Chapter 11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

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

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

Reactions of the Walden Inversion

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

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)

Only the second and fifth steps are reactions at carbon. So inversion certainly occurs in these

substitution steps

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)

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 order

Experiments show that for the reaction

OH- + CH3Br CH3OH + Br-

Rate = k[OH-][CH3Br]

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]

HO-

H3C

H

H3CH2C

BrHO

H CH3

CH2CH3

Br

H3C

H

H3CH2C

Br

(S)-2Bromobutane Transition State

+HO-

CH3

H

CH2CH3

HO

(R)-2-Butanol

+ Br-

The SN2 Reaction

SN2 Transition State• The transition state of an SN2 reaction has a

planar arrangement of the carbon atom and the remaining three groups.

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)

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‡).

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.

Steric Hindrance Raises Transition State Energy

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

Very hindered

Order of Reactivity in SN2

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

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

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

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

Poor Leaving Groups

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

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

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.

SN1 Energy Diagram

Step through highest energy point is rate-limiting

rate = k[RX]

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)

Stereochemistry of SN1 Reaction

• The planar intermediate should lead to loss of chirality– A free

carbocation is achiral

• Product should be racemic

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

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

11.9 Characteristics of the SN1 Reaction

• Tertiary alkyl halide is most reactive by this mechanism–Controlled by stability of carbocation

Delocalized Carbocations

• Delocalization of cationic charge enhances stability

• Primary allyl is more stable than primary alkyl• Primary benzyl is more stable than allyl

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

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

Nucleophiles in SN1

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

Solvent Is Critical in SN1

• Stabilizing carbocation also stabilizes associated transition state and controls rate

Solvation of a carbocation by water

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

Effects of Solvent on Energies

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

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

Zaitsev’s Rule for Elimination Reactions (1875)

• In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates

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

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

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

Geometry of Elimination – E2

• Antiperiplanar allows orbital overlap and minimizes steric interactions

E2 Stereochemistry

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

Allows orbital overlap

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

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

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

11.14 The E1 Reaction

• Competes with SN1 and E2 at 3° centers

• V = k [RX]

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

Comparing E1 and E2

• Strong base is needed for E2 but not for E1

• E2 is stereospecifc, E1 is not

• E1 gives Zaitsev orientation

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)