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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 Brnsted bases produce elimination

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 This chapter continue the topic from CHAPTER 2 PART III

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 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 array 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 Waldens cycle

The SN2 Reaction

Reaction is with inversion at reacting center Follows second order reaction kinetics Ingold nomenclature to describe characteristic step: S=substitution N (subscript) = nucleophilic 2 = both nucleophile and substrate in characteristic step (bimolecular)

Kinetics of Nucleophilic Substitution

Rate (V) is change in concentration with time Depends 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 products A rate constant (k) is the proportionality factor between concentration and rate

Reaction rate = Rate of disappearance of reactant

V = k x [RX] x [-OH]

[RX] = alkyl halide concentration in molarity

[-OH] = -OH concentration in molarity


Reaction Kinetics
The study of rates of reactions is called kinetics Rates decrease as concentrations decrease but the rate constant does not Rate units: [concentration]/time such as L/(mol x s) The rate law is a result of the mechanism The order of a reaction is sum of the exponents of the concentrations in the rate law the example is second order

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


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) and aryl halide


Factor affecting the rate of reaction

1. Substrate (Alkyl halide) - metyl and primary subtrate react faster followed by 2. Nucleophile 3. Solvent -because solvent may/may not surround a nucleophile thus hinder/not the approach carbon 4. Leaving group (stronger acid, good leaving group)


Reactant and Transition State Energy Levels Affect Rate

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 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 18 reactions.

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


Relative Reactivity of Nucleophiles

1. Nucleophilicity roughly parrallels basicity (less basic more reactive) 2. Nucleophilicity usually increases going down a column of periodic table (larger shell,less tight,more reactive) 3. Negatively charged necleophiles are usually more reactive than neutral ones



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

Alkyl fluorides, alcohols, ethers, and amines do not typically undergo SN2 reactions.


The Solvent
Protic solvents that can donate hydrogen bonds (OH or NH) slow down SN2 reactions by solvation by associating with reactants nucleophile 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 by raising the ground-state energy


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 stepsimeltaneously If nucleophile is present in reasonable concentration (or it is the solvent), then ionization is the limiting step



SN1 Energy Diagram

V = k[RX]

Rate-determining step is formation of carbocation


Rate-Limiting Step
The overall rate of a reaction is controlled by the rate of the limiting/(slower) 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) V = k[RX]

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

Stereochemistry of SN1 Reaction


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

Characteristics of the SN1 Reaction

Substrate Tertiary alkyl halide is most reactive by this mechanism Controlled by stability of carbocation Remember Hammond postulate,Any factor that stabilizes a high-energy intermediate stabilizes transition state leading to that intermediate


Allylic and Benzylic Halides

Allylic and benzylic intermediates stabilized by delocalization of charge 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 normally affected by nature or concentration of nucleophile


Solvent in SN1
Stabilizing carbocation also stabilizes associated transition state and controls rate Solvent effects in the SN1 reaction are due largely to stabilization or destabilization of the transition state


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


SN1 and SN2 reactions are well known in biological chemistry Unlike what happens in the laboratory, substrate in biological substitutions is often organodiphosphate rather than an alkyl halide

Biological Substitution Reactions


Elimination Reactions of Alkyl Halides: Zaitsevs Rule

Elimination is an alternative pathway to substitution Involves the loss of two atoms groups from substrate Generates an alkene (usually formation of pi bond) Can compete with substitution and decrease yield, especially for SN1 processes


Zaitsevs Rule for Elimination Reactions

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



Mechanisms of Elimination Reactions

E1: X- leaves first to generate a carbocation then a base abstracts a proton from the carbocation E2: Concerted transfer of a proton to a base and departure of leaving group at the same time E1cB: Base abstraction of the proton occur first, giving carbon anion or carbonion intermediate




E2 reaction
Concerted mechanisms require specific geometric arrangement IN ORDER FOR orbital of the bonds being broken can overlap with those being formed and the electron can flow smoothly from one bond to another Geometric arrangement for SN2 is back- side attack E2 occur with periplanar geometry (H, X, and C=C lie in the same plane)





Geometry of Elimination E2
Syn-periplanar geometry the H and the X are on the same side (eclipsed, high energy) Anti periplanar geometry the H and the X are on opposite side (staggered, low energy) Anti coplanar (theta=180 degree) or antiperiplanar arrangement is most commonly seen in E2 Antiperiplanar preferred because allows orbital overlap and minimizes steric interactions


E2 Stereochemistry
Overlap of the developing orbital in the transition state requires periplanar geometry, anti arrangement


Predicting Product
E2 is stereospecific Meso-1,2-dibromo-1,2-diphenylethane with base gives cis 1,2-diphenyl. None isomeric Z alkene formed, because it requires syn periplanar, higher energy RR or SS 1,2-dibromo-1,2-diphenylethane gives trans 1,2-diphenyl


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- not anti periplanar-thus no reaction


The E1and E1cB Reactions

Competes with SN1 and E2 at 3 centers V = k [RX], same as SN1


Comparing E1 and E2
Strong base is needed for E2 but not for E1 E2 is stereospecifc, E1 is not E1 gives Zaitsev orientation


E1cB Reaction
Takes place through a carbanion intermediate


Biological Elimination Reactions

All three elimination reactions occur in biological pathways E1cB very common Typical example occurs during biosynthesis of fats when 3-hydroxybutyryl thioester is dehydrated to corresponding thioester