Chapter 9 Lecture PowerPoint Nucleophilic Substitution and Elimination Reactions 1

The Competition among SN2, SN1, E2, and E1 Reactions Competition can exist between reaction mechanisms. This can lead to the formation of different products. an SN2 example…

Competition continued… an SN1 example… an E2 example…

Competition continued… an E1 example… an E1 example…

Reasons for the Competition The products of all four mechanisms can be different. The stereochemistry of each unimolecular reaction is different from that of the corresponding bimolecular reaction.

Kinetic Control or Thermodynamic Control Before you decide how to predict the major product of any competition, you must know whether the competition takes place under kinetic control or thermodynamic control.

Rate-Determining Steps Revisited Because substitution and elimination reactions generally take place under kinetic control, predicting the outcome of an SN2/SN1/E2/E1 competition means we have to know how to predict the relative rates of the competing reactions. The rate-determining step of a reaction dictates the rate of the overall reaction.

SN2 Rate Determining Step The SN2 mechanism consists of just a single step so that single step must be rate determining.

SN1 Rate Determining Step The SN1 reaction takes place in two steps. The first step is rate determining because formation of the carbocation is much slower than formation of the final product.

A Way of Viewing the SN2 versus SN1 Rate Determining Steps The rate of an SN2 reaction is highly sensitive to factors that affect the nucleophile’s ability to attack the substrate and to factors that affect the ability of the leaving group to depart. The rate of an SN1 reaction is highly sensitive only to factors that help the leaving group depart. The SN1 reaction rate is independent of the nucleophile.

E2 Rate Determining Step Like an SN2 reaction, an E2 reaction consists of a single step that must be rate determining.

E1 Rate Determining Step As in an SN1 reaction, the rate-determining step of an E1 reaction is the first of its two steps. Just as with the SN1 reaction rate, the E1 reaction rate is independent of the attacking species—in this case, the base.

A Way of Viewing the E2 versus E1 Rate Determining Steps In the E2 reaction, the substrate is deprotonated at the same time the leaving group leaves. In an E1 reaction, the base does not enter the picture until the second step, even though it is in solution throughout the reaction.

Factor 1: Strength of the Attacking Species Because the SN2, SN1, E2, and E1 reactions are sensitive to the attacking species in different ways, the identity of the attacking species can play a major role in the outcome of the SN2/SN1/E2/E1 competition.

The Nucleophile Strength in SN2 and SN1 Reactions The rate of the SN2 reaction depends very heavily upon the identity of the nucleophile. For example, when DMF is the solvent, Cl⁻ undergoes the SN2 reaction about twice as fast as Br⁻, and the SN2 reaction involving the cyanide anion (NC⁻) is about 250 times faster than that involving Br⁻.

The Nucleophile Strength in SN2 and SN1 Reactions continued… These rate differences reflect differences in nucleophile strength, or nucleophilicity.

Hammond Postulate Differences in rate reflect differences in the sizes of the energy barriers. The smaller the energy barrier, the faster the reaction. In turn, the size of the energy barrier is determined by the energy of the transition state relative to that of the reactants. This problem can be greatly simplified by applying the Hammond postulate.

Hammond Postulate continued… The Hammond postulate can be used to provide insight into the structure and energy of a transition state by considering the reactants that immediately precede it and the products that immediately follow it.

Hammond Postulate continued…

The Hammond Postulate Applied to SN2 Reactions Cl⁻ is less stable (smaller in size) than Br⁻ An SN2 reaction with Cl⁻ as the nucleophile is more exothermic than with Br⁻ as the nucleophile The SN2 reaction is faster with Cl⁻ as the nucleophile.

Rate of an SN1 Reaction

Nucleophile Strength and SN2 versus SN1 Strong nucleophiles tend to favor SN2 over SN1. Weak nucleophiles tend to favor SN1 over SN2.

Generating Carbon Nucleophiles Nucleophilic carbon atoms are often important in synthesis, especially in the formation of carbon–carbon bonds. In uncharged molecules, carbon atoms are typically non-nucleophilic for two reasons: (1) They do not possess a lone pair of electrons, and (2) they are rarely considered electron-rich because they are generally bonded to atoms with electronegativities comparable to or greater than their own.

Generating Carbon Nucleophiles continued… A carbon atom is quite nucleophilic when it bears a formal negative charge—that is, when it is a carbanion. Carbanions possess a lone pair of electrons that can be used to form a bond.

Generating Carbon Nucleophiles continued… The simplest way to generate carbon nucleophiles is to deprotonate the uncharged carbon. Alkanes have pKa values around 50, so they are such weak acids that deprotonation is unfeasible. The pKa values of alkynes are lower than corresponding alkanes.

The Base Strength in E2 and E1 Reactions The relative rates of E2 reactions depend on the identity of the base—more specifically, on the strength of the base.

The Base Strength in E2 and E1 Reactions continued…

Rate Dependence with E2 and E1 Reactions The base does not participate in an E1 reaction until the leaving group has left, at which point it removes the proton on the substrate. Because the base does not help the leaving group to leave, the specific identity of the base has little effect on the reaction rate.

Base Strength and Competition Reactions

Strong, Bulky Bases The tert-butoxide anion, (CH3)3CO⁻, should be both a strong nucleophile (because it has a full negative charge) and a strong base (because it is stronger than HO⁻). Thus, it should favor both SN2 and E2 reactions. The tert-butoxide anion usually favors just E2 products because (CH3)3CO⁻ is a much weaker nucleophile (due to its steric bulk) than we would expect based on charge stability.

Steric Hindrance in SN2 Reactions Steric hindrance prevents the O atom from forming a bond to a C atom to displace a leaving group, which slows the reaction. The basicity of the anion remains relatively unaffected by steric hindrance because protons are very small and are usually well exposed.

Structures of Some Strong, Bulky Bases

Factor 2: Concentration of the Attacking Species The dependence of each reaction upon the concentration of the substrate and the attacking species is summarized in its respective empirical rate law.

Concentration Effects and SN2/SN1/E2/E1 Reactions Note that the SN2 and E2 reaction rates depend on the concentration of the attacking species, [Att⁻], whereas the SN1 and E1 reactions do not. SN2 and E2 reactions proceed faster with higher concentration of the attacking species because the role of the attacking species is to force off the leaving group.

Concentration Effects and SN2/SN1/E2/E1 Reactions continued… In both the SN1 and E1 mechanisms the attacking species does not participate in the reaction until the leaving group has departed. Therefore, a higher concentration of the attacking species simply means more attacking species waiting for the leaving group to come off, but the reaction rate does not change. Therefore, a high concentration of the attacking species tends to favor SN2 and E2 reactions A low concentration tends to favor SN1 and E1.

Factor 3: Leaving Group Ability A leaving group must leave in the rate-determining step of an SN2, SN1, E2, or E1 reaction. The identity of the leaving group has an effect on the rate of each reaction.

Factor 3: Leaving Group Ability continued…

Leaving Group Ability, Charge Stability, and Base Strength

Leaving Group Ability, Charge Stability, and Base Strength continued… Relative leaving group abilities are governed largely by the stabilities of the leaving groups in the form in which they come off the substrate. The stability as a leaving group is reflected in its base strength.

Sulfonate Anions as Leaving Groups The tosylate anion (TsO⁻), the mesylate anion (MsO⁻), and the triflate anion (TfO⁻) are among the best leaving groups. They are weak bases, as they are similar in structure to the conjugate base of H2SO4.

Leaving Group Ability and SN2/SN1/E2/E1 Reactions SN1 reactions are more sensitive to leaving group ability than SN2 reactions are. Excellent leaving groups favor SN1 and E1 reactions over corresponding SN2 and E2 reactions.

Converting a Bad Leaving Group into a Good Leaving Group Frequently, a desired nucleophilic substitution or elimination reaction is unfeasible because the leaving group is unsuitable. The HO⁻ leaving group, for example, is a very poor leaving group, so the following will not lead to a reaction under neutral conditions. .

Converting a Bad Leaving Group into a Good Leaving Group continued… Under acidic conditions a reaction does take place. The acidic conditions facilitate the substitution reaction because the O atom on the OH group is weakly basic.

Water Leaving Group Mechanism The leaving group leaves as H2O, not HO⁻. Being uncharged, H2O is much more stable than HO⁻, and is an excellent leaving group.

Factor 4: Type of Carbon Bonded to the Leaving Group An important characteristic of the carbon atom bonded to the leaving group is its hybridization. This is partly because sp2- and sp-hybridized carbons form stronger σ bonds than sp3 hybridized carbons. A stronger bond makes it more difficult for the leaving group to leave.

SN2 Reactions and the Hybridization of the Carbon SN2 reactions are further hindered by electrostatic repulsion when the leaving group is attached to an sp2- or sp-hybridized carbon.

SN1 and E1 Reactions and the Hybridization of the Carbon SN1 and E1 reactions are further hindered by charge stability in the carbocation intermediate. Because sp- and sp2-hybridized carbon atoms possess greater s character than an sp3- hybridized carbon does, these atoms have a higher effective electronegativity.

The Number of Alkyl Groups on the Carbon Bonded to the Leaving Group Nucleophilic substitution and elimination reactions can be strongly influenced by the number of alkyl groups bonded to the carbon atom with the leaving group. A carbon atom bonded to three alkyl groups is called a tertiary (3°) carbon; if it is bonded to two alkyl groups, then it is called a secondary (2°) carbon; and if it is bonded to one alkyl group, then it is called a primary (1°) carbon. If the carbon is bonded only to hydrogen atoms, then it is called a methyl carbon and the substrate takes the form CH3-L.

The Number of Alkyl Groups on the Carbon Bonded to the Leaving Group continued…

The Number of Alkyl Groups on the Carbon Bonded to the Leaving Group continued…

Rate of SN2 and Steric Hindrance With each additional alkyl group bonded to the carbon, steric hindrance of the nucleophile increases, which slows the reaction

Rate of SN1 and E1 versus Carbocation Stability

E2 Reactions

Summary of the Influence of the Number of Alkyl Groups on the Carbon

Leaving Groups Bonded to an Allyl or Benzyl Group Exceptions arise when the leaving is attached to the allyl (CH2=CH-CH2-L) or benzyl (C6H5-CH2-L) group. The allyl cation or the benzyl cation that is formed is stabilized by resonance. Insert yellow text box top of page 30 p492_Karty1_CH09_yellow text box

Formation of the Allyl Cation and Benzyl Cation

Factor 5: Solvent Effects There are two types of solvent in which SN2, SN1, E2, and E1 reactions can take place: polar protic solvents and polar aprotic solvents.

Protic Solvents, Aprotic Solvents, and the SN2/SN1/E2/E1 Competition The choice of solvent can have a significant influence on the outcome of nucleophilic substitution and elimination reactions.

Solvation With protic solvents, strong ion–dipole interactions weaken the attacking species. With aprotic solvents, ion–dipole interactions are much weaker because the positive end of the net dipole is typically buried inside the solvent molecule.

Solvation and Relative Nucleophile Strength Some nucleophilicities are reversed in protic versus aprotic solvents.

Factor 6: Heat When substitution and elimination reactions are both favored under a specific set of conditions, it is often possible to influence the outcome by changing the temperature under which the reactions take place.

Elimination Favored by Heat

Factor 6: Heat continued… This temperature effect is due to entropy. ∆S °rxn is more positive for an elimination reaction than for a substitution reaction.

Predicting the Outcome of Nucleophilic Substitution and Elimination Reactions The leaving group, Cl⁻, is at least as stable as F⁻, so proceed to Step 2.

Predicting the Outcome of Nucleophilic Substitution and Elimination Reactions continued… The leaving group in (S)-2-chloropentane is attached to a 2° carbon, so all four reactions must be considered. If it were a 3° carbon, don’t consider SN2. If it were a 1° or methyl carbon, don’t consider SN1 or E1 unless the resulting carbocation is resonance stabilized.

Predicting the Outcome of Nucleophilic Substitution and Elimination Reactions continued…

Predicting the Outcome of Nucleophilic Substitution and Elimination Reactions continued…

Predicting the Outcome of Nucleophilic Substitution and Elimination Reactions continued… In this case, heat is not factored in because SN2 is the clear winner.

Regioselectivity in Elimination Reactions: Zaitsev’s Rule A substrate can possess two or more distinct hydrogen atoms that can be removed in an elimination reaction, leading to two or more possible alkene products. This elimination reaction exhibits regioselectivity.

Another Example of Zaitsev’s Rule

An Exception to Zaitsev’s Rule An E2 reaction can exhibit anti-Zaitsev regiochemistry with a strong, bulky base.

Intermolecular Reactions versus Intramolecular Cyclizations A chemical reaction between two separate species is an intermolecular (between molecule) reaction. Reactions typically require two separate functional groups. Those functional groups need not be on separate molecules. Instead, they can be part of the same molecule, attached at different places on the molecule’s backbone. In that case, the reaction is said to be intramolecular (within the same molecule).

Example of an Intramolecular Reaction

Example of an Intermolecular Reaction

Reversible Reactions For products from competing reactions to be in equilibrium, there must be a way that those products can interconvert. This can happen with reversible competing reactions, which take place readily in both the forward and reverse directions.

Irreversible Reactions If competing reactions are irreversible, in which case they do not take place readily in the reverse direction, then equilibrium is not established between the products from the respective reactions. This is illustrated using irreversible reaction arrows to connect reactants to products.

Reversibility and Kinetic versus Thermodynamic Control Reversible reactions tend to take place under thermodynamic control. Irreversible reactions tend to take place under kinetic control.

Free Energy Diagram to Determine Whether a Reaction is Reversible or Irreversible Whether a reaction is reversible or irreversible can be determined by carefully examining its free energy diagram. In the free energy diagram of an irreversible reaction, the products are much lower in energy than the reactants, making ∆G°rxn substantially negative.

Free Energy Diagram of an Irreversible Reaction ∆G°‡ reverse is much larger than ∆G °‡ forward, so the reaction in the reverse direction is much slower than the reaction in the forward direction, thus making the reaction virtually irreversible.

A Reversible SN2 Reaction

A Reversible SN2 Reaction continued… The products are higher in energy than the reactants, making ∆G°rxn somewhat positive. This is primarily because Br⁻ is less stable than I⁻. Consequently, ∆G°‡reverse is smaller than ∆G°‡forward, making the reaction faster in the reverse direction than in the forward direction under standard conditions.

Summary and Conclusions SN2, SN1, E2, and E1 reactions compete with one another under kinetic control. The fastest reaction yields the major product. SN2 reaction rates are highly sensitive to nucleophilicity, whereas SN1 reactions are not. E2 reaction rates are highly sensitive to the strength of the attacking base, whereas E1 reactions are not. Nucleophilicity can be weakened significantly by bulky alkyl groups surrounding the nucleophilic site. Base strength, however, is not significantly affected.

Summary and Conclusions continued… If a nucleophile is strong, then high concentration favors SN2 and low concentration favors SN1. All four reaction rates are affected by leaving group ability. Leaving group ability is determined largely by charge stability. Nucleophilic substitution and elimination reactions generally do not occur when leaving groups are on sp2 - or sp-hybridized carbon atoms.

Summary and Conclusions continued… Aprotic solvents favor SN2 and E2; protic solvents favor SN1 and E1. Heat favors elimination over substitution due to the greater entropy in the elimination products. When multiple elimination products are possible, the major product is usually the one that is the most stable, in accordance with Zaitsev’s rule. Intramolecular cyclization reactions are favored over their corresponding intermolecular reactions when a five- or six- membered ring can be formed.