11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

Based on McMurry’s Organic Chemistry, 6th

edition©2003 Ronald KlugerDepartment of ChemistryUniversity of Toronto

Alkyl Halides React with Nucleophilesand Bases

Alkyl halides are polarized at the carbon-halide bond, making the carbon electrophilicNucleophiles will replace the halide in C-X bonds of many alkyl halides(reaction as Lewis base)Nucleophiles that are Brønsted bases 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 reagentsThis established that optical rotation was directly related to chirality and that it changes with chemical alteration

Reaction of (-)-malic acid with PCl5 gives (+)-chlorosuccinic acidFurther reaction with wet silver oxide gives (+)-malicacidThe reaction series starting with (+) malic acid gives (-) acid

Reactions of the Walden Inversion

Significance of the Walden Inversion

The reactions alter the array at the chirality centerThe reactions involve substitution at that centerTherefore, nucleophilic substitution can invert the configuration at a chirality centerThe 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 NucleophilicSubstitution

Isolate step so we know what occurred (Kenyon and Phillips, 1929) using 1-phenyl-2-propanolOnly the second and fifth steps are reactions at carbonSo inversion certainly occurs in the substitution step

Hughes’ Proof of InversionReact S-2-iodo-octane with radioactive iodideObserve, initially that racemization of mixture is twice as fast as incorporation of label so it must be with inversion

Racemization in one reaction step would occur at same rate as incorporation

The Nature of Substitution

Substitution, by definition, requires that a "leaving group", which is also a Lewis base, departs from the reacting molecule.A nucleophile is a reactant that can be expected to participate effectively in a substitution reaction.

Substitution Mechanisms

SN1Two steps with carbocation intermediateOccurs in 3°, allyl, benzyl

SN2Two steps combine - without intermediateOccurs in primary, secondary

Reactant and Transition-state Energy Levels

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

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

Two Stereochemical Modes of Substitution

Substitution with inversion:

Substitution with retention:

11.3 Kinetics of NucleophilicSubstitution

Rate (V) is change in concentration with timeDepends on concentration(s), temperature, inherent nature of reaction (barrier on energy surface)A rate law describes relationship between the concentration of reactants and conversion to productsA rate constant (k) is the proportionality factor between concentration and rate

Example: for S converting to P

V = d[S]/dt = k [S]

Reaction KineticsThe study of rates of reactions is called kineticsRates decrease as concentrations decrease but the rate constant does notRate units: [concentration]/time such as L/(mol x s)The rate law is a result of the mechanismThe order of a reaction is sum of the exponents of the concentrations in the rate law – the example is second order

11.4 The SN2 Reaction

Reaction is with inversion at reacting centerFollows second order reaction kineticsIngold nomenclature to describe characteristic step:

S=substitutionN (subscript) = nucleophilic2 = both nucleophile and substrate in characteristic step (bimolecular)

SN2 Process

The reaction involves a transition state in which both reactants are together

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 SN2Reaction

Sensitive to steric effectsMethyl halides are most reactivePrimary are next most reactiveSecondary might reactTertiary are unreactive by this pathNo reaction at C=C (vinyl halides)

Reactant and Transition-state Energy Levels Affect Rate

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

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

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 statesSevere 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 baseReaction increases coordination at nucleophile

Neutral nucleophile acquires positive chargeAnionic nucleophile becomes neutralSee 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 tableAnions are usually more reactive than neutrals

The Leaving Group

A good leaving group reduces the barrier to a reactionStable 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 SolventSolvents that can donate hydrogen bonds (-OH or –NH) slow SN2 reactions by associating with reactantsEnergy is required to break interactions between reactant and solventPolar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reaction

11.6 The SN1 ReactionTertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to addition of the nucleophileCalled an SN1 reaction – occurs in two distinct steps while SN2 occurs with both events in same stepIf nucleophile is present in reasonable concentration (or it is the solvent), then ionization is the slowest step

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]

Rate-Limiting StepThe overall rate of a reaction is controlled by the rate of the slowest stepThe rate depends on the concentration of the species and the rate constant of the stepThe 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 and 11.9 – the same step is rate-determining in both directions)

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 RealityCarbocation is biased to react on side opposite leaving groupSuggests reaction occurs with carbocation loosely associated with leaving group during nucleophilicadditionAlternative that SN2 is also occurring is unlikely

Effects of Ion Pair FormationIf leaving group remains associated, then product has more inversion than retentionProduct is only partially racemic with more inversion than retentionAssociated carbocationand leaving group is an ion pair

Delocalized Carbocations

Delocalization of cationic charge enhances stabilityPrimary allyl is more stable than primary alkylPrimary benzyl is more stable than allyl

11.9 Characteristics of the SN1Reaction

Tertiary alkyl halide is most reactive by this mechanism

Controlled by stability of carbocation

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 groupReactivity: 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 halidep-Toluensulfonate (TosO-) is excellent leaving group

Nucleophiles in SN1

Since nucleophilic addition occurs afterformation 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 IonizationPolar, 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 PPolar 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 substitutionOpposite of additionGenerates an alkeneCan 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 carbocationE2: 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 departTransition state combines leaving of X and transfer of HProduct alkene forms stereospecifically

E2 Reaction Kinetics

One step – rate law has base and alkyl halideTransition state bears no resemblance to reactant or productV=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 π orbital in the transition state requires periplanar geometry, anti arrangement

Allows orbital overlap

Predicting ProductE2 is stereospecificMeso-1,2-dibromo-1,2-diphenylethane with base gives cis 1,2-diphenylRR 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 EffectSubstitute deuterium for hydrogen at α positionEffect on rate is kinetic isotope effect (kH/kD = deuterium isotope effect)Rate is reduced in E2 reaction

Heavier isotope bond is slower to breakShows C-H bond is broken in or before rate-limiting step

11.14 The E1 Reaction

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

Stereochemistry of E1 Reactions

E1 is not stereospecific and there is no requirement for alignmentProduct 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 E1E2 is stereospecifc, E1 is notE1 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 conditionsBased on patterns, we can predict likely outcomes (See Table 11.4)