Chapter 8 Lecture PowerPoint An Introduction to Multistep Mechanisms

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.

Overall Reactants, Overall Products, and Intermediates The overall reaction describes the net changes that occur, and can be obtained by simply adding together all of the elementary steps.

Overall Reactants, Overall Products, and Intermediates continued… We must also be able to distinguish between overall reactants, overall products, and intermediates.

Free Energy Diagram of an SN1 Reaction The Gibbs free energy of the species involved in the reaction is plotted as a function of the reaction coordinate. This has two humps connecting reactants to products, not one. This is because there are two separate elementary steps for the SN1 mechanism.

Free Energy Diagram of an SN1 Reaction continued… Each step is an individual reaction that has its own reactants and products and proceeds through a transition state; each transition state occurs at a local energy maximum along the reaction coordinate. For each elementary step, as the reaction coordinate increases from left to right, the species that are involved less closely resemble the reactants and more closely resemble the products.

Characteristics of the Intermediate The intermediate is higher in energy than the overall reactants or products due to the loss of an octet and the gain of two charges.

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.

SN1 and E1 Notice that the first step in an E1 reaction is precisely the same as the first step in an SN1 reaction. The difference between the SN1 and E1 mechanisms is in the second step. Whereas the second step of an SN1 mechanism is a coordination step, H+ is eliminated in the second step of an E1 mechanism, thus forming a π bond.

E1 Mechanism This is an example of the overall reaction of a general E1 mechanism.

E1 Reaction Free Energy Diagram Again, there are two transition states as there were with the SN1 free energy diagram. The energy of the intermediate is substantially higher than either the reactants or products due to the appearance of charges and the loss of an octet on carbon.

The Kinetics of SN2, SN1, E2, and E1 Reactions Some of the most important evidence supporting the different mechanisms proposed for SN1 and SN2 nucleophilic substitution reactions, as well as for the E1 and E2 reactions, comes from reaction kinetics.

Empirical Rate Laws The rates of SN1 and SN2 reactions differ in the way they depend on reactant concentrations.

Rate Constants and Empirical Rate Laws The proportionality constant, kSN2 , is the rate constant for the SN2 reaction. Similarly, the rate constant for the SN1 reaction is denoted kSN1.

Theoretical Rate Laws A theoretical rate law is derived from a proposed mechanism. Each elementary step has an associated theoretical rate law.

The Theoretical Rate Law of an SN2 reaction Because the mechanism of an SN2 reaction consists of just a single step, the theoretical rate law of the one step is the same as the theoretical rate law of the overall reaction. The theoretical rate law agrees with the empirical rate law.

The Theoretical Rate Law of an SN1 reaction The empirical rate law of an SN1 reaction is essentially the same as the theoretical rate law of the first step of the mechanism. The first step of the SN1 mechanism is the rate-determining step.

Energy Barriers and Rate Constants: Transition State Theory The reason that the first step of an SN1 or E1 mechanism is much slower than the second step can be seen in each reaction’s free energy diagram. Each step must overcome an energy barrier, called the standard free energy of activation, DG°‡

Dependence of k on DG°‡ Notice that the energy barrier for the first step, DG°‡(1), is much larger than the energy barrier for the second step, DG°‡(2). The first step tends to be much more sluggish than the second.

Transition State Theory The quantitative relationship between reaction rates and free energies of activation is a result from transition state theory. kelementary step is the rate constant for an elementary step, C is a constant, T is the absolute temperature (in kelvin), DG°‡ is the standard Gibbs free energy of activation, and R is the universal gas constant.

kelementary step

Percentage of molecules able to surmount an energy barrier 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.

Stereochemistry of Nucleophilic Substitution and Nucleophile Elimination Reactions The stereochemistry of an SN1 reaction differs from that of an SN2 reaction, and the stereochemistry of an E1 reaction differs from that of an E2 reaction. Stereochemistry is pertinent to an SN1 reaction when the atom that is attached to the leaving group is a stereocenter, because the breaking and formation of bonds to the stereocenter can impact the stereochemical configuration of that atom.

Stereochemistry of an SN1 Reaction If an SN1 reaction is carried out on a stereochemically pure substrate, then a mixture of both the R and S enantiomers is produced.

The Stereocenter in the Mechanism The mechanism explains why the reaction produces both configurations of the stereocenter. In the first step of the mechanism, Cl⁻ simply departs, leaving behind a planar carbocation.

The Stereocenter in the Mechanism continued… The C atom initially bonded to Cl is no longer a stereocenter in the carbocation (i.e., the stereochemistry of that C atom has been lost). In the second step, in which I⁻ forms a bond to the carbocation, that same C atom becomes a stereocenter once again.

The Stereocenter in the Mechanism continued…

How Much of Enantiomer Expected? If the intermediate contains a plane of symmetry, then one side of the carbocation is the mirror image of the other and approach from either side of the plane is equally likely.

Racemic Mixture With an equal probability of producing each enantiomer, a racemic mixture would be obtained.

Production of Diastereomers In an SN1 Reaction

Production of Diastereomers In an SN1 Reaction continued… When I⁻ forms a bond in the second step, the C atom once again becomes a stereocenter. I⁻ can approach from either side of the C atom’s plane, therefore the R and S configurations can be produced. Diastereomers are not formed in equal amounts.

Stereospecificity of an SN2 Reaction

Backside Attack 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.

Frontside Attack In a frontside attack, the three groups would remain on the same side in the products. Frontside attack does not occur in SN2 reactions. Frontside attack does not occur in SN2 reactions due, in part, to steric hindrance of the leaving group and also charge repulsion.

Frontside Attack and Charge Repulsion

Stereochemistry of an E1 Reaction When an E1 reaction produces a new double bond, stereochemistry is an issue if both E and Z configurations about the double bond exist. In this case, a mixture of both the E and Z isomers would be produced. Insert eq 8-22, pg 23 here 26_p440_Karty1_CH08 Jmk: I changed “Stereoselectivity” to “Stereochemistry” Jmk2: I added the second bullet.

Understanding Why There is a Mixture of E and Z Products

Stereospecificity of an E2 Reaction Unlike the E1 reaction, which can yield a mixture of both the E and Z alkene products, an E2 reaction involving the same substrate often produces only one diastereomer.

Why E2 Reactions Are Stereospecific

Anticoplanar/Antiperiplanar The conformation in which the H and the leaving group are anti to each other is referred to as anti- coplanar or antiperiplanar.

Mixture of Diastereomers from E2 If there are two H atoms that can be eliminated from the same C atom, then a mixture of diastereomers can form in an E2 reaction.

Formation of Diastereomers in E2

Phosphorylation Phosphorylation is a process that regulates the function of certain enzymes, such as glycogen phosphorylase, which catalyzes the breaking down of glycogen. The process is essentially a nucleophilic substitution reaction, and is facilitated by another enzyme called a kinase . Adenosine triphosphate (ATP), acting as the substrate, undergoes nucleophilic attack to produce the phosphorylated product and adenosine diphosphate (ADP).

Phosphorylation continued…

Proton Transfers in Multistep Mechanisms

Basic Conditions In the proposed mechanism, the first step should not be SN2 because the product (ROH2+) would be a strong acid. Instead, the alcohol must be deprotonated first, followed by SN2 reaction.

Mechanism for Phenylmethanol to Methoxyphenylmethane

Acidic Conditions The presence of hydroxide would be incompatible with this mechanism. The leaving group, therefore, cannot be HO⁻. Instead, the leaving group is H2O, after the alcohol is protonated.

Mechanism for 2-Methyl-2-propanol to 2-Bromo-2-methylpropane

Intramolecular versus Solvent-Mediated Proton Transfer Reactions Some mechanisms must account for the removal of a proton at one site within a molecular species and the addition of a proton at another site within the same species.

Solvent-Mediated Proton Transfer The direct proton transfer from the N to the O, called an intramolecular proton transfer reaction, is generally unlikely. Solvent molecules invariably participate in the transfer of a proton from one site to another in a particular species, via a solvent-mediated proton transfer.

Carbocation Rearrangements In Multistep Mechanisms Carbocations, because of their net positive charge and lack of an octet, are inherently quite reactive. SN1 reactions provide clear evidence that these carbocation intermediates can undergo rearrangement.

SN1 Mechanism for 2-Iodo-3-methylbutane

Driving Force for a Carbocation Rearrangement There are two major factors that can contribute to the driving force for an elementary step: charge stability and bond energies. Charge stability significantly favors the 3o carbocation over the 2o, because the additional alkyl group stabilizes the positive charge. Carbocation rearrangements that result in significantly greater stability tend to be quite rapid.

Summary and Conclusions A unimolecular nucleophilic substitution (SN1) reaction and unimolecular elimination (E1) reaction consist of two elementary steps. An overall reaction is obtained by summing all of the elementary steps in a mechanism. Intermediates do not appear in the overall reaction—just overall reactants and overall products. The free-energy diagram of an E1 reaction and an SN1 reaction show energy maxima (representing transition states) flanking the local energy minimum (representing the carbocation intermediate).

Summary and Conclusions continued… Most of what we know about mechanisms comes from reaction kinetics. SN2 and E2 reactions are both second-order reactions. SN1 and E1 reactions are both first order. If an SN1 reaction takes place at a tetrahedral stereocenter, the products contain a mixture of both stereochemical configurations. In an SN2 reaction, the nucleophile attacks the substrate only from the side opposite the leaving group (backside attack).

Summary and Conclusions continued… Strong bases are unreasonable in the mechanism for a reaction that takes place under acidic conditions. Strong acids are unreasonable in the mechanism for a reaction that takes place under basic conditions. Intramolecular proton transfer reactions are generally unreasonable. Carbocation rearrangements are fast if the resulting carbocation is significantly more stable than the initial one.