11.

Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

Based on McMurrys Organic Chemistry, 6th edition

Nucleophiles and Leaving Groups:

Alkyl Halides React with Nucleophiles

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 strong Brnsted bases can produce elimination

Reaction Kinetics
The study of rates of reactions is called kinetics The order of a reaction is sum of the exponents of the

concentrations in the rate law the first example is first order, the second one second order.

CH3 NaOH + CH3 v = k[C4H9Br] C Br CH3 NaBr + CH3

CH3 C OH CH3

NaOH + CH3Br v = k[CH3Br][NaOH]

NaBr + CH3OH

11.4 The SN1 and SN2 Reactions

Follow first or second order reaction kinetics
Ingold nomenclature to describe characteristic step:

S=substitution N (subscript) = nucleophilic 1 = substrate in characteristic step (unimolecular) 2 = both nucleophile and substrate in characteristic step (bimolecular)

Stereochemical Modes of Substitution

Substitution with inversion:

Substitution with retention:

Substitution with racemization: 50% - 50%

SN2 Process
The reaction involves a transition state in which both

reactants are together

Walden Inversion

SN2 Transition State

The transition state of an SN2 reaction has a planar

arrangement of the carbon atom and the remaining three groups

Steric Effects on SN2 Reactions

The carbon atom in (a) bromomethane is readily accessible resulting 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

Very hindered

Steric effects destabilize transition states

Severe steric effects can also destabilize ground

state

Order of Reactivity in SN2

The more alkyl groups connected to the reacting

carbon, the slower the reaction

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)

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

Stereochemistry of SN1 Reaction

The planar

intermediate leads to loss of chirality A free carbocation is achiral Product is racemic or has some inversion

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

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

SN1 Energy Diagram

k1 k-1 k2
Step through highest energy point is rate-limiting (k1 in forward direction)

V = k[RX]

Rate-determining step is

formation of carbocation

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

Comparison: Substitution Mechanisms

SN1

Two steps with carbocation intermediate Occurs in 3, allyl, benzyl Two steps combine - without intermediate Occurs in primary, secondary

SN2

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

Super Leaving Groups

Poor Leaving Groups

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

reaction

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

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

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

Polar Solvents Promote Ionization

Polar, protic and unreactive Lewis base solvents

facilitate formation of R+ Solvent polarity is measured as dielectric polarization (P)

Solvent Is Critical in SN1

Stabilizing carbocation also stabilizes

associated transition state and controls rate

Solvation of a carbocation by water

Effects of Solvent on Energies

Polar solvent stabilizes transition state and

intermediate more than reactant and product

Polar aprotic solvents

Form dipoles that have well localized negative

sides, poorly defined positive sides. Examples: DMSO, HMPA (shown here)

O P CH3 N N N CH3 CH3 CH3 CH3 CH3

Common polar aprotic solvents

O CH3 S CH3 dimethylsulfoxide (DMSO)

O P CH3 N N N CH3 CH3 CH3 CH3 CH3

O H C N CH3 CH3 N,N-dimethylformamide (DMF) hexamethylphosphoramide (HMPA)

sulfolane O

Polar aprotic solvents solvate cations well, anions poorly + + + + + + + + +

+ + +

good fit!

bad fit!

+ + +

+ + +

Na -

+ + +

+ + +

Cl

SN1: Carbocation not very encumbered, but needs to be solvated in rate determining step
(slow)

Polar protic solvents are good because they solvate both the leaving group and the carbocation in the rate determining step k1! The rate k2 is somewhat reduced if the nucleophile is highly solvated, but this doesnt matter since k2 is inherently fast and not rate determining.

SN2: Things get tight if highly solvated nucleophile tries to form pentacoordiante transition state

Polar aprotic solvents favored! There is no carbocation to be solvated.

Nucleophiles in SN1
Since nucleophilic addition occurs after

formation of carbocation, reaction rate is not affected normally affected by nature or concentration of nucleophile

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

Zaitsevs 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 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

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

(E)-1bromo-1,2-diphenylethene

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

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

Special cases, both SN1 and SN2 blocked (or exceedingly slow)
Br

Carbocation highly unstable, attack from behind blocked

Br

Carbocation cant flatten out as required by sp2 hybridization, attack from behind blocked Also: elimination not possible, cant place double bond at bridgehead in small cages (Bredts rule) Carbocation highly unstable, attack from behind blocked

Br

CH3 CH3

CH2Br CH3

Carbocation would be primary, attack from behind difficult due to steric blockage

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 ratelimiting step

 www.ulm.edu/~junk/examkeys/pp230_10_ch

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