NUCLEOPHILIC SUBSTITUTION AND ELIMINATION OF ALKYL HALIDES

Ch.8:NUCLEOPHILIC SUBSTITUTION AND ELIMINATION

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TABLE OF CONTENTS FOR THIS PAGE

1.Substitution and Elimination: General
2.The S_N1 and S_N2 Mechanisms
3.Kinetics
4.Stereochemistry
5.TS Models for Both Types of Substitution Mechanism
6.The Effect of Structure on Reaction Rates and Mechanisms
7. The Effect of Solvent on Reaction Rates and Mechanisms
8.Secondary Systems: The Prediction of Reaction Mechanism
9.Polar Aprotic Solvents
10.Nucleophilicity
11.Leaving Group Ability
12.Rearrangements
13.Neighboring Group Participation
14.Phase Transfer Catalysis
15.Beta Elimination
16.The E2 Mechanism: TS Models
17.The E1 Mechanism
18.Substitution vs Elimination

SUBSTITUTION AND ELIMINATION:GENERAL

In contrast to addition, in which two molecules add together, substitution (Symbol S)is a reaction type in which in a single molecule, one group or atom replaces another.

In the example given below, a hydroxyl group replaces a chlorine atom, thus converting an alkyl halide into an alcohol.

Whereas alkenes undergo addition to their pi bonds, because they can add another group, saturated carbon compounds (which have only tetrahedrally hybridized carbon atoms) normally do not undergo addition, but rather substitution.

Most commonly, this occurs by a nucleophilic substitution mechanism , i.e., in which the organic compound reacts with a nucleophile. To do this, the organic molecule must have a good leaving group, which can depart with and stabilize the electron pair of its former bond to carbon. Good leaving groups are relatively stable anions (such as bromide or chloride ions( or, even better, neutral molecules like water or nitrogen. This is necessary because the reacting nucleophile, by definition, brings its own electron pair to bond formation.

The mechanistic symbol is S_N. There are two specific types of S_N mechanisms.

Elimination (E) is a reaction type which is the reverse of addition. In this process a single molecule splits up into two parts.

Most eliminations are base catalyzed, and they also require a good leaving group such as a halide ion, but also a proton beta to the leaving group, which is pulled off by the base.

Since elimination is the reverse of addition, it forms alkenes (e.g., from alkyl halides) rather than using alkenes as reactants.

MECHANISMS OF NUCLEOPHILIC SUBSTITUTION

THE S_N2 MECHANISM

In this mechanism,a nucleophile reacts directly with an organic substrate such as an alkyl halide in a concerted (one step) reaction. The nucleophile (Nu) provides the electron pair for the new bond, and the leaving group (L) departs with the pair of electrons which previously formed the C-L bond.

The formation of the new bond (C-Nu) and the breaking of the old bond (C-L) are simultaneous or concerted. The energy lowering obtained by forming the new bond provides part of the energy needed to break the old bond.

THE S_N1 MECHANISM

In this mechanism, the formation of the new bond and the breaking of the old one are not concerted, but stepwise. In particular, the old bond is first broken, to give a carbocation (remember? a carbocation is a species having a positively charged, trivalent carbon atom; it is trigonally hybridized (planar), and has a vacant 2p orbital).

The first step is the rds, since is is obviously highly endothermic.

The subsequent formation of the new bond to the carbocation does not involve the breaking of any bonds, so it is hgihly exothermic and very fast.

KINETICS

The RATE LAW for a reaction is a description of the rate of the reaction as it depends upon the concentrations of various species. It includes a rate constant, k(small k, not an equilibrium constant, K), which is equal to the rate of the reaction at unit concentrations of all reagents. As noted previously, it is a measure of the inherent rate of the reaction, independent of concentrations.

A first order rate law is one which depends upon the concentration of a single reactant taken to the first power, i.e., the rate is linearly dependent upon the concentration of that reagent. The order of the rate law is the sum of the exponents of all concentration expressions in the rate law.

The rate law for the S_N1 reaction is first order, depending only upon the concentration of the alkyl halide, and not at all upon the concentration of the nucleophile. That is because the first step is the rate determining one. The subsequent step which involves the nucleophile is very fast.

The "1" of S_N1 is the molecularity (the number of molecules present) of the rate determining step, in which only the alkyl halide is involved.

In contrast, the S_N2 reaction is second order, depending upon the concentrations of both the alkyl halide and the nucleophile, each linearly. The rate determining step (indeed the only step) is bimolecular, so that the mechanistic designation is S_N2.

The reason the rate of this reaction is dependent upon the concentrations of both reactants is simply that they must collide in order to react. The number of collisions between the two reagents is directly proportional to the concentrations of both.

STEREOCHEMISTRY

Stereochemistry of the S_N2 Reaction

An especially interesting, and useful, aspect of the S_N2 reaction is that the new bond does not directly replace the old one in space. Instead, the nucleophile approaches from the opposite side (or face) of the molecule from which the leaving group departs, resulting in what we call INVERSION OF CONFIGURATION.

Thus, (S)-2-chlorobutane is converted to (R)-2-butanol. The reactant and the product are said to have OPPOSITE RELATIVE CONFIGURATIONS.

There are two other hypothetically possible stereochemical results for substitution which could have occurred, but do not. One is RETENTION OF CONFIGURATION, in which the nucleophile approaches from the same side as the leaving group departs. This would have resulted in the formation of (S)-2-butanol.
A third hypothetically possible result is racemization, in which both retention and inversion occur to the same extent, giving racemic 2-butanol.

Stereochemistry of the S_N1 Reaction

Since a carbocation is formed as an intermediate in this reaction, and since the carbocation is planar and therefore achiral, the result is racemization. The carbocation can be seen to be achiral because it has a plane of symmetry, which is the trigonal plane.
Mechanistically, we can see how racemization arises. Since the carbocation 2p_z AO has two equivalent lobes, the nucleophilie can react at either lobe equally rapidly, to give both enantiomers of the product in equal amounts. You should be able to illustrate this on an exam.

TRANSITION STATE MODELS

TS FOR THE S_N2 REACTION

The carbon atom which is undergoing substitution is sp² hybridized, with the leaving group bonding to one lobe of a 2p orbital and the nucleophile bonding to the other.
The TS does not have carbocation, radical, etc. character but is characterized as having pentacovalent (or pentacoordinate) carbon character.
Pentacovalent carbon has more groups around it than normal for carbon, so these groups are more proximate (closer) than usual. Therefore, pentacovalent carbon is especially sensitive to steric effects.

TS for the RDS of the S_N1 Reaction

The first step of the S_N1 reaction is rate limiting, so we are interested only in the TS of this step for rate considerations.
Using resonance theory in the usual way, we can derive (and you should be able to derive) the transition state shown, with a partial carbon-L bond, and positive partial charge on carbon (negative on the leaving gorup).
This TS has carbocation character. Since the breaking of a strong bond without the formation of any other bond is bound to be highly endothermic, the Hammond postulate indicates that the TS resembles the products. Therefore, the TS has extensive carbocation scharacter.

THE EFFECT OF STRUCTURE ON THE RATES OF REACTION

THE S_N1 REACTION

We consider the transition state energies for reactions involving the generation of methyl, primary, secondary, and tertiary carbocation character. As a specific example, it might be methyl, ethyl, isopropyl, and tert-butyl chlorides. We know that the order of carbocation stability is tertiary>secondary>primary>methyl and that the differences are large. The same order avails for transition states which have extensive carbocation character.
Thus, the S_N1 reaction of tert-butyl chloride or any other tertiary halide would be much faster that for a secondary halide, than for a primary halide, than for a methyl halide.

THE S_N2 REACTION

We note that the order of reactivity is now exactly the reverse for this mechanism, i.e., the methyl substrate is fastest, followed by the primary, the secondary, and finally the tertiary halide.
This is because of the steric sensitivity of the S_N2 TS. In the case of the methyl substrate, the groups attached to the pentacovalent carbon (other than the nucleophile and the leaving group) are all hydrogens (smallest atom), whereas in the tert-butyl case, they are all methyl groups. This gives rise to substantial steric repulsions between the five groups around carbon in the TS.

MECHANISTIC TENDENCIES BASED UPON STRUCTURE

As a result of the opposing rate tendencies in the two mechanisms, it turns out that tertiary systems, which are the fastest at the S_N1 and slowest at the S_N2, virtually always can be relied upon to undergo reaction via the S_N1 mechanism, i.e., via a carbocation mechanism.
In contrast, methyl and primary systems which are good at S_N2 and slow at S_N1 virtually always react via the S_N2 mechanism.
Secondary systems are more difficult to predict, but the main factor here is the strength of the nucleophile. Remember that the nucleophile is present in the S_N2 transition state but not in the S_N1 TS. The stronger the nucleophile, the faster the S_N2 reaction, but increasing the nucleophilic strength has no effect on the S_N1 reaction. So, with weak nucleophiles like water or methanol, secondary systems prefer the S_N1 mechanism, but with strong ones like hydroxide or other negatively charged ions they will proceed via an S_N2 mechanism.

ALLYLIC HALIDES

Allylic halides undergo the S_N1 reaction very rapidly, because allylic cations, which are formed in the rds are highly resonance stabilized. The transition state has allylic cation character. Allylic systems and tertiary systems undergo these reactions at comparable rates.

Allylic halides under the the S_N2 reaction very rapidly if the halide is attached to a primary carbon atom. Thus, the simplest allylic halide, 3-chloropropene (allyl chloride), undergoes both S_N reaction mechanisms extremely rapidly.

In the latter case, the mechanism which is followed usually is determined by the strength of the nucleophile. A strong nucleophile favors the S_N2 mechanism.

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NUCLEOPHILIC SUBSTITUTION AND ELIMINATION OF ALKYL HALIDES

Ch.8:NUCLEOPHILIC SUBSTITUTION AND ELIMINATION

TABLE OF CONTENTS FOR THIS PAGE

SUBSTITUTION AND ELIMINATION:GENERAL

MECHANISMS OF NUCLEOPHILIC SUBSTITUTION

THE SN2 MECHANISM

THE SN1 MECHANISM

KINETICS

STEREOCHEMISTRY

Stereochemistry of the SN2 Reaction

Stereochemistry of the SN1 Reaction

TRANSITION STATE MODELS

TS FOR THE SN2 REACTION

TS for the RDS of the SN1 Reaction

THE EFFECT OF STRUCTURE ON THE RATES OF REACTION

THE SN1 REACTION

THE SN2 REACTION

MECHANISTIC TENDENCIES BASED UPON STRUCTURE

ALLYLIC HALIDES

THIS CHAPTER IS CONTINUED ON THE FOLLOWING WEB PAGE

THE S_N2 MECHANISM

THE S_N1 MECHANISM

Stereochemistry of the S_N2 Reaction

Stereochemistry of the S_N1 Reaction

TS FOR THE S_N2 REACTION

TS for the RDS of the S_N1 Reaction

THE S_N1 REACTION

THE S_N2 REACTION