11.

Reactions of Alkyl Halides:

Nucleophilic Substitutions and
Eliminations

Based on McMurry’s Organic Chemistry, 7th edition

 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 Brø nsted bases produce elimination

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 Why this Chapter?
◼ Nucleophilic substitution, base induced elimination are among most
widely occurring and versatile reaction types in organic chemistry

◼ Reactions will be examined closely to see:

- How they occur
- What their characteristics are
- How they can be used

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 11.1 The Discovery of Nucleophilic
Substitution Reactions
◼ In 1896, Walden showed that (-)-malic acid could be converted to
(+)-malic acid by a series of chemical steps with achiral reagents
◼ Walden’s cycle (inversion)

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 Significance of the Walden
Inversion
◼ The reactions alter the array at the chirality center
◼ The reactions involve substitution at that center
◼ Therefore, nucleophilic substitution can invert the configuration at a
chirality center

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 Nucleophilic Substitution
◼ Walden inversion = Nucleophilic substitution

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 Nucleophilic Substitution
◼ Problem 11.1
◼ (S)-2-bromohexane + CH3CO2- ?

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 11.2 The SN2 Reaction
◼ Reaction is with inversion at reacting center
◼ Follows second order reaction kinetics
◼ Ingold nomenclature to describe characteristic step:
◼ S (substitution), N (nucleophilic), 2 (both nucleophile and
substrate in characteristic step, bimolecular)
◼ Reaction rate = Rate of disappearance of reactant
= Rate of appearance
= k x [RX] x [OH-] (k: rate constant)

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 SN2 Process: Essential Feature
◼ Single step, No intermediate
◼ Substrate, Nucleophile, Leaving group
◼ Inversion of configuration

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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

Umbrella Inversion

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 11.3 Characteristics of SN2 Reaction

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

Higher TS energy level (red curve) = slower reaction (larger G‡).

For faster reaction: 1) Less stable reactant, 2) More stable TS

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 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.

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 Order of Reactivity in SN2
◼ The more alkyl groups connected to the reacting carbon, the slower
the reaction
◼ SN2 reactions occur only at relatively unhindered sites and are
normally useful only with CH3X, 1o RX, and a few simple 2o RX.

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 Order of Reactivity in SN2
◼ Vinylic halides and aryl halides are unreactive toward SN2 reaction

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 The Nucleophile
◼ Neutral or negatively charged Lewis base
◼ Unshared paired electrons
◼ Reaction increases coordination at nucleophile
◼ Neutral nucleophile acquires positive charge
◼ Anionic nucleophile becomes neutral

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 Relative Reactivity of Nucleophiles
◼ Nucleophilicity?
◼ Depends on reaction and conditions (substrate, solvent, conc.)
◼ More basic nucleophiles react faster
◼ 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
◼ X- : Stable anions (weak bases) are usually excellent leaving groups
and can delocalize charge
◼ ROH, RNH2, ROR, RF: No SN2 reaction

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 The Leaving Group
◼ (1o, 2o) ROH → RCl, RBr, ROTs ◼ Exceptions: Epoxides

Good leaving group: Ring strain

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 The Solvent
◼ Worst: Protic solvent (-OH, -NH)
◼ MeOH, EtOH; Solvation of reactant nucleophile
◼ Energy is required to break interactions between reactant and
solvent

◼ Best: Polar aprotic solvent

◼ Raise ground-state energy of the nucleophile (Increase rate)
◼ THF, CH3CN, DMF [(CH3)2NCHO], DMSO [(CH3)2SO], HMPA
{[(CH3)2N]3PO}
◼ Dissolve salts, solvate metal cations, Bare unsolvated
nucleophile

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 Summary of SN2 Reaction
Characteristics
◼ Substrate
◼ Steric hindrance
◼ Methyl > 1o > 2o
◼ Nucleophile
◼ Basic, Negatively charged: Higher ground-state E: ↓ ΔGǂ
◼ Leaving group
◼ Good leaving group (stable anion): Lower TS E: ↓ ΔGǂ
◼ Solvent
◼ Protic: solvate Nu, decrease ground-state E: ↑ ΔGǂ
◼ Polar aprotic: solvate cation, bare nucleophile, increase
ground-state E: ↓ ΔGǂ

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Summary of SN2 Reaction
Characteristics

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 11.4 The SN1 Reaction
◼ 3o RX 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

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 11.4 The SN1 Reaction
◼ First-order kinetics
◼ Rate = k ˣ [RX]
◼ RDS

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 SN1 Energy Diagram

V = k[RX]

◼ Rate-determining step is formation of carbocation

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 Stereochemistry of SN1
Reaction
◼ The planar intermediate leads to loss of chirality
◼A free carbocation is achiral
◼ Product is racemic or has some inversion

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 SN1 in Reality
◼ Lack of complete racemization
◼ 50:50 but minor excess of inversion (ex. 60:40)… Why?

◼ Carbocation and leaving group are loosely associated (an ion pair)
◼ Shielding

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 11.5 Characteristics of the SN1
Reaction: Substrate
◼ Tertiary alkyl halide is most reactive by this mechanism
◼ Controlled by stability of carbocation
◼ Hammond postulate: “Any factor that stabilizes a high-energy
intermediate stabilizes transition state leading to that intermediate”

Resonance-stabilized
Also reactive in SN2 (1o)

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 Effect of Leaving Group on SN1
◼ Critically dependent on leaving group
◼Reactivity: the larger halides ions are better leaving groups
◼ p-Toluensulfonate (TosO-) is excellent leaving group

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 Effect of Leaving Group on SN1
◼ In acid, OH of an alcohol is protonated and leaving group is H2O
◼ 3o alcohol + HBr (HCl)

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 Nucleophiles in SN1
◼ Since nucleophilic addition occurs after formation of carbocation,
reaction rate is not normally affected by nature or concentration of
nucleophile
◼ Neutral nucleophiles are just as effective as negatively charged
ones (Neutral or acidic conditions)

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 Solvent in SN1
◼ Stabilizing carbocation also stabilizes associated transition state
and controls rate (cf. SN2: stabilize/destabilize reactant)
◼ Solvent effects in the SN1 reaction are due largely to stabilization or
destabilization of the transition state (carbocation)

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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)
◼ Nonpolar solvents have low P
◼ Polar solvents have high P values

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11.5 Characteristics of the SN1
Reaction: Summary
◼ Worked Ex. 11.2
◼ SN1? or SN2?

◼ Problem 11.13
◼ SN1? or SN2?

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 11.7 Elimination Reactions of
Alkyl Halides: Zaitsev’s Rule
◼ 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
◼ 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
◼ E2: Concerted transfer of a proton to a base and departure of
leaving group
◼ E1cB (conjugate base): Carbanion intermediate

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Mechanisms of Elimination
Reactions

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 11.7 Elimination Reactions of
Alkyl Halides: Zaitsev’s Rule
◼ Worked Ex. 11.3

◼ Problem 11.15
◼ Major product? (Ignore double-bond stereochemistry)

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 11.8 The E2 Reaction and the
Deuterium Isotope Effect
◼ 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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 11.8 The E2 Reaction and the
Deuterium Isotope Effect
◼ 1st evidence: Second-order of kinetics: rate = k ˣ [RX] ˣ [Base]
◼ 2nd evidence: Deuterium isotope effect
◼ C-H is weaker than C-D
◼ HBr formation is 7.11 times faster than DBr formation
◼ C-H (or C-D) bond is broken in the RDS

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 Geometry of Elimination – E2
◼ 3rd evidence of E2 elimination
◼ Periplanar geometry
◼ Syn/Anti periplanar
◼ Antiperiplanar is energetically preferred (Staggered)

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 Geometry of Elimination – E2
◼ 3rd evidence of E2 elimination
◼ Periplanar geometry
◼ sp3 σ (C-H), sp3 σ (C-X) → p π
◼ Periplanar for maximum overlap

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 Geometry of Elimination – E2
◼ 3rd evidence of E2 elimination
◼ E2 is stereospecific
◼ Meso-1,2-dibromo-1,2-diphenylethane with base gives E alkene
only

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 Geometry of Elimination – E2
◼ Problem 11.17
◼ E2 elimination of (1R,2R)-1,2-dibromo-1,2-diphenylethane?
◼ Draw Newman projection

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 11.9 The E2 Reaction and
Cyclohexane Formation
◼ Abstracted proton and leaving group should align trans-diaxial to be
anti periplanar (app) in approaching transition state
◼ Equatorial groups are not in proper alignment

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11.9 The E2 Reaction and
Cyclohexane Formation

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 11.9 The E2 Reaction and
Cyclohexane Formation
◼ Problem 11.19
◼ Which one is faster? Draw stable chair conformation
◼ E2 elimination of trans-1-bromo-4-tert-butylcyclohexane or cis-1-
bromo-4-tert-butylcyclohexane

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11.10 The E1and E1cB Reactions
◼ E1 mechanism

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11.10 The E1and E1cB Reactions
◼ Competes with SN1 and E2 at 3° centers
◼ V = k [RX], same as SN1
◼ No deuterium isotope effect (C-H bond cleavage is not RDS)

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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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 E1cB Reaction
◼ Takes place through a carbanion intermediate (RDS)
◼ X-C-C-C=O (leaving group two carbons away from carbonyl)
◼ Carbonyl compound… (later in Ch. 22)

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 11.12 Summary of Reactivity: SN1,
SN1, E1,E1cB, E2
◼ Alkyl halides undergo different reactions in competition, depending
on the reacting molecule and the conditions
◼ Based on patterns, we can predict likely outcomes

SN1 SN2 E1 E1cB E2

1o RX Good Nu X-CC-C=O Strong B

Allylic/benzylic
Weakly basic with weakly Weakly basic Strong B
2o RX Nu (protic solv) basic Nu (polar Nu (protic solv)
X-CC-C=O
(predominates)
aprotic solv)

Neutral (with Neutral (with

3o RX E1) SN1)
X-CC-C=O Base

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 11.12 Summary of Reactivity: SN1,
SN1, E1,E1cB, E2
◼ Worked Ex. 11.5
◼ Predict product

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 11.12 Summary of Reactivity: SN1,
SN1, E1,E1cB, E2
◼ Problem 11.20
◼ SN1, SN2, E1, E1cB, E2

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