Chapter -14
Alkyl Halides Nucleophilic Aliphatic Substitution Elimination
Structure and nomenclature
We shall consider as alkyl halides all compounds of the general formula R X, where R is any simple alkyl or substituted alkyl group. For example:
Substituted alkyl halides undergo, of course, the reactions characteristic of their other functional groups nitration of benzyl chloride, oxidation of ethylene bromohydrin, addition to allyl bromide but as halides they react very much like ethyl or isopropyl or tert-butyl halides.
Physical properties
Because of greater molecular weight, haloalkanes have considerably higher boiling points than alkanes of the same number of carbons. For a given alkyl group, the boiling point increases with increasing atomic weight of the halogen, so that a fluoride is the lowest boiling, an iodide the highest boiling.
In spite of their polarity, alkyl halides are insoluble in water, probably because of their inability to form hydrogen bonds. They are soluble in the typical organic solvents.
Industrial source
On an industrial scale alkyl halide chiefly the chlorides because of the cheapness of chlorine are most often prepared by direct halogenation of hydrocarbons at the high temperatures needed for these free-radical reactions (Sees. 3.19, 6.21, and 12.12-12.13). Even though mixtures containing isomers and compounds of different halogen content are generally obtained, these reactions are useful industrially since often a mixture can be used as such or separated into its components by distillation.
An alkyl iodide is often prepared from the corresponding bromide or chloride by treatment with a solution of sodium iodide in acetone; the less soluble bromide or sodium chloride precipitates from solution and can be removed by filtration.
Reactions
A halide ion is an extremely weak base. Its reluctance to share its electrons is shown by its great tendency to release a hydrogen ion, that is, by the high acidity of the hydrogen halides.
When attached to carbon, halogen can be readily displaced as halide ion by other, stronger bases. These bases possess an unshared pair of electrons and are seeking a relatively positive site, that is, are seeking a nucleus with which to share their electrons.
As we already know (Sees. 5.12 and 8.12), alkyl halides undergo not only substitution but also elimination, a reaction that is important in the synthesis of alkenes. Both elimination and substitution are brought about by basic reagents, and hence there must always be competition between the two reactions. We shall be interested to see how this competition is affected by such factors as the structure of the halide or the particular nucleophilic reagent used
Alkyl sulfonates
In following sections, we shall discuss the mechanisms of nucleophilic aliphatic substitution and of elimination using alkyl halides as our examples. But we should realize that these reactions take place in exactly the same ways with a variety of other compounds: compounds which, like alkyl halides, contain good leaving gropes
Of these other compounds, alkyl esters of sulfonic acids, ArSO2OR, are most commonly used in place of alkyl halides: usually in the study of reaction mechanisms, but also in synthesis. As the anions of strong acids, sulfonate anions are weak bases and hence are good leaving groups in either nucleophilic substitution elimination:
Most commonly used are esters of / Moluenesulfonic acid: the /? -toluenesiilfonates. The name of the />-toluene sulfonyl group is often shortened to toys' (Ts); /Moluenesulfonyl chloride thus becomes tonsil chloride (Tecle), and /Holuenesulfonates become bodyfats (Tisor).
Before we discuss nucleophilic substitution involving alkyl halides, let us return briefly to the matter of what determines the rate of a reaction.
We have seen (Sec. 2.18) that the rate of a chemical reaction can be expressed as a product of three factors:
So far, we have used this relationship to understand problems of orientation and relative reactivity; in doing this we have compared rates of different reactions. When the conditions that we can control (temperature, concentration) are kept the same, closely related reactions proceed at different rates chiefly because they have different energy factors, that is to say, different Enacts> We have been able to account surprisingly well for many differences in act's by using structural theory to estimate stabilities of the transition
It is also useful to study an individual reaction to see how its rate is affected by deliberate changes in experimental conditions. We can determine act, for example, if we measure the rate at different temperatures (Sec. 2.18). But perhaps the most valuable information about a reaction is obtained by studying the effect of changes in concentration on its rate.
How does a change in concentration of reactants affect the rate of a reaction at a constant temperature? An increase in concentration cannot alter the fraction of collisions that have sufficient energy, or the fraction of collisions that have the proper orientation; it can serve only to increase the total number of collisions. If more molecules are crowded into the same space, they will collide more often and the reaction will go faster. Collision frequency, and hence rate, depends in a very exact way upon concentration.
The field of chemistry that deals with rates of reaction, and in particular with dependence of rates on concentration, is called kinetics. Let us see what kinetics can tell us about nucleophilic aliphatic substitution.
Kinetics of nucleophilic aliphatic substitution. Second-order and first order reactions
Let us take a specific example, the reaction of methyl bromide with sodium hydroxide to yield methanol:
CH3Br + OH" > CH3OH + Br
This reaction would probably be carried out in aqueous ethanol, in which both reactants are soluble
If the reaction results from collision between a hydroxide ion and a methyl bromide molecule, we expect the rate to depend upon the concentration of both these reactants. If either OH" concentration, [OH~], or CH3 Br concentration, [CH3Br], is doubled, the collision frequency should be doubled, and the reaction rate doubled. If either concentration is cut in half, the collision frequency, and consequently the rate, should be halved.
Recognition of the duality of mechanism for nucleophilic aliphatic substitution, formulation of the mechanisms themselves, and analysis of the factors influencing competition between them all are largely due to Sir Christopher Ingold (of University College, London) and the people who worked with him; and this is only a fraction of their total contribution to the theory of organic chemistry.
The SN2 reaction: mechanism and kinetics
The reaction between methyl bromide and hydroxide ion to yield methanol follows second-order kinetics; that is, the rate depends upon the concentrations of both reactants:
CH3Br + OH- > CH3OH + Br~
rate = *[CH3Br] [OH-]
The simplest way to account for the kinetics is to assume that reaction requires a collision between a hydroxide ion and a methyl bromide molecule. On the basis of evidence, we shall shortly discuss, it is known that in its attack the hydroxide ion stays as far away as possible from the bromine; that is to say, it attacks the molecule from the rear.
This is the mechanism that is called SN2: substitution nucleophilic bimolecular. The term ^/molecular is used here since the rate-determining step involves collision of two particles.
What evidence is there that alkyl halides can react in this manner? First of all, as we have just seen, the mechanism is consistent with the kinetics of a reaction like the one between methyl bromide and hydroxide ion. In general, an SN 2 reaction follows second-order kinetics. Let us look at some of the other evidence.
The SN2 reaction: stereochemistry
Both 2-bromooctane and 2-octanol are chiral; that is, they have molecules that are not superimposable on their mirror images. Consequently, these com- pounds can exist as enantiomers, and can show optical activity. Optically active 2-octanol has been obtained by resolution of the racemic modification (Sec. 7.9), and from it optically active 2-bromooctane has been obtained by resolution of the racemic modification.
When ()-2-bromooctane is allowed to react with sodium hydroxide under conditions where second-order kinetics are followed, there is obtained (+)-2- octanol.
We see that the OH group has not taken the position previously occupied by Br; the alcohol obtained has a configuration opposite to that of the bromide. A reaction that yields a product whose configuration is opposite to that of the reactant is said to proceed with inversion of configuration.
(In this particular case, inversion of configuration happens to be accompanied by a change in specification, from R to S, but this is not always true. We cannot tell whether a reaction proceeds with inversion or retention of configuration simply by looking at the letters used to specify the reactant and product; we must work out and compare the absolute configurations indicated by those letters.)
Now the question arises: does a reaction like this proceed with complete inversion? That is to say, is the configuration of every molecule inverted? The answer is yes. An SN2 reaction proceeds with complete stereochemical inversion.
To answer a question like this, we must know the optical purity both of the reactant that we start with, and of the product that we obtain: in this case, of 2-bromooctane and 2-octanol. To know these we must, in turn, know the maximum rotation of the bromide and of the alcohol; that is, we must know the rotation of an optically pure sample of each
Inversion of configuration is the general rule for reactions occurring at chiral centers, being much commoner than retention of configuration. Oddly enough, it is the very prevalence of inversion that made its detection difficult. Paul Walden (at the Polytechnic in Riga, Latvia) discovered the phenomenon of inversion in 1896 when he encountered one of the exceptional reactions in which inversion does not take place
The SN2 reaction: reactivity
In what way would we expect changes in structure of the alkyl group to affect reactivity in an SN2 substitution? In contrast to the free-radical and carbonium ion reactions we have studied, this time the structure of the transition state is not intermediate between the structures of the reactant and product; this time we cannot simply assume that factors stabilizing the product will also stabilize the transition state
First of all, let us compare transition state and reactants with regard to electron distribution. In the transition state, there is a partly formed bond between carbon and hydroxide ion and a partly broken bond between carbon and halide ion: hydroxide ion has brought electrons to carbon, and halide ion has taken electrons away. Unless one of the two processes, bond-making or bond-breaking, has gone much further than the other, the net charge on carbon is not greatly different from what it was at the start of the reaction. Electron withdrawal or electron release by substituents should affect stability of transition state and reactant in much the same way, and therefore should have little influence on reaction rate.
To understand how structure does influence the rate, let us compare transition state and reactants with regard to shape, starting with the methyl bromide reaction. The carbon in reactant and product is tetrahedral, whereas carbon in the transition state is bonded to five atoms. As indicated before, the C H bonds are arranged like the spokes of a wheel, with the C--OH and C Br bonds lying along the axle
In agreement with this prediction, differences in rate between two SN2 reactions seem to be due chiefly to steric factors, and not to electronic factors; that is to say, differences in rate are related to the bulk of the substituents and not to their ability to withdraw or release electrons. As the number of substituents attached to the carbon bearing the halogen is increased, the reactivity toward SN2 substitution decreases. These substituents may be aliphatic, or aromatic, or both, as shown in the following two sequences:
(To give an idea of how large these differences may be, the relative rates for a particular SN2 reaction, substitution by iodide ion, are indicated below the formulas in the first sequence.)
The SN 1 reaction: mechanism and kinetics. Rate-determining step
The reaction between tert-butyl\ bromide and hydroxide ion to yield ten butyl alcohol follows first-order kinetics; that is, the rate depends upon the concentration of only one reactant, tert-butyl bromide.
How are we to interpret the fact that the rate is independent of [OH"]? If the rate of reaction does not depend upon [OH~], it can only mean that the reaction whose rate we are measuring does not involve
When iodine is added to a benzene solution of dimer I (Sec. 1 2. 1 5), the color of the iodine gradually fades, at a rate that depends upon [dimer] but is independent of\2]. When a benzene solution of the dimer is shaken under an atmosphere of NO gas, the pressure of the gas gradually drops, at a rate that depends upon [dimer] but is independent 0/the NO pressure. The rate constants for the two reactions are identical. Account for these results.
The SN1 reaction: stereochemistry
We have proposed that, under the conditions we have described, methyl bromide reacts with hydroxide ion by the SN2 mechanism, and that fern-butyl bromide reacts by the SN 1 mechanism. Since sec-alkyl bromides are intermediate in structure between these two halides, it is not surprising to find that they can react by either or both mechanisms.
An increase in [OH"] speeds up the second-order reaction but has no effect on the first-order reaction. At high [OH~], therefore, the second-order reaction is so much the faster that sec-alkyl bromides react almost entirely by the SN2 mechanism. The behavior of optically active 2-bromooctane in an SN2 reaction has been studied (Sec. 14.10) by use of high IOH~].
In the same way, a decrease in [OH~] slows down the second order reaction but has no effect on the first-order reaction. The behavior of optically active 2-bromooctane in an SN 1 reaction has been studied by use of low [OH~]
The product has the opposite configuration from the starting materials, as in the SN2 reaction, but this time there is a loss in optical purity. Optically pure bromide yields alcohol that is only about two-thirds optically pure. Optically pure starting material contains only the one enantiomer, whereas the product clearly must contain both. The product is thus a mixture of the inverted compound and the racemic modification, and we say that the reaction has proceeded with partial racemization. How can we account for these stereochemical Resul
Suppose that, under SN 1 conditions, 2-bromooctane of specific rotation -21.6 was found to yield 2-octanol of specific rotation +4.12. Using the rotations for optically pure samples given en p. 462, calculate: (a) the optical purity of reactant and of product; (b) the percentage of racemization and of inversion accompanying the reaction; (c) the percentage of front-side and of back-side attack on the carbonium ion.
The SN 1 reaction: reactivity
The rate-determining step of an SN 1 reaction is the formation of a carbonium ion. Judging from our previous experience, therefore, \Ve expects the reactivity of an alkyl halide to depend chiefly upon how stable a carbonium ion it can form.
The rate of an SN2 reaction, we saw, is affected largely by steric factors, that is, by the bulk of the substituents. In contrast, the rate of an SN 1 reaction is affected largely by electronic factors, that is, by the tendency of substituents to release or withdraw electrons.
The SN 1 reaction: rearrangement
If the SN 1 reaction involves intermediate carbonium ions, we might expect it to show one of the characteristic features of carbonium ion reactions: rearrangement. In an SN2 reaction, on the other hand, the halide ion does not leave until the nucleophilic reagent has become attached; there is no free intermediate particle and hence we would expect no rearrangement. These expectations are correct.
The following example illustrates this point. We shall see (Sec. 16.5) that the neopentyl cation is particularly prone to rearrange to the more stable ten pentyl cation. Neopentyl bromide reacts (slowly) with ethoxide ion by an SN2 mechanism to yield neopentyl ethyl ether; it reacts (slowly) with ethyl alcohol by an SN 1 reaction to yield almost entirely rearranged products.
SN 2 vs. SN 1
The strength of the evidence for the two mechanisms, SN l and SN2, lies in its consistency. Nucleophilic substitutions that follow first-order kinetics also show racemization and rearrangement, and the reactivity sequence 3 > 2 > 1 > CH3 X, Reactions that follow second-order kinetics show complete stereochemical inversion and no rearrangement and follow the reactivity sequence CH3 X > 1 > 2 > 3. (The few exceptions to these generalizations are understandable exceptions; see Problem 16.5, p. 525.)
Because there are two opposing reactivity sequences, we seldom encounter either of them in a pure form but find instead a sequence that is a combination of the two. Most typically for halides, as we go along the series CH3 , 1, 2, 3, reactivity passes through a minimum, usually at 2:
Reactivity by the SN2 mechanism decreases from CH3 to 1, and at 2 is so low that the SN 1 reaction begins to contribute significantly; reactivity, now by SN 1, rises sharply to 3. The change in mechanism at 2 is confirmed by kinetics and other evidence.
Solvolysis
Let us turn briefly to the special case of nucleophilic aliphatic substitution in which the solvent is the nucleophile: solvolysis. In its various aspects, solvolysis is and has been for many years the most intensively studied reaction in organic chemistry. Yet it is the reaction about which there is probably the most intense disagreement.
There is no added strong nucleophile and so, for many compounds, solvolysis falls into the category we have called SN 1 : that is, reaction proceeds by two or more -steps, with the intermediate formation of a carbonium ion. It is this intermediate that lies at the center of the problem: its nature, how it is formed, and how it reacts. In studying solvolysis one is studying all SN 1 reactions and, in many ways, all reactions involving intermediate carbonium ions
Elimination: 2 and El
We encountered dehydrohalogenation in Sec. 5.12 as one of the best methods of preparing alkenes. A. that time we said that the mechanism involves a single step: base pulls a hydrogen ion away from carbon, and simultaneously a halide ion separates- aided, of course, by solvation.
But we have just learned that alkyl hands, particularly tertiary ones, can dissociate into halide ions and carbonium ions, and we already know (Sec. 5.20) that a carbonium ion can lose a hydrogen ion to a base to form an alkene.
Evidence for the El mechanism
Finally, first-order elimination is accompanied by the same kind of rearrangement that we expect for a reaction proceeding by way of carbonium ions. The 2-methyl-2-butene formed from neopentyl bromide (Sec. 14.15) is clearly the product of El elimination. Indeed, the reaction in which we first encountered rearrangement, dehydration of alcohols, is simply El elimination involving the prolongated alcohol.
Evidence for the E2 mechanism
Under conditions where reactions follow second-order kinetics, dehydrobrominations of ordinary isopropyl bromide by sodium ethoxide takes place seven times as fast as that of the labeled compound, (CD3) 2 Chabra. An isotope effect of this size, we have seen (Sec. 11.15), reveals the breaking of a carbon -hydrogen bond in the transition state of the rate-determining step
Now, in these elimination reactions, the reactivity of alkyl halides follows the same sequence as for substitution and with element effects, of just about the same size. Clearly, the rate of breaking the carbon halogen bond does affect the overall rate of reaction. On this evidence, if carbanions were formed, they \\could find step (2) difficult and would revert to starting material many times before finally losing halide ion. But such reversible carbanion formation has been ruled out by the absence of isotopic exchange.
Orientation of elimination. The variable E2 transition stat
Where elimination can produce a. mixture of isomers, which one predominates? We saw earlier (Sec. 5.14) that in dehydrohalogenation the more stable alkene is formed faster: sec-butyl bromide, for example, yields more 2-butene than l-butene. We attributed this orientation to the alkene character of the transition.
In E2 elimination with bases like KOH and CH3 ONa, most alkyl halides give Saytzeff orientation. Certain other compounds (quaternary ammonium salts, Sec. 23.5, for example) give Hofmann orientation. Alkyl sulfonates fall in between. With each kind of compound, orientation is affected sometimes drastically by the choice of base and solvent, and by stereochemistry. (The percentage of 1-hexene from 2-hexyl chloride, for example, jumps from 33% in CH3ONa/ CH3OH to 91% in /-BuOK//-BuOH, evidently for steric reasons.) In all this, we should remember that orientation is a matter of relative stabilities of competing transition states; these stabilities are determined by electronic factors alkene character and carbanion character with superimposed conformational factors.
So far, we have spoken only of E2 elimination. In El elimination, orientation is determined in the second step: conversion of carbonium ion to alkene. As we might expect, orientation is essentially the same regardless of what leaving group has departed earlier in the formation of the carbonium ion. Orientation is strongly Saytzeff, reflecting much alkene character in the transition
Stereochemistry of elimination
Dehydrohalogenation of l-bromo-l,2-diphenylpropane gives, as we would expect, 1,2-diphenylpropene. But the halide contains two chiral centers, and we
can easily show that it can exist as two pairs of enantiomers; each pair is diastereomeric with the other pair. On E2 elimination, one pair of enantiomers yields only the oy-alkene, and the other pair yields only the /raw-alkene. The reaction is completely stereospecific (Sec. 7.11).
As this example and many others show, the bimolecular reaction of alkyl halides involves ^//-elimination: in the transition state the hydrogen and the leaving group are located as far apart as possible, in the anti-relationship (Sec. 3.3) as opposed to gauche or eclipsed (see Fig. 14.4, p.
chlorine, and which can take up a conformation anti to it. Either hydrogen can be eliminated, and the ratio of products is determined in the usual way, by the relative stabilities of the alkenes being formed. In methyl chloride, on the other hand, only one hydrogen is trans to the chlorine, and it is the only one that is eliminated, despite the fact that this yields the less stable alkene.
In recent years it has become clear that E2 reactions can also proceed by Syn elimination: in the transition state the hydrogen and leaving group are in the eclipsed (or gauche) relationship. Although uncommon for alkyl halides, Syn elimination \* often observed for quaternary ammonium salts and sometimes for alkyl selenates. On electronic grounds, the mo?4 stable transition states seem to be those in which the hydrogen and leaving group are peril/ajar (in the same plane) to permit overlap of incipient p orbitals in the partially formed double bond. Of the two periplanar eliminations, the anti is probably easier than the syn other things being equal. But various factors may throw the stereochemistry one way or the other. Conformational effects enter in, and the degree of carbanion character; the stereochemistry is affected by the strength of the base and by its bulk and by the bulk of the leaving group. Ring systems present special situations: it is difficult for ra-l,2-substituents to become sivi-penplanar in cyclohexane's, but easy in cyclopentanes.
enantiomer) gave r/>2-butene without loss of deuterium and trans-2-bu\Ene with loss of deuterium; diastereomer VI (and its enantiomer) gave //Y/w-2-butene without loss of deuterium. How do your account for these findings? What is the stereochemistry of elimination here?
Elimination 175. substitution
Let us return to a problem we encountered before, in the reaction between acetylides and alkyl halides (Sec. 8.12): competition between substitution and elimination. Both reactions result from attack by the same nucleophilic reagent: attack at carbon causes substitution, attack at hydrogen causes elimination.
We can see more clearly now why reaction with acetylides to form alkynes is limited in practice to primary halides. Under the conditions of the reaction a solvent of low polarity (liquid ammonia or ether) and a powerful nucleophilic reagent (acetylide ion) we would expect substitution, that is, alkyne formation, to take place by an SN2 mechanism. Primary halides should therefore form alkynes fastest tertiary halides the slowest.
Analysis of alkyl halides
Simple alkyl halides respond to the common characterization tests in the same manner as alkanes: they are insoluble in cold concentrated sulfuric acid; they are inert to bromine in carbon tetrachloride, to aqueous permanganate, and to chromic anhydride. They are readily distinguished from alkanes, however, by qualitative analysis (Sec. 2.25), which shows the presence of halogen.
In many cases, the presence of halogen can be detected without a sodium fusion or Schoninger oxidation. An unknown is warmed for a few minutes with alcoholic silver nitrate (the alcohol dissolves both the ionic reagent and the organic compound); halogen is indicated by formation of a precipitate that is insoluble in dilute nitric acid
As in almost all reactions of organic halides, reactivity toward alcoholic silver nitrate follows the sequence Rl > Brr > RC1. For a given halogen atom, reactivity decreases in the order 3 > T > 1, the sequence typical of carbonium ion formation; allyl and benzyl halides are highly reactive. Other evidence (stereochemistry, rearrangements) suggests that this reaction is of the SN 1 type. Silver ion is believed to dispose reaction toward this mechanism (rather than the SN2) by pulling halide away from the alkyl halide
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