Chapter 6
Alkyl Halides: Nucleophilic Substitution and Elimination
06-02-03UN

Labeled
Title
 Bond Polarization in Alkyl Halides
Caption
 In an alkyl halide, the halogen atom is bonded to an sp3 hybrid carbon atom. The halogen is more electronegative than carbon, and the bond is polarized with a partial positive charge on carbon and a partial negative charge on the halogen.
Notes
 The more electronegative the halide atom, the greater the polarization between the carbon-halide bond.
Keywords
 alkyl halide, electronegative
06-03

Labeled
Title
 Space-filling drawings of the ethyl halides
Caption
 Figure 6-3 Space-filling drawings of the ethyl halides. The heavier halogens are larger, with much greater surface areas.
Notes
 Electronegativity increases to the right and up in the periodic table. The size increases to the right and down so the size of the halogens increase in the order of F < Cl < Br < I
Keywords
 halogens
06-03-03UN

Labeled
Title
 Allylic Halogenation
Caption
 Bromination of cyclohexene gives a good yield of 3-bromocyclohexene, where bromine has substituted for an allylic hydrogen on the carbon atom next to the double bond
Notes
 When low concentrations of bromine are used the allylic positions are selectively brominated.
Keywords
 allylic carbons, allylic position
06-03-04UN

Labeled
Title
 Mechanism of Allylic Bromination
Caption
 This selective allylic bromination occurs because the allylic intermediate is resonance-stabilized. Abstraction of an allylic hydrogen atom gives a resonance-stabilized allylic radical. This radical reacts with Br2, regenerating a bromine radical.
Notes
 Allylic bromination occurs through a radical mechanism which produces an allylic radical. Allylic radicals are stabilized by resonance with the pi bond next to it.
Keywords
 allylic bromination, radical, resonance
06-03-05UN

Labeled
Title
 Overall Reaction: Allylic Bromination
Caption
 This selective allylic bromination occurs because the allylic intermediate is resonance-stabilized. Abstraction of an allylic hydrogen atom gives a resonance-stabilized allylic radical. This radical reacts with Br2, regenerating a bromine radical.
Notes
 When low concentrations of bromine are used the allylic positions are selectively brominated.
Keywords
 allylic bromination, resonance, allylic radical
06-03-06UN

Labeled
Title
 N-bromosuccinimide (NBS)
Caption
 A large excess of bromine must be avoided because bromine can add to the double bond (Chapter 8). N-Bromosuccinimide is often used as the bromine source in free-radical brominations because it combines with the HBr side product to regenerate a nearly constant low concentration of bromine.
Notes
 NBS is a simple way to assure a low concentration of bromine.
Keywords
 n-bromosuccinimide, NBS, free-radical
06-03-11UN

Labeled
Title
 Nucleophilic Substitution and Elimination Reactions
Caption
 Alkyl halides are easily converted to many other functional groups. The halogen atom can leave with its bonding pair of electrons to form a stable halide ion; we say that a halide is a good leaving group. When another atom replaces the halide ion, the reaction is a substitution. When the halide ion leaves with another atom or ion (often H+), the reaction is an elimination.
Notes
 In a nuclephilic substitution reaction the halide atom is substituted by a nucleophile. In an elimination reaction the halide is "eliminated" from the molecule after abstraction of a hydrogen by a strong base. Elimination reactions produce alkenes.
Keywords
 nucleophilic substitution, nucleophile, substitution, elimination, leaving group, alkenes
06-03-18UN

Labeled
Title
 Nucleophilic Substitution of Iodomethane with Hydroxide Ion
Caption
 Hydroxide ion is a good nucleophile (donor of an electron pair) because the oxygen atom has unshared pairs of electrons and a negative charge. Iodomethane is called the substrate, meaning the compound that is attached by the reagent. The carbon atom of iodomethane is electrophilic because it is bonded to an electronegative iodine atom. Electron density is drawn away from carbon by the halogen atom, giving the carbon atom a partial positive charge. The negative charge of hydroxide ion is attracted to this partial positive charge.
Notes
 The hydroxide ion attacks the iodomethane molecule displacing the iodide ion and forming a carbon oxygen bond.
Keywords
 nucleophile, electrophilic carbon, electronegative
06-03-20UN

Labeled
Title
 SN2 Mechanism
Caption
 The following mechanism shows attack by the nucleophile (hydroxide), the transition state, and the departure of the leaving group (iodide).
Notes
 The hydroxide ion attacks the carbon of the iodomethane molecule. In the transition state there is a bond starting to form between the carbon and the oxygen and the carbon iodide bond is breaking. The reaction produces an alcohol. This is a concerted mechanism in which everything happens in one single step.
Keywords
 transition state, concerted mechanism
06-04

Labeled
Title
Caption
 Figure 6-4 The reaction-energy diagram for the reaction of methyl iodide with hydroxide shows only one energy maximum: the transition state. There are no intermediates.
Notes
 SN2 mechanism are examples of concerted reactions. The bond formation and bond breaking takes place at the same time. There is only one transition state formed by both molecules (the hydroxide ion and the iodomethane). There are no intermediates in this reaction.
Keywords
 nucleophilic substitution, transition state
06-04-03UN

Labeled
Title
 Halogen Exchange Reactions
Caption
 Iodide is a good nucleophile, and many alkyl chlorides react with sodium iodide to give alkyl iodides. Alkyl fluorides are difficult to synthesize directly, and they are often made by treating alkyl chlorides or bromides with KF under conditions that use a crown ether and an aprotic solvent to enhance the normally weak nucleophilicity of the fluoride ion (see Section 6-10).
Notes
 The halide of an alkyl halide can be exchanged by a different halide. This exchange reaction is often used to synthesize alkyl fluorides. Fluoride ion is not a good nucleophile but its nucleophilicity can be enhanced by carrying out the reaction in aprotic solvents and using a crown ether to "pull" the cation away from the fluoride.
Keywords
 exchange reactions, nucleophile, crown ether
06-04-04UN

Labeled
Title
 Transition States for Strong and Weak Nucleophile Attacks
Caption
 Methoxide ion has nonbonding electrons that are readily available for bonding. In the transition state, the negative charge is shared by the oxygen of the methoxide ion and by the halide leaving group. Methanol, however, has no negative charge; the transition state has a partial negative charge on the halide but a partial positive charge on the methanol oxygen atom. As in the case of methanol and the methoxide ion, a base is always a stronger nucleophile than its conjugate acid.
Notes
 The reaction of a weak nucleophile such as methanol with an alkyl halide will have a higher activation energy because the transition state is not stable. A conjugate base such as the methoxide ion can easily attack the alkyl halide to form a transition state that is stable and low in energy.
Keywords
 nucleophile, transition state
06-04-06UN

Labeled
Title
 Basicity and Nucleophilicity
Caption
 We might be tempted to say that methoxide is a much better nucleophile because it is much more basic. This would be a mistake because basicity and nucleophilicity are different properties. Basicity is defined by the equilibrium constant for abstracting a proton. Nucleophilicity is defined by the rate of attack on an electrophilic carbon atom. In both cases, the nucleophile (or base) forms a new bond. If the new bond is to a proton, it has reacted as a base; if the new bond is to a carbon, it has reacted as a nucleophile. Predicting which way a species will react may be difficult; most (but not all) good nucleophiles are also strong bases, and vice versa.
Notes
 By looking at the product formed we can decide if the conjugate base has acted as a base or as a nucleophile. If the new bond is a proton, it has reacted as a base; if the new bond is with carbon it has reacted as a nucleophile.
Keywords
 base, nucleophile
06-04-07T6.03

Labeled
Title
 Common Nucleophiles
Caption
 Table 6-3 Some common nucleophiles in decreasing order of their nucleophilicity in common solvents such as water and the alcohols.
Notes
 A base is a stronger nucleophile than its conjugate acid. In general, the more electronegative the atom the less nucleophilic.
Keywords
 nucleophiles
06-05

Labeled
Title
 Effect of Nucleophile Polarizability in SN2 Reactions
Caption
 Figure 6-5 Comparison of fluoride ion and iodide ion as nucleophiles in the SN2 reaction. Fluoride has tightly bound electrons that cannot begin to form a bond until the atoms are close together. Iodide has more loosely bound outer electrons that begin bonding earlier in the reaction.
Notes
 In general nucleophilicity increases with increasing polarizability of the atom, and polarizability increases as the size of the atom increases.
Keywords
 polarizability
06-05-02UN

Labeled
Title
 Solvent Effect on Nucleophilicity
Caption
 Small anions are solvated much more strongly than large anions in a protic solvent because the solvent approaches a small anion more closely and forms stronger hydrogen bonds. When an anion reacts as a nucleophile, energy is required to Òstrip offÕÕ some of the solvent molecules, breaking some of the hydrogen bonds that stabilized the solvated anion. More energy is required to strip off solvent from a small, strongly solvated ion such as fluoride than from a large, diffuse, less strongly solvated ion like iodide.
Notes
 Polar protic solvents will surround the nucleophile and will reduce its nucleophilicity. The smaller the atom the more solvated it will be and the greater the decrease in reactivity.
Keywords
 solvation, polar protic solvent
06-05-05T04

Labeled
Title
 Common Leaving Groups
Caption
 Table 6-4 Weak Bases that Are Common Leaving Groups
Notes
 Sulfonates, sulfates, and phosphates are good leaving groups because they can delocalize the negative charge over the oxygen atoms. Neutral molecules are the leaving groups when the reaction is carried out in acidic media.
Keywords
 leaving group
06-06

Labeled
Title
 Steric Effects of the Substrate on SN2 Reactions
Caption
 Figure 6-6 SN2 attack on a simple primary alkyl halide is unhindered. Attack on a secondary halide is hindered, and attack on the tertiary halide is nearly impossible.
Notes
 To form a bond the nucleophile has to get within bonding distance of the carbon. A sterically hindered alkyl halide will prevent the nucleophile from getting close enough to react.
Keywords
 steric hindrance, bonding distance, sterically hindered
06-07

Labeled
Title
 Molecular View of an SN2 Attack
Caption
 Figure 6-7 The SN2 reaction takes place through nucleophilic attack on the back lobe of carbons's sp3 hybrid orbital. This backside attack inverts the carbon atom's tetrahedron, like the wind inverts an umbrella.
Notes
 The nucleophile attacks the carbon from the back, opposite the leaving group. SN2 reactions will always result in inversion of configuration of the carbon being attacked. Stereocenters that are not involved in the reaction will not be inverted.
Keywords
 inversion, configuration, backside attack
06-07-01UN

Labeled
Title
 Mechanism of Inversion
Caption
 Inversion of configuration in the SN2 reaction
Notes
 The transition state of the SN2 reaction has a trigonal bypiramidal geometry with the nucleophile and the leaving group at 180o from each other.
Keywords
 inversion
06-07-02UN

Labeled
Title
Caption
 In some cases, inversion of configuration is readily apparent. For example, when cis-1-bromo-3-methylcyclopentane undergoes SN2 displacement by hydroxide ion, inversion of configuration gives trans-3-methylcyclopentanol.
Notes
 Inversion of configuration not only can change the absolute configuration, in the case of cyclic compounds it will also change the geometry from cis to trans or vice versa. SN2 reactions are stereospecific.
Keywords
 inversion, stereospecific
06-07-07UN

Labeled
Title
 Mechanism of an SN1 Reaction
Caption
 This type of substitution is called the SN1 reaction, for Substitution, Nucleophilic, unimolecular. The term unimolecular means there is only one molecule involved in the transition state of the rate-determining step. The mechanism of the SN1 reaction of t-butyl bromide with methanol is shown below. Ionization of the alkyl halide (first step) is the rate-determining step.
Notes
 The first step of the mechanism is the carbocation formation. This step is slow and it is the rate determining step. The second step is the nucleophilic attack of the nucleophile on the carbocation. If the nucleophile was a water or an alcohol molecule, a proton will have to be lost in order to obtain a neutral product.
Keywords
 carbocation, nucleophile, rate determining step
06-07-08UN

Labeled
Title
 Key Steps of the SN1 Mechanism
Caption
 The SN1 mechanism is a multistep process. The first step is a slow ionization to form a carbocation. The second step is a fast attack on the carbocation by a nucleophile. The carbocation is a strong electrophile; it reacts very fast with both strong and weak nucleophiles. In the case of attack by an alcohol or water, loss of a proton gives the final uncharged product. Following is the general mechanism for the SN1 reaction.
Notes
 The main mechanism consists of two steps: carbocation formation and nucleophilic attack. Depending on the nucleophile a third step might be needed. If an alcohol or a water molecule acted as a nucleophile, a proton will have to be lost in order to obtain a neutral product.
Keywords
 carbocation, nucleophile, electrophile
06-08

Labeled
Title
 Reaction Energy Diagrams of SN1 and SN2 Reactions
Caption
 Figure 6-8 Reaction-energy diagrams of the SN1 and SN2 reactions. The SN1 is a two-step mechanism with two transition states (à1 and à2) and a carbocation intermediate. The SN2 has only one transition state and no intermediate.
Notes
 SN1 reaction has carbocation intermediates and will give a mixture of enantiomers. SN2 reaction will result in inversion of configuration.
Keywords
 transition state, intermediate
06-08-01UN

Labeled
Title
 Inductive Effect and Hyperconjugation
Caption
 The rate-determining step of the SN1 reaction is ionization to form a carbocation: a strongly endothermic process. The transition state for this endothermic process resembles the carbocation (Hammond postulate); consequently, rates of SN1 reactions depend strongly on carbocation stability.
Notes
 In Section 4-16A, we saw that alkyl groups stabilize carbocations by donating electrons through sigma bonds (the inductive effect) and through overlap of filled orbitals with the empty p orbital of the carbocation (hyperconjugation). Highly substituted carbocations are therefore more stable.
Keywords
 inductive effect, hyperconjugation, carbocation stability
06-09

Labeled
Title
 Transition State of the SN1 Reaction
Caption
 Figure 6-9 In the transition state of the SN1 ionization, the leaving group is taking on a negative charge. The bond is breaking, and a polarizable leaving group can still maintain substantial overlap.
Notes
 The transition state resembles the carbocation.
Keywords
 polarizability, overlap
06-09-01UN

Labeled
Title
 Ion Solvation
Caption
 The SN1 reaction goes much more readily in polar solvents that stabilize ions. The rate-determining step forms two ions, and ionization is taking place in the transition state. Polar solvents solvate these ions by an interaction of the solventÕs dipole moment with the charge of the ion. Protic solvents such as alcohols and water are even more effective solvents because anions form hydrogen bonds with the hydrogen atom, and cations complex with the nonbonding electrons of the oxygen atom.
Notes
 Polar protic solvents such as alcohols can solvate better the ions formed during an SN1 reaction.
Keywords
 solvent, polar solvent, protic solvent
06-10

Labeled
Title
 Racemization in the SN1 Reaction
Caption
 Figure 6-10 A chiral carbon atom undergoes racemization when it ionizes to a planar, achiral carbocation. A nucleophile can attack the carbocation from either face, giving either enantiomer of the product.
Notes
 Carbocations have sp2 hybrid orbitals and an empty p orbital. The nucleophile can approach the plane of the carbocation from the top or from the bottom. If the nucleophile attacks on the same side of the leaving group, there will be retention of configuration, but if the nucleophile attacks on the opposite side of the leaving group the configuration will be inverted. SN1 reactions form mixtures of enantiomers (racemization).
Keywords
 racemization, retention of configuration, inversion
06-11

Labeled
Title
 SN1 Reaction on a Ring
Caption
 Figure 6-11 In the SN1 reaction of cis-1-bromo-3-deuteriocyclopentane with methanol, the carbocation can be attacked from either face. Because the leaving group (bromide) partially blocks the front side as it leaves, back-side attack (inversion of configuration) is slightly favored.
Notes
 The deuterium atom is used to distinguish the faces of the cyclopentane.
Keywords
 carbocation, leaving group, back-side attack, inversion of configuration
06-11-02UN

Labeled
Title
 Hydride Shift in an SN1 Reaction
Caption
 The rearranged product, 2-ethoxy-2-methylbutane, results from a hydride shift: the movement of a hydrogen atom with its bonding pair of electrons. A hydride shift is represented by the symbol ~H. In this case, the hydride shift converts the initially formed secondary carbocation to a more stable tertiary carbocation. Attack by the solvent gives the rearranged product.
Notes
 Once the carbocation is formed, a hydrogen shifts (moves) from one of the neighboring carbons to the carbocation to produce a more stable carbocation. The mechanism will continue with the nucleophilic attack. Since there are two carbocation intermediates, there will be two products.
Keywords
 hydride shift, carbocation
06-11-04UN

Labeled
Title
 Methyl Shift in SN1 Reaction
Caption
 When neopentyl bromide is boiled with ethanol, it gives only a rearranged substitution product. This product results from a methyl shift (represented by the symbol ~CH3), the migration of a methyl group together with its pair of electrons. Without rearrangement, ionization of neopentyl bromide would give a very unstable primary carbocation. The methyl shift occurs while bromide ion is leaving, so that only the more stable tertiary carbocation is formed.
Notes
 The formation of a primary carbocation is unlikely so the methyl shift and the carbocation formation occur in a single step to produce a 3o carbocation. Attack by the nucleophile on the carbocation gives the only product obtained from this reaction.
Keywords
 methyl shift
06-11-14UN

Labeled
Title
 Elimination Reactions: E1 and E2
Caption
 An elimination involves the loss of two atoms or groups from the substrate, usually with formation of a pi bond. Depending on the reagents and conditions involved, an elimination might be a first-order (E1) or second-order (E2) process. The following examples illustrate the types of eliminations we cover in this chapter.
Notes
 The same way there is an SN1 and an SN2, there are two mechanisms for elimination, E1 and E2. Which elimination will occur is a matter of the conditions employed during the reaction.
Keywords
 elimination
06-11-15UN

Labeled
Title
 E1 Mechanism
Caption
 In a fast second step, a base abstracts a proton on the carbon atom adjacent to the C1. The electrons that once formed the carbonÑhydrogen bond now form a pi bond between two carbon atoms. The general mechanism for the E1 reaction is as follows:
Notes
 Much like the SN1, the E1 reaction involves carbocation intermediates. The first step is the ionization of the molecule to form the carbocation, followed by the abstraction of a proton of the neighboring carbon. The main product of elimination reactions are alkenes.
Keywords
 unimolecular elimination, E1, carbocation
06-11-17UN

Labeled
Title
 Competition Between the SN1 and E1 Reactions
Caption
 The first product (2-methylpropene) results from dehydrohalogenation, an elimination of hydrogen and a halogen atom. Under these first-order conditions (the absence of a strong base), dehydrohalogenation takes place by the E1 mechanism: Ionization of the alkyl halide gives a carbocation intermediate, which loses a proton to give the alkene. The substitution product results from nucleophilic attack on the carbocation. Ethanol serves as a base in the elimination and as a nucleophile in the substitution.
Notes
 The first step of both mechanisms is the same: formation of the carbocation intermediate. The alcohol can act as a base or as a nucleophile. If it acts as a base, abstraction of a proton will produce an alkene. If the alcohol acts as a nucleophile, the substitution product will be obtained.
Keywords
 substitution, elimination, dehydrohalogenation
06-11-18UN

Labeled
Title
 Orbital Model for the E1 Elimination
Caption
 In the second step of the E1 mechanism, the adjacent carbon atom must rehybridize to sp2 as the base attacks the proton and electrons flow into the new pi bond.
Notes
 Weak bases can be used in E1 reactions since they are not involved in the rate determining step of the reaction.
Keywords
 rehybridize
06-12

Labeled
Title
 Reaction Energy Diagram for E1 Reactions
Caption
 Figure 6-13 Reaction-energy diagram of the E1 reaction. The first step is a rate-determining ionization. Compare this energy profile with that of the SN1 reaction, Figure 6-9.
Notes
 The E1 mechanism involves 2 steps and an intermediate. The formation of the intermediate carbocation has the highest activation energy so it will be the rate determining step of the reaction.
Keywords
 rate determining step
06-12-01UN

Labeled
Title
 Rearrangements in the E1 Mechanism
Caption
 Like other carbocation reactions, the E1 may be accompanied by rearrangement. Compare the following E1 reaction (with rearrangement) with the SN1 reaction of the same substrate, shown on page 244.
Notes
 When the reaction involves carbocation intermediates there will be a possibility of rearrangements, so a mixture of products will be obtained.
Keywords
 hydride shift, methyl shift
06-12-05UN

Labeled
Title
 E2 Reactions
Caption
 Elimination can also take place under second-order conditions with a strong base present. As an example, consider the reaction of t-butyl bromide with methoxide ion in methanol.
Notes
 E2 shows the same substrate preference as E1, 3o > 2o > 1o . E2 needs a strong base.
Keywords
 E2, elimination
06-12-06UN

Labeled
Title
 E2 Mechanism
Caption
 The rate of this elimination is proportional to the concentrations of both the alkyl halide and the base, giving a second-order rate equation. This is a bimolecular process, with both the base and the alkyl halide participating in the transition state. Therefore, this mechanism is abbreviated E2 for Elimination, bimolecular.
Notes
 The reaction takes place in a single step so it is a concerted reaction.
Keywords
 concerted reaction, elimination, bimolecular
06-12-07UN

Labeled
Title
 Mixture of Products in E2 Reactions
Caption
 The E2 reaction requires abstraction of a proton on a carbon atom next to the carbon bearing the halogen. If there are two or more possibilities, mixtures of products may result. The following examples show how abstraction of different protons leads to different products.
Notes
 In general, the more substituted alkene will be the major product of the reaction.
Keywords
 elimination, E2
06-13

Labeled
Title
 Transition State for E2 Reactions
Caption
 Figure 6-14 Concerted transition states of the E2 reaction. The orbitals of the hydrogen atom and the halide must be aligned so they can begin to form a pi bond in the transition state.
Notes
 The hydrogen being abstracted should be anti-coplanar to the leaving group to minimize any steric hindrance between the base and the leaving group. A syn-coplanar orientation between the hydrogen and the leaving group will create a repulsive interaction and will raise the energy of the transition state.
Keywords
 anti-coplanar, syn-coplanar
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