Chapter7, 8 and 9 Lecture PowerPoint Nucleophilic Substitution and Elimination Reactions Chapter7, 8 and 9 Lecture PowerPoint

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”.

Do not undergo reactions in Chapter 7 & 8 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

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.

Reaction Types for Alkyl Halides

The Bimolecular Nucleophilic Substitution (SN2) Reaction Recall that an SN2 reaction takes place in a single step. The Nu–C bond forms at the same time the C–L 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 B–H s bond and the C=C p bond form at the same time the H–C s bond and the C–L 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 E1 E2

SN2: Substitution, Nucleophilic, Bimolecular SN2 reaction takes place in a single step – “concerted” The Nu–C bond forms at the same time the C–L bond breaks.

SN2: Substitution, Nucleophilic, Bimolecular SN2 free energy diagram - maps change in energy as reaction progress DE -DH only means the reaction is spontaneous; it does not indicate whether or not it will occur or how fast reaction progress

SN2: Substitution, Nucleophilic, Bimolecular SN2 free energy diagram - maps change in energy as reaction progress The EA is the energy required to get the reaction going. The lower the EA, the faster the reaction DE reaction progress

SN2: Substitution, Nucleophilic, Bimolecular SN2 free energy diagram - maps change in energy as reaction progress EA depends on the energy of ‡. Lower its energy—i.e. stabilize it—the faster the reaction will proceed DE reaction progress

Hammond Postulate Thermodynamics is the study of energy states and the changes that occur during a reaction. Just because a reaction is thermodynamically possible, does not indicate whether it will occur or at what rate Kinetics is the study of reaction rates. Just because a reaction is fast does not indicate anything about DH or DS (or by extension DG).

Hammond Postulate In studying organic reactions, Hammond noted that kinetics and thermodynamics are connected through structure The Hammond Postulate is as follows:

Hammond Postulate This postulate allows us to relate the all important energy of the ‡ to species on the free energy diagram. For an endothermic reaction step, the ‡ structure resembles the products, as they are close in energy For an exothermic reaction step, the ‡ structure resembles the reactants, as they are close in energy

Hammond Postulate Exothermic Endothermic

The Kinetics of the SN2 Reaction Evidence supporting the different mechanisms proposed for SN1, SN2,E1 and E2 reactions includes the empirical study of the reaction kinetics. For a typical SN2 reaction: [OH⊖]t=0 [CH3Cl]t=0 Initial rate mole L-1, s-1 Result 1.0 M 0.0010 M 4.9 × 10-7 0.0020 M 9.8 × 10-7 Doubled 2.0 M 19.6 × 10-7 Quadrupled

The Kinetics of the SN2 Reaction This evidence shows that there are two species in the rate limiting step. Rate = k[OH⊖][CH3Cl] or in general: This reaction is said to be second order overall We also say that the reaction is bimolecular

SN2: Substitution, Nucleophilic, Bimolecular For SN2 the ‡ resembles the reactants There are two species involved in the rate limiting (only) step Rate (SN2) = k[Nu][R-X] DE reaction progress

SN2: Substitution, Nucleophilic, Bimolecular For SN2 the ‡ resembles the reactants To increase the rate of SN2, increase the energy of the Nu: and/or choose the substrate so the ‡ has the lowest energy DE reaction progress

Factor 1: Structure of R-X/LG Empirical evidence: As alkyl substitution increases on the sp3-carbon center for substitution, the rate decreases

Factor 1: Structure of R-X/LG With each additional alkyl group bonded to the carbon, steric hindrance of the nucleophile increases, which slows the reaction

Factor 1: Structure of R-X/LG Increasing the number of R groups on the carbon with the leaving group also increases crowding in the transition state, thereby decreasing the reaction rate. The SN2 reaction is fastest with unhindered halides.

Factor 1: Structure of R-X/LG Compare the free energy diagrams:

Factor 2: Strength of the Nu: A nucleophile is a species that seeks positive charge centers—literally “nucleus loving” In general, nucleophiles are electron pair donors, or Lewis bases in structure via a lone pair or p-bond Nucleophiles can be negatively charged or neutral Counter-ions are often omitted for negatively charged nucleophiles

Factor 2: Strength of the Nu: Although nucleophilicity and basicity are interrelated, they are fundamentally different. Basicity is a measure of how stable a species becomes after it has accepted a proton It is characterized by an equilibrium constant, KA in an acid-base reaction, making it a thermodynamic property Nucleophilicity is a measure of how rapidly an atom donates its electron pair to other atoms to form bonds. It is characterized by a rate constant, k, making it a kinetic property.

Factor 2: Strength of the Nu: Hammond Postulate and SN2 : A stronger Nu: is closer in energy to the ‡, which lowers the EA giving a faster SN2 reaction. A weaker Nu: is farther in energy to the ‡, which raises the EA giving a slower SN2 reaction. ‡ closer to raised energy of reactants Lower EA Stronger Nu: Weaker Nu:

Factor 2: Strength of the Nu: Nucleophilicity parallels basicity in three instances: For two nucleophiles with the same nucleophilic atom, the stronger base is the stronger nucleophile. The relative nucleophilicity of HO¯ and CH3COO¯, is determined by comparing the pKa values of their conjugate acids (H2O = 15.7, and CH3COOH = 4.8). HO¯ is a stronger base and stronger nucleophile than CH3COO¯. HO¯ is a stronger base and stronger nucleophile than H2O.

Factor 2: Strength of the Nu: Nucleophilicity parallels basicity in three instances: A negatively charged nucleophile is always a stronger nucleophile than its conjugate acid. Right-to-left across a row of the periodic table, nucleophilicity increases as basicity increases:

Factor 2: Strength of the Nu: Common nucleophiles for an SN2 reaction:

Factor 2: Strength of the Nu: Steric Effects on Nucleophile Strength Nucleophilicity does not parallel basicity when steric hindrance becomes important. Steric hindrance is a decrease in reactivity resulting from the presence of bulky groups at the site of a reaction. Steric hindrance decreases nucleophilicity but not basicity. Sterically hindered bases that are poor nucleophiles are called non-nucleophilic bases.

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. A good leaving group is necessary for the reaction to be exothermic (and spontaneous) via a -DH

Factor 3: Leaving Group Ability Experimental Data: Never LGs Good LGs

Factor 3: Leaving Group Ability The halides and neutral molecules are weak bases and therefore good LGs:

Factor 3: Leaving Group Ability Sulfonate ions are also excellent LGs The tosylate anion (TsO⁻), the mesylate anion (MsO⁻), and the triflate anion (TfO⁻) are among the best leaving groups. They are weak bases, as their conjugate acids are very strong (e.g. pKA TfOH is -13) They are structurally similar to H2SO4 and its weak conjugate acid HSO4- (bisulfate)

Factor 3: Leaving Group Ability Overall: Are never LGs!

Factor 4: 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.

Factor 4: Solvent Effects Review: Polar protic solvents bear -OH groups; good H-bond donors Polar aprotic have strong dipoles, but cannot donate in H-bonding

Factor 4: Solvent Effects Nucleophilicity can be affected by the nature of the solvent! If the solvent stabilizes the Nu: too strongly, its energy will be reduced and by the Hammond postulate the reaction will slow Stronger Nu: Weaker Nu:

Factor 4: Solvent Effects Polar protic solvents solvate both cations and anions well. If the salt NaBr is used as a source of the nucleophile Br¯ in H2O: Na+ is solvated by ion-dipole interactions with H2O molecules. Br¯ is solvated by strong hydrogen bonding interactions. H-bonds have reduced the ability of Br- to act as a Nu:

Factor 4: Solvent Effects Polar aprotic solvents solvate cations by ion-dipole interactions. Anions are not well solvated because the solvent cannot hydrogen bond to them. These anions are said to be “naked” and therefore, more reactive.

Factor 4: Solvent Effects Since it is the anion (nucleophile) that matters in SN2, solvents that do not stabilize negative charge give faster reactions. In aprotic solvents, ion–dipole interactions are much weaker because the positive end of the net dipole is typically buried inside the solvent molecule.

Factor 4: Solvent Effects Since it is the anion (nucleophile) that matters in SN2, solvents that do not stabilize negative charge give faster reactions. In aprotic solvents, ion–dipole interactions are much weaker because the positive end of the net dipole is typically buried inside the solvent molecule.

Factor 4: Solvent Effects Solvent effects can cause reversal of nucleophilicity trends: In polar protic solvents, nucleophilicity increases down a column of the periodic table as the size of the anion increases-opposite of basicity! In polar aprotic solvents, nucleophilicity parallels basicity, and the stronger base is the stronger nucleophile.

Factor 4: Solvent Effects More empirical evidence; note how in a polar protic solvent, the larger, less basic nucleophiles give faster reactions:

Factor 5: 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. All of these reactions have an EA that needs to be surmounted. Heat will accelerate the rate of all reactions; the object is not to overheat to allow higher EA reaction pathways to compete

Factor 5: Heat At a particular temperature, only a certain percentage of molecules possess enough energy to surmount an energy barrier. As the energy barrier increases, the percentage of molecules decreases. As the temperature increases, the percentage of molecules increases. In general a 10o rise in temperature will double the rate of a reaction.

Factor 6: Stereospecificity of SN2

Factor 6: Stereospecificity of SN2 The backside attack requires the remaining three groups of the substrate to “flip over” to the other side. This is known as a Walden inversion. In general R usually becomes S and vice-versa, but be careful as the product may have a different set of priority numbers!

Summary SN2 SN1 SN2 E1 E2 Optimize SN2 rate: Factor 1: CH3>1o>2o; never 3o Factor 2: Strong, small Nu: Factor 3: Good LG is weak CB Factor 4: Polar aprotic solvent Factor 5: DS = 0, so T only affects rate of collisions SN1 SN2 E1 E2

A Note on 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.