Chapter 7: Substitution and Elimination

This compound has two β positions, and each β position bears a proton. But, neither of these protons can be anti-periplanar with the leaving group. Since the leaving group is on a wedge, an E2 reaction will only occur if there is a neighboring proton on a dash.

(Bad) Stereospecificity of E2 Reactions on Substituted Cyclohexanes

an E2 reaction only occurs from the chair conformation in which the leaving group is axial. From this, it follows that an E2 reaction can only take place when the leaving group and the proton are on opposite sides of the ring (one on a wedge and the other on a dash)

(Good) Stereospecificity of E2 Reactions on Substituted Cyclohexanes

In the following example, there are also two possible regiochemical outcomes for elimination, but one of those outcomes leads to two possible stereoisomeric alkenes:

2 possible regiochemical outcomes (depends on which H), where 1 leads to two isomers

number of alkyl groups connected to a double bond

Alkene degrees of substitution

an alkyl group has been transferred to the nucleophile. It is an SN2 process, which means there are limitations on the type of alkyl group that can be used. Tertiary alkyl groups cannot be transferred. Secondary alkyl groups can be transferred, but slowly. Primary alkyl groups and methyl groups are transferred most readily.

Alkylation

Both mechanisms begin with the same first step—loss of a leaving group to give a carbocation intermediate

Both Sn1 and E1 being....

it is not possible for a bridgehead carbon of a bicyclic system to possess a double bond if it involves a trans π bond being incorporated in a small ring (bigger rings, at least 8 carbons is okay)

Bredt's rule

with a primary substrate, the SN2 product is often observed to be the exclusive product, because cyanide is not a strong base, so the E2 pathway cannot effectively compete. For secondary substrates, we saw earlier that the E2 pathway generally predominates over the SN2 pathway. But in this case, the reagent is cyanide, which is a moderate base and a strong nucleophile. As such, the SN2 product predominates, despite the steric effects associated with a secondary substrate. For tertiary alkyl halides, the SN2 pathway cannot compete, so treatment with cyanide will generally lead to E2 products,

CN - ion for Sn2 and E2 reactions

presence of a charge Hydroxide has a negative charge, and it is therefore a strong nucleophile. In contrast, water lacks a charge and is a weak nucleophile

Charge Factor for Weak and Strong Nucleophiles

Determining the Function of the Reagent

Determining the Function of the Reagent (Nucleophile or Base?)

a tertiary alkyl halide undergoes ionization in a polar solvent, such as EtOH, the solvent can function as a base (rather than as a nucleophile) and deprotonate the intermediate carbocation, resulting in a two-step elimination process

E1 Reaction

the rate-determining step is the first step (loss of the leaving group), because that step has the highest energy transition state. Notice that the solvent only functions as a base in the second step of our process (not in the rate-determining step). The rate-determining step is said to be unimolecular because it involves only one chemical entity (the substrate). The term E1 is used to refer to unimolecular elimination reactions

E1 rate determining

a proton is removed from the β position, the halide is ejected as a leaving group (X−) from the α position, and a double bond is formed between the α and β positions.

E2 MECHANISM

we expect both cis and trans isomers, although the trans isomer is expected to predominate:

E2 Stereoselective

count the number of protons at the β position. If the β position has only one proton, we expect the reaction to be stereospecific. That is, we expect only one particular stereoisomeric product, not both.

E2 Stereospecific

stereospecific E2 confromation

E2 stereospecificity anti-perplanar example

A substitution reaction occurs when the reagent functions as a nucleophile and attacks the α position, while an elimination reaction occurs when the reagent functions as a base and abstracts a proton from a β position. With a tertiary substrate, steric hindrance prevents the reagent from functioning as a nucleophile at an appreciable rate, but the reagent can still function as a base without encountering much steric hindrance

Effect of Substrate Structure on the Rate of an E2 Process

The less substituted product (alkene) of an elimination reaction.

Hofmann product

The halogen withdraws electron density via induction, rendering the adjacent carbon atom electrophilic, and therefore subject to attack by a nucleophile. The halogen can serve as a leaving group, and substitution/elimination processes can only occur when a leaving group is present.

In an alkyl halide, the halogen serves two critical functions

Alkenes are more stable when they are highly substituted. Tetrasubstituted alkenes are more stable than trisubstituted alkenes. The reason for this trend is NOT a steric effect (through space), but rather an electronic effect (through bonds). hyperconjugation, is a stabilizing effect because it enables the delocalization of electron density. In a similar way, alkyl groups can also stabilize the neighboring sp2-hybridized carbon atoms of a π bond. Once again, the resulting delocalization of electron density is a stabilizing effect.

Increasing stability of Alkene

Good leaving groups are the conjugate bases of strong acids. For example, iodide (I−) is the conjugate base of a very strong acid (HI), and therefore, iodide is a very weak base, which makes it an excellent leaving group In contrast, hydroxide is a bad leaving group, because it is not a stabilized base. In fact, hydroxide is a relatively strong base, and therefore, it rarely functions as a leaving group.

Leaving Group Differences

he β positions of the alkyl halide are not equivalent, and there are two possible regiochemical outcomes Both elimination products are formed, and the more-substituted alkene is generally observed to be the major product. That is, the trisubstituted alkene is favored over the disubstituted alkene.

Multiple E1 products

nucleophilicity is a kinetic phenomenon and refers to the rate of reaction, and is determined by factors such as the presence of high electron density and polarizability basicity is a thermodynamic phenomenon and refers to the position of equilibrium. and is determined by the stability of a base

Nucleophilicity Vs. Basicity

polarizability describes the ability of an atom to distribute its electron density unevenly as a result of external influences directly related to the size of the atom and, more specifically, to the number of electrons that are distant from the nucleus. A sulfur atom is very large and has many electrons that are distant from the nucleus, and it is therefore highly polarizable. As a result, hydrosulfide (HS−) and thiolate (RS−) ions are particularly strong nucleophiles. Many of the halogens share this same feature. *Ex: Iodine is bigger than Clorine* CH3CH2Br w/ NaI is faster SN2 Rx than CH3CH2Br w/ NaCl

Polarizabilty Factor for Weak and Strong Nucleophiles

STEP 1: Identify all β positions bearing protons. STEP 2: Draw all possible regiochemical outcomes. STEP 3: Identify the Zaitsev and Hofmann products. STEP 4: Analyze the base to determine which product predominates

Predicting the regiochemical outcome of an E2 reaction

A solvent that contains at least one hydrogen atom connected directly to an electronegative atom.

Protic solvents

Guidelines for determining Regiochemical and Stereochemical Outcomes of Substitution and Elimination reactions

Regiochemical and Stereochemical Outcomes of Sub and Elim reactions

If you have 1 or 2 degree substrate, the reaction will generally proceed via an SN2, with inversion of configuration. If 3 degree substrate, reaction will proceed via an SN1 mechanism, with racemization.

SN2 or SN1?

usually a slight preference for the inversion product. The accepted explanation involves the formation of ion pairs. When the leaving group first leaves, it is initially very close to the intermediate carbocation, forming an intimate ion pair:

Slight preference of Sn1 for backside attack = inversion of config

A unimolecular nucleophilic substitution reaction. the solvent only functions as a nucleophile in the second step of our process (not in the rate-determining step). The rate-determining step (the leaving group leaving!) is said to be unimolecular because it involves only one chemical entity (the substrate) -

Sn1

SN1 mechanism is comprised of two core steps: 1) loss of a leaving group to give a carbocation intermediate; and 2) nucleophilic attack. If the nucleophile is uncharged (which is often the case for SN1 processes), then there will be an additional step at the end of the mechanism, in which the extra proton is removed by a solvent molecule.

Sn1 Reaction

hey share the same first step—ionization of the alkyl halide to give a carbocation intermediate. These mechanisms differ in the second step, where the solvent can either function as a nucleophile or as a base

Sn1 vs E1 reactions

Sn2/E2 : rate = k[alkyl halide] [nucleophile] (second order) Sn1/E1 : rate = k[substrate] (first order)

Sn2 / E2 and Sn1 / E1 Rate Equations

Sn2 = a bimolecular (2) nucleophilic (N) substitution (S) reaction A nucleophile attacks the alkyl halide causing the loss of a leaving group in a concerted fashion (simultaneously)

Sn2 reaction

Protic solvents have electronegative atoms with lone pairs that can stabilize Na+ ions, and protic solvents also have the ability to form hydrogen bonds with the Cl− ions, thereby stabilizing them as well. A polar aprotic solvent can only stabilize the cations (Na+), not the anions (Cl-). so nucleophiles are less stabilized (higher in energy) when placed in a polar aprotic solvent. A polar aprotic solvent will speed up the rate of an SN2 process by many orders of magnitude raising the energy of the nucleophile, giving a smaller Ea

Solvent Effects in SN2 Reactions

common name treats compound as an alkyl substituent connected to a halide: CC-Cl : ethyl chloride systematic name treats the halogen as a substituent: CC-CL : Chloroethane

Systematic vs. Common names of Halogenated Organic Compounds

tertiary alkyl halide can undergo E1 and SN1 processes when dissolved in a protic solvent, such as water

Tertiary Alkyl Halide to Sn1 and E1 reaction when...

SN2 reactions are most effective for methyl halides and primary alkyl halides, and SN2 reactions cannot be performed with tertiary alkyl halides.

The Effect of Substrate Structure on the Rate of an SN2 Process

SN2 processes are limited to primary and secondary substrates tertiary substrates cannot be used in SN2 reactions, because of steric effects. For secondary substrates, the nucleophile cannot also be a strong base, or else E2 products will predominate. When treated with a reagent that is both a strong nucleophile and a strong base, there will be a competition between SN2 and E2 products. substitution is favored for primary substrates, and elimination is favored for secondary substrates

Tosylates SN2 and E2 processes

when both( the substrate) and the BASE are sterically hindered, the less substituted alkene is often the major product. when sterically hindered bases are used, the Hofmann product becomes the major product. This case illustrates a critical concept: The regiochemical outcome of an E2 reaction can often be controlled by carefully choosing the base.

When does a Hofmann product form?

The more substituted product (alkene) of an elimination reaction.

Zaitsev product

compounds in which a halogen (such as Cl, Br, or I) is connected to an sp3 hybridized carbon atom (aryl halides and vinyl halides, in which a halogen is connected to an sp2 hybridized carbon)

alkyl halides

A conformation in which a hydrogen atom and a leaving group are separated by a dihedral angle of exactly 180°.

anti-coplanar

A conformation in which a hydrogen atom and a leaving group are separated by a dihedral angle of approximately 180°.

anti-periplanar

In SN2 reactions, the side opposite the leaving group, which is where the nucleophile attacks

back-side attack

An elimination reaction in which a proton from the beta (β) position is removed together with the leaving group, thereby forming a double bond.

beta elimination

For E2 reactions, this term refers to a conformation of the substrate in which the following four groups occupy the same plane: the leaving group, the beta hydrogen atom, and the alpha and beta carbon atoms. elimination is observed to occur exclusively via the anti-coplanar conformation, which leads to one specific stereoisomeric product

coplanar

A measurable difference in rate between two similar reactions that differ only in the presence or absence of deuterium in the starting material.

deuterium isotope effect

when treated with a base: alkyl halide can undergo an elimination reaction, in which a π bond (an alkene) is formed (can occur for a variety of substrates, not just alkyl halides)

elimination reaction

The systematic name treats the halogen as a substituent, calling the compound a haloalkane. A compound in which a halogen (such as Cl, Br, or I) is connected to an sp3 hybridized carbon atom.

haloalkane

During a reaction, when the configuration of a chiral center is changed. (this example: reactant exhibits the R configuration, while the product exhibits the S configuration) The requirement for inversion of configuration means that the nucleophile can only attack from the back side (the side opposite the leaving group) and never from the front side

inversion of configuration

A measurable difference in rate between two similar reactions that differ only in the presence or absence of a particular isotope (such as deuterium) in the starting material

kinetic isotope effect

The alkylation process that involves the transfer of a methyl group

methylation

The common name treats the compound as an alkyl substituent connected to a halide, and the compound is called an alkyl halide, or more generally, an organohalide. organohalide describes any organic compound containing at least one halogen (including aryl halides and vinyl halides).

organohalide

A conformation in which a hydrogen atom and a leaving group are approximately coplanar. a situation in which the proton and leaving group are nearly coplanar (for example, a dihedral angle of 178° or 179°). In such a conformation, the orbital overlap is significant enough for an E2 reaction to occur.

periplanar

A solvent that is polar, but nevertheless lacks hydrogen atoms connected directly to an electronegative atom. The result is that nucleophiles are less stabilized (higher in energy) when placed in a polar aprotic solvent. Polar aprotic solvents enhance the rate of an SN2 process by raising the energy of the nucleophile, giving a smaller Ea

polar aprotic solvents

the methyl groups provide steric interactions that raise the energy of the SN2 transition state. as a result, the rate of SN2 is too slow to be useful. This is an interesting example, because the substrate is a primary alkyl halide that essentially does not undergo an SN2 reaction.

primary alkyl halide, but it has three methyl groups attached to the β position

A term describing a consideration that must be taken into account for a reaction in which two or more constitutional isomers can be formed.

regiochemistry

A reaction that can produce two or more constitutional isomers but nevertheless produces one as the major product.

regioselective

During a reaction, when the configuration of a chiral center remains unchanged. Sn1 can do this unlike the inversion of configuration in an Sn2 reaction

retention of configuration

a solvent molecule functions as the attacking nucleophile

solvolysis

The requirement for an anti-periplanar arrangement will determine the stereoisomerism of the product. In other words, the stereoisomeric product of an E2 process depends on the configuration of the starting alkyl halide

stereoisomeric product of an E2 process depends on the configuration of the starting alkyl halide

reaction is stereoselective when the substrate produces two stereoisomers in unequal amounts

stereoselective

a stereoselective E2 reaction: The substrate itself is not necessarily stereoisomeric; nevertheless, this substrate can produce two stereoisomeric products, and it is found that one stereoisomeric product is formed in higher yield (trans more than cis formations) a stereospecific E2 reaction: The substrate is stereoisomeric, and the stereochemical outcome is dependent on which stereoisomeric substrate is used.

stereoselectivity vs. stereospecificity

A reaction in which the configuration of the product is dependent on the configuration of the starting material. (SN2 reactions are stereospecific and proceed with inversion of configuration)

stereospecific

when sterically hindered bases are used, the Hofmann product becomes the major product. This case illustrates a critical concept: The regiochemical outcome of an E2 reaction can often be controlled by carefully choosing the base. Sterically hindered bases are employed in a variety of reactions, not just elimination

sterically hindered bases

when treated with a nucleophile: alkyl halide can undergo a substitution reaction, in which the nucleophile replaces the halogen (can occur for a variety of substrates, not just alkyl halides)

substitution reaction

The starting alkyl halide in a nucleophilic substitution or beta elimination reaction.

substrate

A conformation in which a hydrogen atom and a leaving group are separated by a dihedral angle of exactly 0°.

syn-coplanar