Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations
CHM 247 CH.11
Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations • •
Carbon-halogen bond in an alkyl halide is polar and the carbon atom is electron-poor. Thus alkyl halides are electrophiles. Alkyl halides do one of two things when they react with a nucleotide/base, such as hydroxide ion: either they undergo substitution of the X group by the nucleophile, or they undergo elimination of HX to yield an alkene.
11.1 The Discovery of Nucleophilic Substitution Reactions • German chemist Paul Walden found that pure enantiomers of malic acid could be introvconverted through a series of simple substitution reactions.
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Because (-)-malic acid was converted to (+)-malic acid, some reactions in the cycle must have occureed with a change, or inversion, in configuration at the chirality centre. Nucleophilic substitution reaction: A reaction in which one nucleophile replaces another attached to a saturated carbon.
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The inversion of stereochemical configuration must therefore take place in step 2, the nucleophilic substitution of tosylate ion by acetate ion. From this and other similar reactions, workers concluded that the nucleophilic substitution reaction of a primary or secondary alkyl halide or tosylate always proceeds with inversion of configuration.
11.2 The SN2 Reaction • Kinetics: referring to reaction rates. Kinetic measurements are useful for helping to determine reaction mechanisms. • Direct relationship between the rate at which the reaction occurs and the concentrations of the reactants. • Second-order reaction: A reaction whose rate limiting step is bimolecular and whose kinetics are therefore dependent on the concentration of two reactants.
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SN2 reaction: A bimolecular nucleophilic substitution reaction.
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SN2 is short for substitution, nucleophilic, bimolecular. An essential feature of an SN2 mechanism is that it takes place in a single step without intermediates when the incoming nucleophile reacts with the alkyl halide or tosylate from a direction opposite the group that is displaced.
• 11.3 Characteristics of the SN2 Reaction • The rate of a chemical reaction is determined by the activation energy ΔG‡, the energy difference between reactant ground state and transition state. • A change in conditions can affect the activation energy either by changing the reactant energy level or by changing the transition-state energy level. • Lowering the reactant energy or raising the transition-state energy increases the activation energy and decreases the reaction rate; raising the reactant energy or decreasing the transition-state energy decreases the activation energy and increases the reaction rate. The Substrate: Steric Effects in the SN2 • The first SN2 reaction variable to look at it the structure of the substrate. A hindered substrate should prevent easy approach of the nucleophile, making bond formation difficult. The transition state for a sterically hindered substrate is higher in energy and forms more slowly than the corresponding transition state for a less hindered substrate.
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Vinylic halides and aryl halides are not shown on this reactivity because they are unreactive towards SN2 displacement. The Nucleophile
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The nature of the nucleophile has a major effect on the SN2 reaction. Any species that it neutral or negatively charged can act as a nucleophile (as long as it has an unpaired set of electrons and is a lewis base). • If the nucleophile is negatively charged, the product is neutral; if the nucleophile is neutral, the product is positively charged. • Reactivity of a given nucleophile can change from one reaction to another. • Nucleophile strength: Nucleophilicity roughly parallels basicity. Nucleophilicity usually increases going down a column of the periodic table. I- > Br- > Cl-. Negatively charged nucleophiles are usually more reactive than neutral ones. The Leaving Group • Another variable that can affect the SN2 reaction is the nature of the group displaced by the incoming nucleophile. The leaving group is expelled with a negative charge in most SN2 reactions, so the best leaving groups are those that best stabilize the negative charge in the transition state. • The greater the extent of charge stabilization by the leaving group, the lower the energy of the transition state and the more rapid the reaction. • Weak bases makes good leaving groups.
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Weak bases such as Cl-, and Br- and tosylate ions make good leaving groups. Alkyl fluorides, alcohols, ethers, and amines do not typically undergo SN2 reactions. Converting an alcohol to a better leaving group is a good leaving group will allow a reaction to occur.
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Ethers don’t typically undergo SN2 reactions, but epoxides, due to angle strain, are much more reactive than other ethers.
• The Solvent • Rates strongly affected by the solvent. Protic solvents ( -OH or –NH) are generally worst for SN2 reactions while polar aprotic solvents are the best. • Protic solvent: A solvent such as water or alcohol that can act as a proton donor. • Solvation: The clustering of solvent molecules around a solute particle to stabilize it. • Protic solvents slow down the reaction by salvation of the reactant nucleophile. The solvent molecules hydrogen bind the nucleophile and form a cage around it. • Polar aprotic solvents increase the rate of SN2 reactions by raising the ground-state energy of the nucleophile.
• A Summary of SN2 Reaction Characteristics • Substrate: Steric hindrance raises the energy of the SN2 transition state, increasing the activation energy and decreasing the reaction rate. As a result, SN2 reactions are best for methyl and primary substrates. Secondary substrates react slowly, and tertiary substrates do not react by an SN2 mechanism. • Nucleophile: Basic, negatively charged nucleophiles are less stable and have a higher ground-state energy than neutral ones, decreasing the activation energy and increasing the SN2 reaction rate. • Leaving group: Good leaving groups (more stable anions) lower the energy of the transition state, decreasing the activation energy and increasing the SN2 reaction rate. • Solvent: Protic solvents solvate the nucleophile, thereby lowering its ground-state energy, increasing the activation energy, and decreasing the SN2 reaction rate. Polar aprotic solvents surround the accompanying cation but not the nucleophilic anion, thereby raising the groundstate energy of the nucleophiles, decreasing the activation energy, and increasing the reaction rate. 11.4 The SN1 Reaction • The reaction of a tertiary halide with water to give alcohol is a lot faster than one would think.
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SN1 reaction: A unimolecular nucleophilic substitution reaction. First-order reaction: A reaction whose rate-limiting step is unimolecular and whose kinetics therefore depend on concentration of only one reactant.
SN1 reaction reacts equally well for both forms of the enantiomers and is therefore a racemic mixture with no optical activity. There is a lack of complete racemisation though due to ion pairs being involved. The leaving group hangs around a bit on one side and is partially blocking the side from bonding, leading to a slight favour in one direction.
11.5 Characteristics of the SN1 Reaction • Factors that lower the activation energy, either by lowering the energy level of the transition state or by raising the energy level of the ground state, favour faster SN1 reactions. The Substrate • Any factor stabilizing the high-energy intermediate also stabilizes the transition state leading to that intermediate. The reaction is favoured when the substrate yields a stable carbocation. • Benzylic: The position next to an aromatic ring.
• The Leaving Group • The leaving group has to be stable. • •
SN1 often carried out under acidic conditions, neutral water is sometimes the leaving group.
• The Nucleophile • Nucleophile does not affect reaction rate. The Solvent • Solvent effects in SN1 reactions are largely due to stabilization or destabilization of the transition state. Hammond postulate, stabilize the carbocation intermediate and you will increase the reaction rate. • Solvent molecules orient themselves so that the electrons face the carbocation. • SN1 reactions take place much more rapidly in strongly polar solvents. • SN2 are disfavoured in protic solvents while SN1 are favoured. A Summary of SN1 Reaction Characteristics • Substrate: The best substrates yield the most stable carbocations. As a result, SN1 reactions are best tertiary, allylic, and benzylic halides.
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Leaving group: Good leaving groups increase the reaction rate by lowering the energy level of the transition state for carbocation formation. Nucleophile: The nucleophile must be nonbasic to prevent a competitive elimination of HX, but otherwise does not affect the reaction rate. Neutral nucleophiles work well. Solvent: Polar solvents stabilize the carbocation intermediate by salvation, thereby increasing the reaction rate.
11.6 Biological Substitution Reactions • Substrate in a biological substitution reaction is usually an organodiphosphate. Thus the leaving group is the diphosphate ion, abbreviated PPi. • Dissociation of an organodiphosphate in a biological reaction is typically assisted by complexation to a divalent metal cation such as Mg2+ to help neutralize charge and make the diphosphate a better leaving group.
• 11.7 Elimination Reactions: Zaitsev’s Rule • Zaitsev’s rule: A rule stating that E2 elimination reactions normally yield the more highly substituted alkene as a major product. • Elimination is making of a double bond. A double bond in the centre is better than at the end.
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In E1 reactions, the C-X bond breaks first to give a carbocation intermediate that undergoes subsequent base abstraction of H+ to yield the alkene. In the E2 reaction, base-induced C-H bond cleavage is simultaneous with C-X bond cleavage, giving the alkene in a single step. In the E1cB reaction (cB for conjugate base), base abstraction of the proton occurs first, giving a carbanion (R:-) intermediate. This anion, the conjugate base of the reactant ‘acid,’ then undergoes loss of X- in a subsequent step to give the alkene.
11.8 The E2 Reaction and the Deuterium Isotope Effect • E2 reaction: A bimolecular elimination reaction in which C-H and C-X bond cleavages are simultaneous.
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Rate law for this: rate = k X [RX] X [Base]. Deuterium isotope effect: A tool used in mechanistic investigations to establish whether a C-H bond is broken in the rate-limiting step of a reaction. E2 reactions occur with periplanar geometry. Periplanar: A conformation in which bonds to neighbouring atoms have a parallel arrangement. In an eclipsed conformation, the neighbouring bonds are syn periplanar; in a staggered conformation, the bonds are anti periplanar. Syn periplanar: Describing a stereochemical relationship in which two bonds on adjacent carbons lie in the same plane and are eclipsed. Anti periplanar: Describing the stereochemical relationship in which two bonds on adjacent carbons lie in the same plane at an angle of 180.
11.9 The E2 Reaction and Cyclohexane Conformation • The anti periplanar requirement for E2 reactions overrides Zaitsev’s rule and can be met in cyclohexanes only if the hydrogen and the leaving group are trans diaxial. • If either the leaving group OR the hydrogen is equatorial, E2 elimination can’t occur.
• 11.10 The E1 and E1cB Reactions The E1 Reaction • A unimolecular elimination reaction in which the substrate spontaneously dissociates to give a carbocation intermediate, which loses a proton in a separate step.
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Often times with E1 reactions, SN1 reactions also occur.
• • No geometric requirement for this reaction to occur. Zaitsev’s rule applies here. The E1cB Reaction • E1cB reaction: A unimolecular elimination reaction in which a proton is first removed to give a carbanion intermediate, which then expels the leaving group in a separate step.
E2 - Can occur, strong base needed
Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations • •
Carbon-halogen bond in an alkyl halide is polar and the carbon atom is electron-poor. Thus alkyl halides are electrophiles. Alkyl halides do one of two things when they react with a nucleotide/base, such as hydroxide ion: either they undergo substitution of the X group by the nucleophile, or they undergo elimination of HX to yield an alkene.
11.1 The Discovery of Nucleophilic Substitution Reactions • German chemist Paul Walden found that pure enantiomers of malic acid could be introvconverted through a series of simple substitution reactions.
• • • •
Because (-)-malic acid was converted to (+)-malic acid, some reactions in the cycle must have occureed with a change, or inversion, in configuration at the chirality centre. Nucleophilic substitution reaction: A reaction in which one nucleophile replaces another attached to a saturated carbon.
• • •
The inversion of stereochemical configuration must therefore take place in step 2, the nucleophilic substitution of tosylate ion by acetate ion. From this and other similar reactions, workers concluded that the nucleophilic substitution reaction of a primary or secondary alkyl halide or tosylate always proceeds with inversion of configuration.
11.2 The SN2 Reaction • Kinetics: referring to reaction rates. Kinetic measurements are useful for helping to determine reaction mechanisms. • Direct relationship between the rate at which the reaction occurs and the concentrations of the reactants. • Second-order reaction: A reaction whose rate limiting step is bimolecular and whose kinetics are therefore dependent on the concentration of two reactants.
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SN2 reaction: A bimolecular nucleophilic substitution reaction.
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SN2 is short for substitution, nucleophilic, bimolecular. An essential feature of an SN2 mechanism is that it takes place in a single step without intermediates when the incoming nucleophile reacts with the alkyl halide or tosylate from a direction opposite the group that is displaced.
• 11.3 Characteristics of the SN2 Reaction • The rate of a chemical reaction is determined by the activation energy ΔG‡, the energy difference between reactant ground state and transition state. • A change in conditions can affect the activation energy either by changing the reactant energy level or by changing the transition-state energy level. • Lowering the reactant energy or raising the transition-state energy increases the activation energy and decreases the reaction rate; raising the reactant energy or decreasing the transition-state energy decreases the activation energy and increases the reaction rate. The Substrate: Steric Effects in the SN2 • The first SN2 reaction variable to look at it the structure of the substrate. A hindered substrate should prevent easy approach of the nucleophile, making bond formation difficult. The transition state for a sterically hindered substrate is higher in energy and forms more slowly than the corresponding transition state for a less hindered substrate.
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Vinylic halides and aryl halides are not shown on this reactivity because they are unreactive towards SN2 displacement. The Nucleophile
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The nature of the nucleophile has a major effect on the SN2 reaction. Any species that it neutral or negatively charged can act as a nucleophile (as long as it has an unpaired set of electrons and is a lewis base). • If the nucleophile is negatively charged, the product is neutral; if the nucleophile is neutral, the product is positively charged. • Reactivity of a given nucleophile can change from one reaction to another. • Nucleophile strength: Nucleophilicity roughly parallels basicity. Nucleophilicity usually increases going down a column of the periodic table. I- > Br- > Cl-. Negatively charged nucleophiles are usually more reactive than neutral ones. The Leaving Group • Another variable that can affect the SN2 reaction is the nature of the group displaced by the incoming nucleophile. The leaving group is expelled with a negative charge in most SN2 reactions, so the best leaving groups are those that best stabilize the negative charge in the transition state. • The greater the extent of charge stabilization by the leaving group, the lower the energy of the transition state and the more rapid the reaction. • Weak bases makes good leaving groups.
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Weak bases such as Cl-, and Br- and tosylate ions make good leaving groups. Alkyl fluorides, alcohols, ethers, and amines do not typically undergo SN2 reactions. Converting an alcohol to a better leaving group is a good leaving group will allow a reaction to occur.
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Ethers don’t typically undergo SN2 reactions, but epoxides, due to angle strain, are much more reactive than other ethers.
• The Solvent • Rates strongly affected by the solvent. Protic solvents ( -OH or –NH) are generally worst for SN2 reactions while polar aprotic solvents are the best. • Protic solvent: A solvent such as water or alcohol that can act as a proton donor. • Solvation: The clustering of solvent molecules around a solute particle to stabilize it. • Protic solvents slow down the reaction by salvation of the reactant nucleophile. The solvent molecules hydrogen bind the nucleophile and form a cage around it. • Polar aprotic solvents increase the rate of SN2 reactions by raising the ground-state energy of the nucleophile.
• A Summary of SN2 Reaction Characteristics • Substrate: Steric hindrance raises the energy of the SN2 transition state, increasing the activation energy and decreasing the reaction rate. As a result, SN2 reactions are best for methyl and primary substrates. Secondary substrates react slowly, and tertiary substrates do not react by an SN2 mechanism. • Nucleophile: Basic, negatively charged nucleophiles are less stable and have a higher ground-state energy than neutral ones, decreasing the activation energy and increasing the SN2 reaction rate. • Leaving group: Good leaving groups (more stable anions) lower the energy of the transition state, decreasing the activation energy and increasing the SN2 reaction rate. • Solvent: Protic solvents solvate the nucleophile, thereby lowering its ground-state energy, increasing the activation energy, and decreasing the SN2 reaction rate. Polar aprotic solvents surround the accompanying cation but not the nucleophilic anion, thereby raising the groundstate energy of the nucleophiles, decreasing the activation energy, and increasing the reaction rate. 11.4 The SN1 Reaction • The reaction of a tertiary halide with water to give alcohol is a lot faster than one would think.
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SN1 reaction: A unimolecular nucleophilic substitution reaction. First-order reaction: A reaction whose rate-limiting step is unimolecular and whose kinetics therefore depend on concentration of only one reactant.
SN1 reaction reacts equally well for both forms of the enantiomers and is therefore a racemic mixture with no optical activity. There is a lack of complete racemisation though due to ion pairs being involved. The leaving group hangs around a bit on one side and is partially blocking the side from bonding, leading to a slight favour in one direction.
11.5 Characteristics of the SN1 Reaction • Factors that lower the activation energy, either by lowering the energy level of the transition state or by raising the energy level of the ground state, favour faster SN1 reactions. The Substrate • Any factor stabilizing the high-energy intermediate also stabilizes the transition state leading to that intermediate. The reaction is favoured when the substrate yields a stable carbocation. • Benzylic: The position next to an aromatic ring.
• The Leaving Group • The leaving group has to be stable. • •
SN1 often carried out under acidic conditions, neutral water is sometimes the leaving group.
• The Nucleophile • Nucleophile does not affect reaction rate. The Solvent • Solvent effects in SN1 reactions are largely due to stabilization or destabilization of the transition state. Hammond postulate, stabilize the carbocation intermediate and you will increase the reaction rate. • Solvent molecules orient themselves so that the electrons face the carbocation. • SN1 reactions take place much more rapidly in strongly polar solvents. • SN2 are disfavoured in protic solvents while SN1 are favoured. A Summary of SN1 Reaction Characteristics • Substrate: The best substrates yield the most stable carbocations. As a result, SN1 reactions are best tertiary, allylic, and benzylic halides.
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Leaving group: Good leaving groups increase the reaction rate by lowering the energy level of the transition state for carbocation formation. Nucleophile: The nucleophile must be nonbasic to prevent a competitive elimination of HX, but otherwise does not affect the reaction rate. Neutral nucleophiles work well. Solvent: Polar solvents stabilize the carbocation intermediate by salvation, thereby increasing the reaction rate.
11.6 Biological Substitution Reactions • Substrate in a biological substitution reaction is usually an organodiphosphate. Thus the leaving group is the diphosphate ion, abbreviated PPi. • Dissociation of an organodiphosphate in a biological reaction is typically assisted by complexation to a divalent metal cation such as Mg2+ to help neutralize charge and make the diphosphate a better leaving group.
• 11.7 Elimination Reactions: Zaitsev’s Rule • Zaitsev’s rule: A rule stating that E2 elimination reactions normally yield the more highly substituted alkene as a major product. • Elimination is making of a double bond. A double bond in the centre is better than at the end.
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In E1 reactions, the C-X bond breaks first to give a carbocation intermediate that undergoes subsequent base abstraction of H+ to yield the alkene. In the E2 reaction, base-induced C-H bond cleavage is simultaneous with C-X bond cleavage, giving the alkene in a single step. In the E1cB reaction (cB for conjugate base), base abstraction of the proton occurs first, giving a carbanion (R:-) intermediate. This anion, the conjugate base of the reactant ‘acid,’ then undergoes loss of X- in a subsequent step to give the alkene.
11.8 The E2 Reaction and the Deuterium Isotope Effect • E2 reaction: A bimolecular elimination reaction in which C-H and C-X bond cleavages are simultaneous.
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Rate law for this: rate = k X [RX] X [Base]. Deuterium isotope effect: A tool used in mechanistic investigations to establish whether a C-H bond is broken in the rate-limiting step of a reaction. E2 reactions occur with periplanar geometry. Periplanar: A conformation in which bonds to neighbouring atoms have a parallel arrangement. In an eclipsed conformation, the neighbouring bonds are syn periplanar; in a staggered conformation, the bonds are anti periplanar. Syn periplanar: Describing a stereochemical relationship in which two bonds on adjacent carbons lie in the same plane and are eclipsed. Anti periplanar: Describing the stereochemical relationship in which two bonds on adjacent carbons lie in the same plane at an angle of 180.
11.9 The E2 Reaction and Cyclohexane Conformation • The anti periplanar requirement for E2 reactions overrides Zaitsev’s rule and can be met in cyclohexanes only if the hydrogen and the leaving group are trans diaxial. • If either the leaving group OR the hydrogen is equatorial, E2 elimination can’t occur.
• 11.10 The E1 and E1cB Reactions The E1 Reaction • A unimolecular elimination reaction in which the substrate spontaneously dissociates to give a carbocation intermediate, which loses a proton in a separate step.
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Often times with E1 reactions, SN1 reactions also occur.
• • No geometric requirement for this reaction to occur. Zaitsev’s rule applies here. The E1cB Reaction • E1cB reaction: A unimolecular elimination reaction in which a proton is first removed to give a carbanion intermediate, which then expels the leaving group in a separate step.
E2 - Can occur, strong base needed
