Chapter 6�Ionic Reactions-Nucleophilic Substitution and Elimination Reactions of Alkyl Halides

Chapter 6

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• Introduction
• The polarity of a carbon-halogen bond leads to the carbon having a partial positive charge
• In alkyl halides this polarity causes the carbon to become activated to substitution reactions with nucleophiles

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• Carbon-halogen bonds get less polar, longer and weaker in going from fluorine to iodine

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• Nucleophilic Substitution Reactions
• In this reaction a nucleophile is a species with an unshared electron pair which reacts with an electron deficient carbon
• A leaving group is substituted by a nucleophile

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• Examples of nucleophilic substitution

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• Nucleophile
• The nucleophile reacts at the electron deficient carbon

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• A nucleophile may be any molecule with an unshared electron pair

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• Leaving Group
• A leaving group is a substituent that can leave as a relatively stable entity
• It can leave as an anion or a neutral species

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• Kinetics of a Nucleophilic Substitution Reaction: An S_N2 Reaction
• The initial rate of the following reaction is measured

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• The rate is directly proportional to the initial concentrations of both methyl chloride and hydroxide

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• The rate equation reflects this dependence

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• S_N2 reaction: substitution, nucleophilic, 2nd order (bimolecular)

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• A Mechanism for the S_N2 Reaction

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• A transition state is the high energy state of the reaction
• It is an unstable entity with a very brief existence (10^-12 s)
• In the transition state of this reaction bonds are partially formed and broken
• Both chloromethane and hydroxide are involved in the transition state and this explains why the reaction is second order

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• Transition State Theory: Free-Energy Diagrams
• Exergonic reaction: negative ΔG^o (products favored)
• Endergonic reaction: positive ΔG^o (products not favored)
• The reaction of chloromethane with hydroxide is highly exergonic

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• The equilibrium constant is very large

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• An energy diagram of a typical S_N2 reaction
• An energy barrier is evident because a bond is being broken in going to the transition state (which is the top of the energy barrier)
• The difference in energy between starting material and the transition state is the free energy of activation (ΔG^‡ )
• The difference in energy between starting molecules and products is the free energy change of the reaction, ΔG^o

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• In a highly endergonic reaction of the same type the energy barrier will be even higher (ΔG^‡ is very large)

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• There is a direct relationship between ΔG^‡ and the temperature of a reaction
• The higher the temperature, the faster the rate

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• Near room temperature, a 10^oC increase in temperature causes a doubling of rate
• Higher temperatures cause more molecules to collide with enough energy to reach the transition state and react

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• The energy diagram for the reaction of chloromethane with hydroxide:

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• A reaction with ΔG^‡ above 84 kJ mol^-1 will require heating to proceed at a reasonable rate
• This reaction has ΔG^‡ = 103 kJ mol^-1 so it will require heating

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• The Stereochemistry of S_N2 Reactions
• Backside attack of nucleophile results in an inversion of configuration

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• In cyclic systems a cis compound can react and become trans product

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• The Reaction of tert-Butyl Chloride with Hydroxide Ion: An S_N1 Reaction
• tert-Butyl chloride undergoes substitution with hydroxide
• The rate is independent of hydroxide concentration and depends only on concentration of tert-butyl chloride

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• S_N1 reaction: Substitution, nucleophilic, 1st order (unimolecular)
• The rate depends only on the concentration of the alkyl halide
• Only the alkyl halide (and not the nucleophile) is involved in the transition state of the step that controls the rate

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• Multistep Reactions and the Rate-Determining Step
• In multistep reactions, the rate of the slowest step will be the rate of the entire reaction
• This is called the rate determining step
• In the case below k₁<<k₂ or k₃ and the first step is rate determining

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• A Mechanism for the S_N1 Reaction (next slide)
• Step 1 is rate determining (slow) because it requires the formation of unstable ionic products
• In step 1 water molecules help stabilize the ionic products

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Chapter 6

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• Carbocations
• A carbocation has only 6 electrons, is sp² hybridized and has an empty p orbital

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• The more highly substituted a carbocation is, the more stable it is
• The more stable a carbocation is, the easier it is to form

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• Hyperconjugation stabilizes the carbocation by donation of electrons from an adjacent carbon-hydrogen or carbon-carbon σ bond into the empty p orbital
• More substitution provides more opportunity for hyperconjugation

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• The Stereochemistry of S_N1 Reactions
• When the leaving group leaves from a stereogenic center of an optically active compound in an S_N1 reaction, racemization will occur
• This is because an achiral carbocation intermediate is formed
• Racemization: transformation of an optically active compound to a racemic mixture

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Chapter 6

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• Solvolysis
• A molecule of the solvent is the nucleophile in a substitution reaction
• If the solvent is water the reaction is a hydrolysis

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• Factors Affecting the Rate of S_N1 and S_N2 Reactions
• The Effects of the Structure of the Substrate
• S_N2 Reactions
• In S_N2 reactions alkyl halides show the following general order of reactivity

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• Steric hinderance: the spatial arrangement of the atoms or groups at or near a reacting site hinders or retards a reaction
• In tertiary and neopentyl halides, the reacting carbon is too sterically hindered to react

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• S_N1 reactions
• Generally only tertiary halides undergo S_N1 reactions because only they can form relatively stabilized carbocations
• The Hammond-Leffler Postulate
• The transition state for an exergonic reaction looks very much like starting material
• The transition state for an endergonic reaction looks very much like product
• Generally the transition state looks most like the species it is closest to in energy

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• In the first step of the S_N1 reaction the transition state looks very much like carbocation
• The carbocation-like transition state is stabilized by all the factors that stabilize carbocations
• The transition state leading to tertiary carbocations is much more stable and lower in energy than transition states leading to other carbocations

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• The Effects of the Concentration and Strength of Nucleophile
• S_N1 Reaction
• Rate does not depend on the identity or concentration of nucleophile
• S_N2 Reaction
• Rate is directly proportional to the concentration of nucleophile
• Stronger nucleophiles also react faster
• A negatively charged nucleophile is always more reactive than its neutral conjugate acid
• When comparing nucleophiles with the same nucleophilic atom, nucleophilicities parallel basicities

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• Methoxide is a much better nucleophile than methanol

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• Solvent Effects on S_N2 Reactions: Polar Protic and Aprotic Solvents
• Polar Protic Solvents
• Polar solvents have a hydrogen atom attached to strongly electronegative atoms
• They solvate nucleophiles and make them less reactive

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• Larger nucleophilic atoms are less solvated and therefore more reactive in polar protic solvents

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• Larger nucleophiles are also more polarizable and can donate more electron density
• Relative nucleophilicity in polar solvents:

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• Polar Aprotic Solvents
• Polar aprotic solvents do not have a hydrogen attached to an electronegative atom

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• They solvate cations well but leave anions unsolvated because positive centers in the solvent are sterically hindered

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• Polar protic solvents lead to generation of “naked” and very reactive nucleophiles
• Trends for nucleophilicity are the same as for basicity
• They are excellent solvents for S_N2 reactions

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• Solvent Effects on S_N1 Reactions: The Ionizing Ability of the Solvent
• Polar protic solvents are excellent solvents for S_N1 reactions
• Polar protic solvents stabilize the carbocation-like transition state leading to the carbocation thus lowering ΔG^‡
• Water-ethanol and water-methanol mixtures are most common

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• The Nature of the Leaving Group
• The best leaving groups are weak bases which are relatively stable
• The leaving group can be an anion or a neutral molecule
• Leaving group ability of halides:

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• This trend is opposite to basicity:

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• Other very weak bases which are good leaving groups:

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• The poor leaving group hydroxide can be changed into the good leaving group water by protonation

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• Summary S_N1 vs. S_N2
• In both types of reaction alkyl iodides react the fastest because of superior leaving group ability

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• Organic Synthesis: Functional Group Transformations Using S_N2 Reactions

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• Stereochemistry can be controlled in S_N2 reactions

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• Elimination Reactions of Alkyl Halides
• Dehydrohalogenation
• Used for the synthesis of alkenes
• Elimination competes with substitution reaction
• Strong bases such as alkoxides favor elimination

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• The alkoxide bases are made from the corresponding alcohols

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• The E2 Reaction
• E2 reaction involves concerted removal of the proton, formation of the double bond, and departure of the leaving group
• Both alkyl halide and base concentrations affect rate and therefore the reaction is 2nd order

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• The E1 Reaction
• The E1 reaction competes with the S_N1 reaction and likewise goes through a carbocation intermediate

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• Substitution versus Elimination
• S_N2 versus E2

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• Primary substrate
• If the base is small, S_N2 competes strongly because approach at carbon is unhindered

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• Secondary substrate
• Approach to carbon is sterically hindered and E2 elimination is favored

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• Tertiary substrate
• Approach to carbon is extremely hindered and elimination predominates especially at high temperatures

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• Temperature
• Increasing temperature favors elimination over substitution
• Size of the Base/Nucleophile
• Large sterically hindered bases favor elimination because they cannot directly approach the carbon closely enough to react in a substitution
• Potassium tert-butoxide is an extremely bulky base and is routinely used to favor E2 reaction

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• Overall Summary

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