
Summary of E2 vs. E1 62
S N versus E Many nucleophiles are also strong bases (OH - and RO - ) and S N and E reactions often compete. The ratio of S N /E products depends on the relative rates of the two reactions. 63
S N vs. E 64
S N vs. E (cont d) 65
Participation by Neighboring Groups In an S N 2 reaction, departure of the leaving group is assisted by Nu: whereas in an S N 1 reaction, it is not. These two types of reactions are distinguished by their order of reaction; S N 2 reactions are 2nd order, and S N 1 reactions are 1st order. But some substitution reactions are 1st order and yet involve two successive S N 2 reactions. 66
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 are primary halides and yet undergo rapid hydrolysis in water, a very poor nucleophile. 67
Mustard Gases Step 1: Make a new bond between a nucleophile and an electrophile and simultaneously break a bond to give stable molecules or ions. Step 2: Make a new bond between a nucleophile and an electrophile. Proton transfer to solvent completes the reaction. 68
Problem 9.46 When cis-4-chlorocyclohexanol is treated with sodium hydroxide in ethanol, it gives mainly the substitution product trans-1, 4-cyclohexanediol (1). Under the same reaction conditions, trans-4- chlorocyclohexanol gives 3-cyclohexenol (2) and the bicyclic ether (3). 69
Problem 9.46 (a) Product (1) is formed by an S N 2 reaction. Inversion of configuration is observed because of the S N 2 mechanism. 70
Problem 9.46 (b) Product (2) is formed by an E2 mechanism. The molecule must be in a chair conformation that places both -OH and -Cl in axial positions. Because either of the two axial H atoms can be removed, the product is a racemic mixture. 71
Problem 9.46 The bicyclic ether (3) is formed by intramolecular backside attack of the deprotonated axial -OH group on the axial chlorine atom. Only the trans isomer can adopt the necessary diaxial orientation of reactive groups. 72