11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

Based on McMurry’s 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 Brønsted 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.

NaOH + C

CH3

CH3

CH3 Br NaBr + C

CH3

CH3

CH3 OH

v = k[C4H9Br]

NaOH + NaBr +

v = k[CH3Br][NaOH]

CH3Br 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 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

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

Rate-determining step is formation of carbocation

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

k1 k2k-1

V = k[RX]

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

this mechanismControlled 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

SN2 Two steps combine - without intermediate Occurs in primary, secondary

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

PN N NCH3

CH3CH3 CH3

CH3CH3

Common polar aprotic solvents

CH3

S

O

CH3

O

PN N NCH3

CH3CH3 CH3

CH3CH3

CH

O

NCH3

CH3

SO O

dimethylsulfoxide (DMSO)

hexamethylphosphoramide (HMPA)

N,N-dimethylformamide (DMF)

sulfolane

+

-

+++

-

++

+-

++

+

-++

Na+

+

-

++

+

-

++

+-

++

+ -

++Cl

-

Polar aprotic solvents solvate cations well, anions poorly

good fit! bad fit!

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

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 doesn’t matter since k2 is inherently fast and not rate determining.

(slow)

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

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 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

Br

Br

CH3

CH3CH3

CH2Br

Carbocation highly unstable, attack from behind blocked

Carbocation highly unstable, attack from behind blocked

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

Carbocation can’t flatten out as required by sp2 hybridization, attack from behind blockedAlso: elimination not possible, can’t place double bond at bridgehead in small cages (“Bredt’s rule”)

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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31 januari 2010