Chapter 9 Lecture PowerPoint - Pennsylvania State University

Chapter 9 Lecture PowerPoint - Pennsylvania State University

Organic Chemistry PRINCIPLES AND MECHANISMS Chapter 8-9 Lecture PowerPoint Nucleophilic Substitution and Elimination Reactions

Alkyl Halides Alkyl halides are organic molecules containing a halogen atom bonded to an sp3 hybridized carbon atom. Alkyl halides are classified as primary (1), secondary (2), or tertiary (3), depending on the number of carbons bonded to the carbon with the halogen atom. The halogen atom in halides is often denoted by the symbol X.

2 Types of Alkyl Halides Other types of organic alkyl halides include: Allylic halides have X bonded to the

carbon atom adjacent to a C-C double bond. Benzylic halides have X bonded to the carbon atom adjacent to a benzene ring. NOT ALKYL HALIDES Vinyl halides have a halogen atom (X)

bonded to a C-C double bond. Aryl halides have a halogen atom bonded to a aromatic ring. Do not undergo reactions in Chapter 7 & 8 3

The Polar Carbon-Halogen Bond The electronegative halogen atom in alkyl halides creates a polar C-X bond, making the carbon atom electron deficient. Electrostatic potential maps of four simple alkyl halides illustrate this point. This electron deficient carbon is a key site in the reactivity of

alkyl halides. 4 Reaction Types for Alkyl Halides 5

The Bimolecular Nucleophilic Substitution (SN2) Reaction Recall that an SN2 reaction takes place in a single step. The NuC bond forms at the same time the CL bond breaks.

The Unimolecular Nucleophilic Substitution (SN1) Reaction A nucleophilic substitution reaction taking place in two steps is an example of a unimolecular nucleophilic substitution (SN1) mechanism. The Bimolecular Elimination

(E2) Reaction Recall that an E2 reaction takes place in a single step. The BH s bond and the C=C p bond form at the same time the HC s bond and the CL s bond break. The Unimolecular Elimination (E1) Reaction

Elimination reactions can also take place in two steps, via a unimolecular elimination. 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. Four-way Rate Competition

SN1 SN2 E2

E1 SN2: Substitution, Nucleophilic, Bimolecular SN2 reaction takes place in a single step concerted The NuC bond forms at the same time the CL bond breaks.

SN2: Substitution, Nucleophilic, Bimolecular SN2 free energy diagram - maps change in energy as reaction progresses Number 1 Factor: Structure of R-X/LG Electrostatic potential maps illustrate the effects of steric hindrance around the carbon bearing the leaving group

in a series of alkyl halides The Number of Alkyl Groups on the Carbon Bonded to the Leaving Group continued Factor 2: 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 continued These rate differences reflect differences in nucleophile strength, or nucleophilicity. 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 S N2 reaction involving the cyanide anion (NC) is about 250 times faster than that involving Br.

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 carboncarbon bonds. In uncharged molecules, carbon atoms are typically nonnucleophilic 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 chargethat 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 basemore 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 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 sp2or 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.

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 iondipole interactions weaken the attacking species. With aprotic solvents, iondipole 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, dont consider SN2. If it were a 1 or methyl carbon, dont 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 S N2 is the clear winner. Regioselectivity in Elimination Reactions: Zaitsevs 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 Zaitsevs Rule

An Exception to Zaitsevs 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 molecules 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 Grxn 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 Grxn somewhat positive. This is primarily because Br is less stable than I. Consequently, Greverse is smaller than Gforward, 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 Zaitsevs rule. Intramolecular cyclization reactions are favored over their corresponding intermolecular reactions when a five- or sixmembered ring can be formed.

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