11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

Based on McMurry’s Organic Chemistry, 6th edition

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Alkyl Halides React with Nucleophiles and Bases Alkyl halides are polarized at the carbon-halide bond,

making the carbon electrophilic Nucleophiles will replace the halide in C-X bonds of

many alkyl halides(reaction as Lewis base) Nucleophiles that are also Brønsted bases can

produce elimination

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11.1 The Discovery of the Walden Inversion In 1896, Walden showed that (-)-malic acid could be

converted to (+)-malic acid by a series of chemical steps with achiral reagents

This established that optical rotation was directly related to chirality and that it changes with chemical alteration Reaction of (-)-malic acid with PCl5 gives (+)-

chlorosuccinic acid Further reaction with wet silver oxide gives (+)-malic

acid The reaction series starting with (+) malic acid gives (-)

acid

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Reactions of the Walden Inversion

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Significance of the Walden Inversion The reactions alter the configuration at the chirality

center The reactions involve substitution at that center

Therefore, nucleophilic substitution can invert the configuration at a chirality center

The presence of carboxyl groups in malic acid led to some dispute as to the nature of the reactions in Walden’s cycle

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11.2 Stereochemistry of Nucleophilic Substitution In the 1920’s and 1930’s Kenyon and

Phillips carried out a series of experiments to find out how inversion occurs and determine the precise mechanism of nucleophilic substitution reactions.

Instead of halides they used tosylates (OTos) which are better “leaving groups” than halides.

(alkyl toluene sulfonates)

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Only the second and fifth steps are reactions at carbonSo inversion certainly occurs in these substitution steps

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Problem 11.1

Write a stereochemical equation for this nucleophilic substitution reaction:

(S)-2-bromohexane + CH3COO-

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11.3 Kinetics of Nucleophilic Substitution Rate is change in concentration with time Depends on concentration(s), temperature, inherent

nature of reaction (activation energy) A rate law describes relationship between the

concentration of reactants and rate of conversion to products – determined by experiment.

A rate constant (k) is the proportionality factor between concentration and rate

Example: for S P

an experiment might find

Rate = k [S] (first order)

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Reaction Kinetics

The study of rates of reactions is called kinetics Rates decrease as concentrations decrease but the

rate constant does not The rate law depends on the mechanism The order of a reaction is sum of the exponents of the

concentrations in the rate law – the example below is second orderExperiments show that for the reaction

OH- + CH3Br CH3OH + Br-

Rate = k[OH-][CH3Br]

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11.4 The SN2 Reaction

One type of nucleophilic substitution reaction has the following characteristics:

Reaction occurs with inversion at reacting center

Follows second order reaction kinetics rate = k [Nu:-][RX] Nomenclature suggested by Hughes and

Ingold in 1937: S=substitution N (subscript) = nucleophilic 2 = bimolecular - both nucleophile and substrate in

rate determining step

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SN2 Transition State

The transition state of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups

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11.5 Characteristics of the SN2 Reaction

Sensitive to steric effects Methyl halides are most reactive Primary are next most reactive Secondary might react Tertiary are unreactive by this path No reaction at C=C (vinyl halides)

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Reactant and Transition-state Energy Levels

Higher reactant energy level (red curve) = faster reaction (smaller G‡).

Higher transition-state energy level (red curve) = slower reaction (larger G‡).

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Steric Effects on SN2 Reactions

The carbon atom in (a) bromomethane is readily accessibleresulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower SN2 reactions.

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Steric Hindrance Raises Transition State Energy

Steric effects destabilize transition states Severe steric effects can also destabilize ground

state

Very hindered

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Order of Reactivity in SN2

The more alkyl groups connected to the reacting carbon, the slower the reaction

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The Nucleophile

Neutral or negatively charged Lewis base Reaction increases coordination at nucleophile

Neutral nucleophile acquires positive charge Anionic nucleophile becomes neutral See Table 11-1 for an illustrative list

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Relative Reactivity of Nucleophiles

Depends on reaction and conditions More basic nucleophiles react faster (for similar

structures. See Table 11-2) Better nucleophiles are lower in a column of the

periodic table Anions are usually more reactive than neutrals

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The Leaving Group

A good leaving group reduces the barrier to a reaction

Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge

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Poor Leaving Groups

If a group is very basic or very small, it is prevents reaction

Problem 11.6 Rank in order of SN2 reactivityCH3Br, CH3OTs, (CH3)3Cl, (CH3)2CHCl

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The Solvent

Solvents that can donate hydrogen bonds (-OH or –NH) slow SN2 reactions by associating with reactants

Energy is required to break interactions between reactant and solvent

Polar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reaction

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Problem 11.7

Benzene, ether, chloroform are not protic or very polar. How would they affect SN2 reactions?

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11.6 The SN1 Reaction

Tertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to addition of the nucleophile

Called an SN1 reaction – occurs in two distinct steps while SN2 occurs with both events in same step

If nucleophile is present in reasonable concentration (or it is the solvent), then ionization is the slowest step

Previously we learned that tertiary alkyl halides react extremely slowly in SN2 reactions. But tert-butyl bromide reacts with water 1,000,000 times faster than methyl bromide.

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SN1 Energy Diagram

Step through highest energy point is rate-limiting

rate = k[RX]

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Rate-Limiting Step

The overall rate of a reaction is controlled by the rate of the slowest step

The rate depends on the concentration of the species and the rate constant of the step

The highest energy transition state point on the diagram is that for the rate determining step (which is not always the highest barrier)

This is the not the greatest difference but the absolute highest point (Figures 11.8 – the same step is rate-determining in both directions)

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Stereochemistry of SN1 Reaction

The planar intermediate should lead to loss of chirality A free

carbocation is achiral

Product should be racemic

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SN1 in Reality

Carbocation is biased to react on side opposite leaving group

Suggests reaction occurs with carbocation loosely associated with leaving group during nucleophilic addition

Alternative that SN2 is also occurring is unlikely

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Effects of Ion Pair Formation

If leaving group remains associated, then product has more inversion than retention

Product is only partially racemic with more inversion than retention

Associated carbocation and leaving group is an ion pair

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11.9 Characteristics of the SN1 Reaction Tertiary alkyl halide is most reactive by

this mechanismControlled by stability of carbocation

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Delocalized Carbocations

Delocalization of cationic charge enhances stability Primary allyl is more stable than primary alkyl Primary benzyl is more stable than allyl

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Allylic and Benzylic Halides

Allylic and benzylic intermediates stabilized by delocalization of charge (See Figure 11-13) Primary allylic and benzylic are also more reactive

in the SN2 mechanism

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Effect of Leaving Group on SN1

Critically dependent on leaving group Reactivity: the larger halides ions are better

leaving groups In acid, OH of an alcohol is protonated and leaving

group is H2O, which is still less reactive than halide p-Toluensulfonate (TosO-) is excellent leaving group

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Nucleophiles in SN1

Since nucleophilic addition occurs after formation of carbocation, reaction rate is not affected normally affected by nature or concentration of nucleophile

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Solvent Is Critical in SN1

Stabilizing carbocation also stabilizes associated transition state and controls rate

Solvation of a carbocation by water

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Polar Solvents Promote Ionization

Polar, protic and unreactive Lewis base solvents facilitate formation of R+

Solvent polarity is measured as dielectric polarization (P) (Table 11-3) Nonpolar solvents have low P Polar SOLVENT have high P values

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Effects of Solvent on Energies

Polar solvent stabilizes transition state and intermediate more than reactant and product

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11.10 Alkyl Halides: Elimination

Elimination is an alternative pathway to substitution Opposite of addition Generates an alkene Can compete with substitution and decrease yield,

especially for SN1 processes

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Zaitsev’s Rule for Elimination Reactions (1875) In the elimination of HX from an alkyl halide, the more

highly substituted alkene product predominates

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Mechanisms of Elimination Reactions Ingold nomenclature: E – “elimination” E1: X- leaves first to generate a carbocation

a base abstracts a proton from the carbocation

E2: Concerted (one step) transfer of a proton to a base and departure of leaving group

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11.11 The E2 Reaction Mechanism

A proton is transferred to base as leaving group begins to depart

Transition state combines leaving of X and transfer of H

Product alkene forms stereospecifically

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E2 Reaction Kinetics

One step – rate law has base and alkyl halide Transition state bears no resemblance to

reactant or product Rate = k[R-X][B] Reaction goes faster with stronger base,

better leaving group

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Geometry of Elimination – E2

Antiperiplanar allows orbital overlap and minimizes steric interactions

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E2 Stereochemistry

Overlap of the developing orbital in the transition state requires periplanar geometry, anti arrangement

Allows orbital overlap

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Predicting Product

E2 is stereospecific Meso-1,2-dibromo-1,2-diphenylethane with

base gives cis 1,2-diphenyl RR or SS 1,2-dibromo-1,2-diphenylethane

gives trans 1,2-diphenyl

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Practice problem 11.4 E2 rxn of(1S,2S)-1,2-dibromo-1,2-diphenylethane

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11.12 Elimination From Cyclohexanes

Abstracted proton and leaving group should align trans-diaxial to be anti periplanar (app) in approaching transition state (see Figures 11-19 and 11-20)

Equatorial groups are not in proper alignment

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Kinetic Isotope Effect

Substitute deuterium for hydrogen at position Effect on rate is kinetic isotope effect (kH/kD =

deuterium isotope effect) Rate is reduced in E2 reaction

Heavier isotope bond is slower to break Shows C-H bond is broken in or before rate-

limiting step

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11.14 The E1 Reaction

Competes with SN1 and E2 at 3° centers V = k [RX]

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Stereochemistry of E1 Reactions

E1 is not stereospecific and there is no requirement for alignment

Product has Zaitsev orientation because step that controls product is loss of proton after formation of carbocation

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Comparing E1 and E2

Strong base is needed for E2 but not for E1 E2 is stereospecifc, E1 is not E1 gives Zaitsev orientation

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Homework problems for Chapter 11

21 – 23, 25 (SN2 only), 26, 27, 29 – 32, 36, 37, 39 – 41

OWL for Chapter 11 due Jan 22

Problems 24, 25, 28, 34, 35, 38, 39, 46, 47, 49, 50, 55, 59, 62, 65

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11.15 Summary of Reactivity: SN1, SN2, E1, E2 Alkyl halides undergo different reactions in

competition, depending on the reacting molecule and the conditions

Based on patterns, we can predict likely outcomes (See Table 11.4)

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