3. Aliphatic Nucleophilic Substitution Reactions – Advanced Organic Chemistry

3

Aliphatic Nucleophilic Substitution Reactions

LEARNING OBJECTIVES

By the end of this chapter you should be familiar with

  • Nucleophilic attack on saturated carbon atoms, leading to substitution reactions.
  • Different mechanisms of nucleophilic substitution.
  • How substitution reactions affect stereochemistry.
  • What sort of nucleophiles can substitute, and what sort of leaving groups can be substituted.
  • The types of molecules that can be made by substitution, and what they can be made from.
  • The effect of solvent on the rate of reaction and neighbouring group participation
  • Substitution on the substrates like benzylic, allylic, vinylic and aryl halides.
3.1 INTRODUCTION

Organic chemistry is comparatively simple to learn because most organic chemical reactions follow a single pattern.

Organic compounds in which an sp3 carbon is bonded to an electronegative atom or group can undergo two types of reactions. They can undergo either substitution reactions, in which the electronegative atom or group is substituted by another atom or group, or elimination reactions, in which the electronegative atom or group is eliminated along with a hydrogen from an adjacent carbon. The electronegative atom or group that is eliminated is called the leaving group (nucleofuge). Electrofuge is the leaving group in an electrophilic substitution reaction that departs without the electron-pair. Of the various classes of organic reactions, nucleophilic substitution reactions on carbon have been studied most intensively and are of broad synthetic utility. Alkyl halides are a good family of compounds with which to start our study of these two very important types of reactions: substitution and elimination.

Substitution reactions are important reactions in organic chemistry. In these reactions, alkyl groups are transferred to the nucleophiles. Organic electrophiles of this type are referred to as alkylating agents. Through the use of these reactions, readily available alkyl halides can be converted into a wide variety of other compounds. Substitution reactions are also important in the cells of plants and animals.

There are two important mechanisms for the substitution reaction.

  1. A nucleophile is attracted to the partially positively charged carbon. As the nucleophile approaches the carbon, it causes the carbon–halogen bond to break heterolytically, that is, direct displacement mechanism.
  2. The carbon–halogen bond breaks heterolytically without any assistance from the nucleophile, forming a carbocation. The carbocation then reacts with the nucleophile to form the substitution product that is, the ionization mechanism.

Depending on the nature of the nucleophile (neutral or negatively charged) and RX (neutral or positively charged) there are four charge types:

Regardless of the mechanism by which such a substitution reaction occurs, it is called a nucleophilic substitution reaction because a nucleophile is substituted for the halogen. The mechanism that predominates depends on:

  • the structure of the alkyl halide,
  • the reactivity and structure of the nucleophile,
  • the concentration of the nucleophile, and
  • the solvent in which the reaction is carried out. SN1 reactions are observed
  • always in substitutions on Rtert-X, Ar2CH-X and Ar3C-X;
  • always in substitutions on substituted and unsubstituted benzyl and allyl triflates;
  • in substitutions on Rsec-X that are carried out in the presence of strong Lewis acids;

    SN2 reactions take place

  • almost always in substitutions in sterically unhindered benzyl and allyl positions;
  • always in substitutions in Me-X and Rpri-X;
  • in substitutions on Rsec-X, provided a reasonably good nucleophile is used.
3.2 MECHANISM OF SN2 REACTION

The factors that affect the rate of the reaction are called the kinetics of the reaction. The rate of a nucleophilic substitution reaction, such as the reaction of methyl bromide with hydroxide ion, depends on the concentrations of both reagents.

The energy necessary to break the C–Br bond is supplied by simultaneous formation of the C–O bond. When the transition state is reached, the central carbon atom has gone from its initial sp3 hybridization to a sp2 state, with an approximately perpendicular p orbital. One lobe of this orbital overlaps with the nucleophile and the other with the leaving group. That is, the nucleophile, the central carbon and the leaving group are collinear, and remain so in the transition state for the reaction. This is why a front-side SN2 mechanism has never been observed. During the transition state, the three nonreacting substituents and the central carbon are approximately coplanar. The transition state involves trigonal bipyramidal geometry with a pentacoordinate carbon. The concerted displacement mechanism implies both kinetic and stereochemical consequences.

The rate law for the reaction may be expressed as:

 

rate ∝ [alkyl halide] [nucleophile]

The ‘proportional to’ sign (∝) can be replaced by an equal sign and a proportionality constant (k). Because the rate of the reaction depends on the concentration of two reactants, it is a second-order reaction.

 

rate = k [alkyl halide] [nucleophile]

The rate law tells us what molecules are involved in the transition state of the rate-determining step of the reaction. The transition state is bimolecular, that is, it involves two molecules. This is not always the same as a second order mechanism because, if an excess of nucleophile is present, that is, if it is solvent, the mechanism may still be bimolecular, though the experimentally determined kinetics will be of the first order. Such kinetics is called pseudo-first order, as the concentration of the solvent will not change significantly during the course of the reaction. The rate constant describes how difficult it is to overcome the energy barrier of the reactions (how hard it is to reach the transition state). The lower the rate constant, the more difficult it is to reach the transition state.

The reaction of methyl bromide with hydroxide ion is an example of an SN2 reaction. In 1937, Hughes and Ingold proposed a mechanism for SN2 reactions with the following experimental evidence:

  1. The rate of the reaction depends on the concentration of the alkyl halide and on the concentration of the nucleophile. This means that both reactants are involved in the transition state of the rate-determining step.
  2. When the hydrogens of methyl bromide are successively replaced with methyl groups, the rate of the reaction with a given nucleophile becomes progressively slower.
  3. The reaction of an alkyl halide in which the halogen is bonded to a chirality centre leads to the formation of only one stereoisomer, and its configuration is inverted compared with the configuration of the reacting alkyl halide.

The familiar SN2 and SN1 mechanisms describe only two of a possibly infinite number of pathways on a two-dimensional surface describing nucleophilic aliphatic substitution. There is evidence that not all nucleophilic substitutions are heterolytic processes, meaning that both the electrons from the nucleophile are not always donated to the substrate at the same time. Instead, some reactions have been found to occur by a process in which only one electron is transferred at a time.

A major mechanistic distinction between SN2 and SN1 reactions is the timing of the departure of the leaving group and the arrival of the nucleophile. One tool to help visualize the relationship between these processes is a two-dimensional reaction-coordinate diagram shown in Fig 3.1.

Figure 3.1 Two-dimensional coordinate diagrams

The performance of the SN2 reaction depends both on the nucleophile and on the carbon electrophile. One can make a reaction better by changing either. An SN2 reaction is also called a direct displacement reaction because the nucleophile displaces the leaving group in a single step. Because the nucleophile attacks the back of the carbon that is bonded to the halogen, bulky substituents attached to this carbon will make it harder for the nucleophile to get to the back and, therefore, will decrease the rate of the reaction. The rate of an SN2 reaction depends upon the nucleophile, the carbon skeleton and the leaving group. It also depends, as do all reactions, on factors like temperature and solvents.

With phenols, NaOH is a strong enough base and dimethylsulphate is often used as a electrophile.

Effects due to groups occupying a certain volume of space are called steric effects. A steric effect that decreases reactivity is called steric hindrance. As a consequence of steric hindrance, alkyl halides have the following relative reactivities in an SN2 reaction.

 

methyl halide > 1o alkyl halide > 2° alkyl halide > 3° alkyl halide

It is not just the number of alkyl groups attached to the carbon undergoing nucleophilic attack that determines the rate of an SN2 reaction; the size of the alkyl groups is also important.

The best way to visualize the movement of the groups bonded to the carbon at which substitution occurs is to picture an umbrella that turns inside out. This is called inversion of configuration. The inversion is known as a Walden inversion since Paul Walden, a Latvian-born chemist was the first to discover in 1895 that compounds could invert their configurations as a result of substitution reactions. He reacted hydroxysuccinic acid with the acyl chlorides and realized that one of the steps during reactions was associated with inversion of the configuration, but at that time he was unable to specify which.

Proof that an SN2 reaction proceeds with inversion of configuration was provided by Kenyon et al. (Kenyon-Phillips cycle) in a three-step reaction sequence in which the starting material and the product were enantiomers. Step A not involving bond cleavage at the stereogenic centre means that I and II have the same configuration. Step B involves displacement of OTs by ethanoate ion, and it is here that inversion of configuration takes place. Step C is the hydrolysis, which occurs with retention of configuration.

Caged compounds in which the leaving group is located at a bridgehead position do not undergo SN2 reactions for two reasons: one, the cage structure prevents the approach of the nucleophile by the required route, even if a reaction would take place; two, it is not possible to invert the configuration of the carbon that is bonded to the leaving group. The relative solvolysis rates of the bridgeheads bromides, 1-bromoadamantane, 1-bromobicyclo[2, 2, 2]octane, and 1-bromobicyclo[2, 2, 1]heptane in 80% ethanol at 25°C are shown below.

3.3 NUCLEOPHILE IN SN2 REACTION

When we talk about atoms or molecules that have lone pair-electrons, sometimes we call them bases and sometimes we call them nucleophiles. What is the difference between a base and a nucleophile?

A base shares its lone pair-electrons with a proton. Basicity is a measure of how strongly the base shares those electrons with a proton. The stronger the base, the better it shares its electrons. Basicity (a measure of a thermodynamic phenomenon) is measured by an acid dissociation constant (Ka, that is, an equilibrium constant) that indicates the tendency of the conjugate acid of the base to lose a proton.

A nucleophile uses its lone pair-electrons to attack an electron-deficient atom other than a proton. Nucleophilicity (a measure of a kinetic phenomenon) is a measure of how readily the nucleophile is able to attack such an atom. The rate of reaction is measured by a rate constant (k). In the case of an SN2 reaction, nucleophilicity is a measure of how readily the nucleophile attacks an sp3 hybridized carbon bonded to a leaving group. Nucleophilicity is governed by (1) the solvation energy of the nucleophile; (2) the strength of the bond being formed to the carbon; (3) the size of the nucleophile; (4) the electronegativity of the attacking atom; and (5) the polarizability of the attacking atom.

In comparing molecules with the same attacking atom, there is generally a direct relationship between basicity and nucleophilicity. Both describe a process involving the formation of a new bond to an electrophile by donation of an electron pair. Stronger bases are better nucleophiles. The hydroxide ion is a stronger base than a cyanide ion, but cyanide ion is a stronger nucleophile than hydroxide ion. For example, a compound with negatively charged oxygen is a stronger base and a better nucleophile than a compound with neutral oxygen (Table 3.1).

 

Table 3.1 Some Strong and Weak Bases and Nucleophiles

Stronger Base, Better Nucleophile   Weaker Base Poorer Nucleophile
HO > H2O
CH3O > CH3OH
H2N > H3N
CH3CH2NH > CH3CH2NH2

In comparing molecules with attacking atoms of approximately the same size, the stronger bases are again the better nucleophiles. Within a group of nucleophiles that attack at the electrophile with the same atom, the nucleophilicity decreases with decreasing basicity of the nucleophile. Decreasing basicity is equivalent to decreasing affinity of an electron pair for a proton.

 

RO > HO > C6H5O > RCOO >> ROH, H2O >>> RSO3

This parallel relationship between nucleophilicity and basicity can be reversed by steric effects. Therefore, less basic but sterically unhindered nucleophiles have a higher nucleophilicity than strongly basic but sterically hindered nucleophiles. Thus, although t-butoxide ion is a stronger base than ethoxide ion, the bulky t-butoxide is a weaker nucleophile.

The atoms across the second row of the periodic table have approximately the same size. If hydrogens are attached to the second-row elements, the resulting compounds have the following relative acid strengths.

 

CH4 < NH3 < H2O < HF

Nucleophilicity decreases with increasing electronegativity of the attacking atom. Consequently, the conjugate bases have the following relative base strengths and nucleophilicities. For example, the methyl anion is the strongest base as well as the best nucleophile.

   CH3 > NH2 > HO > F; RS >> Cl; Et3N >> Et2O

In comparing molecules with attacking atoms that are very different in size, the direct relationship between nucleophilicity and basicity is maintained if the reaction occurs in the gas phase. If, however, the reaction occurs in a solvent this relationship between nucleophilicity and basicity depends on the solvent. In a comparison of the atomic centres from the same group of the periodic table, the trend is as follows:

The divergence of nucleophilic ability from basic strength stems from the fact that as the atom-donating electron pair increases in size, the electrons in its outer shell will be further away from, and hence, held less tightly by the atomic nucleus. These outer electrons are thus more polarizable. They are more readily available to form a bond with the atom being attacked. Polarizability appears to be much more important in nucleophilic ability than in the equilibrium situation involved in basicity; thus, species in which the relevant atom is large are commonly found to be better nucleophiles than their strength as bases might suggest.

If the solvent is aprotic (it is not a hydrogen bond donor), the direct relationship between nucleophilicity and basicity holds. For example, both the nucleophilicities and basicities of the halogens decrease with increasing size in an aprotic solvent such as dimethyl formamide.

If the solvent is protic (it is a hydrogen bond donor such as water, alcohols, etc.), the relationship between basicity and nucleophilicity becomes inverted: as basicity decreases, nucleophilicity increases. Thus, iodide ion, which is the weakest base of the halogen family, is the poorest nucleophile of the family in an aprotic solvent and the best nucleophile in a protic solvent.

How does the solvent’s ability to be a hydrogen bond donor affect the relationship between nucleophilicity and basicity? When a negatively charged species is placed in a protic solvent, the solvent molecules arrange themselves so that their partially positively charged hydrogens point toward the negatively charged species. An aprotic solvent does not have a partially positively charged hydrogen.

The interaction between the ion and the dipole of the protic solvent is called an ion–dipole interaction. The change from a direct relationship between basicity and nucleophilicity in an aprotic solvent to an inverse relationship in a protic solvent results from the ion–dipole interactions between the nucleophile and the protic solvent. This occurs because at least one of the ion–dipole interactions must be broken before the nucleophile can participate in an SN2 reaction. Weak bases interact weakly with protic solvents; strong bases interact more strongly because they are better at sharing their electrons. It is, therefore, easier to break the ion–dipole interactions between an iodide ion and the solvent than between the more basic fluoride ion and the solvent, because the latter is a stronger base. As a result, iodide ion is a better nucleophile in a protic solvent.

The nucleophilicity of a given nucleophilic centre is increased by attached heteroatoms that possess free electron-pairs (α- effect). The reason for this is the unavoidable overlap of the orbitals that accommodate the free electron-pairs at the nucleophilic centre and its neighbouring atom.

 

HO–O > H–O;H2N–NH2 > H–NH2

It is worth summarizing the characteristics of the two types of nucleophiles.

  Hard Nucleophile X Soft Nucleophile Y
  small large
  charged neutral
  basic not basic
  low-energy HOMO high-energy HOMO
  like to attack C=O like to attack saturated carbon
  such as RO, NH, MeLi such as RS, I, R3P

The sp3 carbon is a soft electrophile, whereas the proton is a hard electrophile. Thus, according to the HSAB theory, a soft anion should act primarily as a nucleophile, giving the substitution product, whereas a hard anion is more prone to abstract a proton, giving the elimination product. The property of softness correlates with high polarizability and low electronegativity. Hardness reflects a high charge density and is associated with small highly electronegative species. Because there are many different kinds of nucleophiles, a wide variety of organic compounds can be synthesized by means of SN2 reactions.

Table 3.2 shows just a few of the many kinds of organic compounds that can be synthesized in this way.

 

Table 3.2 Some Organic Compounds That Can Be Synthesized By SN2 Reactions

HO + CH3CH2Cl CH3CH2OH + Cl
HS + CH3CH2Br CH3CH2SH + Br
RO + CH3CH2I CH3CH2OR + I
RS + CH3CH2Br CH3CH2SR + Br
H2N + CH3CH2F CH3CH2NH2 + F
RC≡C + CH3CH2Br CH3CH2C≡CR + Br
N≡C + CH3CH2I CH3CH2C≡N + I

If the difference between the basicities of the nucleophile and the leaving group is not very large, the reaction will be reversible. For example, in the reaction of ethyl bromide with iodide ion, Br is the leaving group in one direction and I is the leaving group in the other direction. Because the pKa values of the conjugate acids of the two leaving groups are not very different (pKa of HBr = −9; pKa of HI = −10), the reaction is reversible.

One can drive a reversible reaction toward the desired products by removing one of the products as it forms. Le Chatelier’s principle states that if equilibrium is disturbed, the components of the equilibrium will adjust to offset the disturbance. In other words, if the concentration of product C is decreased, A and B will react to form more C and D so that the equilibrium constant maintains its value.

For example, the reaction of ethyl chloride with methanol is reversible because the difference between the basicities of the nucleophile and the leaving group is not very large. If the reaction is carried out in a neutral solution, the protonated product will lose a proton. This disturbs the equilibrium and drives the reaction toward the products.

The SN2 reactivity of an alkylating agent decreases with an increase in the number of alkyl substituents at the attacked alkyl carbon atom.

The SN2 reactivity of an alkylating agent decreases with an increase in size of the alkyl substituents at the attacked alkyl carbon atom. In other words, β-branching in the alkylating agent reduces its SN2 reactivity.

Allyl and benzyl halides generally react with nucleophiles according to an SN2 mechanism and are as good alkylating agents as methyl iodide.

3.4 LEAVING GROUP IN SN2 REACTION

A good leaving group is the one that becomes a stable ion after its departure. As most leaving groups are negatively charged, the good leaving groups are those that stabilize their charge most effectively. If an alkyl iodide, an alkyl bromide, an alkyl chloride and an alkyl fluoride (all having the same alkyl group) were allowed to react with the same nucleophile under the same conditions, we would find that the alkyl iodide is the most reactive and the alkyl fluoride is the least reactive.

The only difference among these four reactions is the nature of the leaving group. Apparently, the iodide ion is the best leaving group and the fluoride ion is the worst. This brings us to an important rule in organic chemistry that the weaker the base, the better it is as a leaving group.

The relative acidities of hydrogen halides are

 

HI > HBr > HCl > HF

Because we know that the stronger the acid, the weaker its conjugate base, the halide ions have the following relative basicities.

 

I < Br < Cl < F

Further, because weaker bases are better leaving groups, the halides ions have the following relative leaving abilities. This is due to the strength of the bond to carbon, which ranges from ~ 50 kcal/mol for the C-I bond to ~100 kcal/mol for the C-F bond.

 

I > Br > Cl >> F

As a consequence of the relative leaving abilities of the halide ions, alkyl halides have the following relative reactivities in an SN2 reaction.

 

RI > RBr > RC1 > RF

Amongst the good leaving groups, for example, triflate (−OTf), tosylate (−OTs), brosylate (−OBs) and mesylate (−OMs), the triflate ion is one of the best leaving groups known.

The trifluoromethanesulfonate anion (triflate anion) F3C–SO3 is a far better leaving group than the tosylate or mesylate anion. These anions are very stable and can be stabilized still further through solvation in protic solvents. R–F, R–SH(R’), R–S(O)R’, R–S(O2)R’, R–NH2(R’2), R–NO2, R–N+H3(R3), R–P(O)(OR’)2 and R–CN are either very poor leaving groups or not a leaving group. The lower the bond enthalpy of the bond between the carbon and the leaving group, the better the leaving group. A poor leaving group can be made more reactive by coordination to an electrophilic species. Hydroxide is a very poor leaving group.

The less basic the substituent, the more easily it is pulled off by solvent or pushed off by an attacking nucleophile. The order of ease of displacement of groups is not fixed; it depends on the nature of the R group and on the conditions (nature of solvent, that is, protic, aprotic, polar, nonpolar and so on). However, it appears that, in general, the order is:

OTf > OTs > OMs > I > Br > Cl > OH2+ > F > OAc > +NR3 > OR ~ OH > NR2

So far we have seen methods of displacing the OH group by first converting it to a better leaving group. There is one recent invention in which an alcohol may be subjected to SN2 product in one operation. This is the Mitsunobu reaction.

The whole process takes place in one operation. The four reagents are all added in one flask and the products are the phosphine oxide, the reduced azo diester and the product of an SN2 reaction on the alcohol. This reaction is used to replace OH by another group with inversion of configuration.

3.5 INTERMOLECULAR VERSUS INTRAMOLECULAR REACTIONS

A molecule with two functional groups is called a bifunctional molecule. If the two functional groups are able to react with each other, two kinds of reactions can occur. In the case of a molecule that contains both a nucleophile and a leaving group, the nucleophile of one molecule can displace the leaving group of a second molecule of the compound. Such a reaction is called an intermolecular reaction. (Inter is Latin for ‘between’). An intermolecular reaction takes place between two molecules.

Alternatively, the nucleophile of a molecule can displace the leaving group of the same molecule, thereby forming a cyclic compound. Such a reaction is called an intramolecular reaction. (Intra is Latin for ‘within’) An intramolecular reaction takes place within a single molecule. 4-Hydroxybutyric acid lactonizes in the presence of acid rather than esterifying another molecule, and giving eventually polyester.

Intramolecular reactions always have to compete with the corresponding intermolecular processes. Which reaction is more likely to occur when the nucleophile and the leaving group are parts of the same molecule - an intermolecular reaction or an intramolecular reaction? The answer depends on the concentration of the bifunctional molecule and the size of the ring that will be formed in the intramolecular reaction. The intramolecular reaction has an advantage in that the reacting groups are tethered close together and therefore do not have to wander through the solvent to find a group with which to react. As a result, a low concentration of reactant favours an intramolecular reaction because the two functional groups have a better chance of finding one another if they are in the same molecule. A high concentration of reactant helps make up for the advantage gained by tethering.

How much of an advantage an intramolecular reaction has over an intermolecular reaction depends on the length of the tether and, therefore, on the size of the ring that is formed. If the intramolecular reaction would form a five-or six-member ring, it would be highly favoured over the intermolecular reaction because of its stability and, therefore, ease of formation of the five- and six-member rings.

Three- and four-member rings are strained. Consequently, they are less stable than five- and six-member rings, which means that the transition state leading to their formation is less stable than the transition state leading to the formation of five- and six-member rings. The higher activation energy for the formation of three- and four-member rings cancels some of the advantage gained by tethering. The likelihood that the reacting groups can find each other decreases sharply for the formation of seven-member and larger rings; so the intramolecular reaction becomes less favoured as the ring size increases beyond six members.

Intramolecular displacements are of two types: exocyclic and endocyclic. N and L refer to the nucleophile and the leaving group, respectively, and Ca is the carbon that is subject to nucleophilic attack. There is little restriction on intramolecular exocyclic substitutions because N, Ca and L can readily become collinear.

3.5.1 Baldwin’s Rules

The full set of rules is shown in Table 3.3. Each and × simply means that the reaction type is favourable or unfavourable, respectively; they do not refer to permitted or forbidden reactions. Since rings of all the sizes listed can be formed if the centre concerned has the correct geometry, the cases marked × are not thermodynamically unfavourable. The increased barriers to reaction are, therefore, kinetic and stereoelectronic in origin.

 

Table 3.3 Baldwin’s Rules

At least one of the atoms involved in forming the new bond is carbon; the first column of the table defines its hybridization and thus geometry, as tetrahedral, trigonal or digonal (linear), respectively. Column 2 specifies the geometry of the bond being broken at the carbon atom centre concerned. This bond can be exo (outside) with respect to the ring being formed or endo (inside).

3.6 MECHANISM OF SN1 REACTION

Given our understanding of the SN2 reaction, if we were to measure the rate of reaction of tert-butyl bromide with water, we would expect a relatively slow substitution reaction, as water is a poor nucleophile and tert-butyl bromide is sterically hindered to attack by a nucleophile. However, we would actually discover that the reaction is surprisingly fast. In fact, it is over one million times faster than the reaction of methylbromide—a compound with no steric hindrance with water. Clearly, the reaction must be taking place by a mechanism different from that of the SN2 reaction.

As we have seen, a study of the kinetics of a reaction is one of the first steps undertaken when investigating the mechanism of a reaction. If we were to investigate the kinetics of the reaction of tert-butyl bromide with water, we would find that doubling the concentration of the alkyl halide doubles the rate of the reaction. We would also find that changing the concentration of the water has no effect on the rate of the reaction. Knowing that the rate of this nucleophilic substitution reaction depends only on the concentration of the alkyl halide, we can write a rate law for the reaction.

rate = k[alkyl halide]

Because the rate of the reaction depends on the concentration of only one reactant, it is a first-order reaction.

Since the rate law for the reaction of tert-butyl bromide with water clearly differs from the rate law for the reaction of methyl bromide with hydroxide ion, the two reactions must follow different mechanisms. We have seen that the reaction between methyl bromide and hydroxide ion is an SN2 reaction. The reaction between tert-butyl bromide and water is an SN1 reaction: S for substitution, N for nucleophilic and 1 for unimolecular. The mechanism of an SN1 reaction is based on the following experimental evidence.

  1. The rate law shows that the rate of the reaction depends only on the concentration of the alkyl halide. This means that we must be observing a reaction whose rate-determining transition state involves only the alkyl halide. The rate-determining transition state is unimolecular; it involves only one molecule.
  2. When the methyl groups of tert-butyl bromide are successively replaced by hydrogens, the rate of the SN1 reaction decreases progressively. This is opposite to the order of reactivity exhibited by alkyl halides in SN2 reactions.
  3. The reaction of an alkyl halide in which the halogen is bonded to a chirality centre leads to the formation of two stereoisomers: one with the same relative configuration as the reacting alkyl halide and the other with the inverted configuration. Since the cation is planar, it is achiral. Hence, starting with an optically active substrate, one gets racemic products.

The energy required to break the bond is supplied by the formation of many bonds between the ions (that are produced) and the solvent. The dipole moment associated with the transition state is much more than the substrate. Thus, the solvent stabilizes the transition state much more effectively than the substrate.

An SN1 reaction has two steps. In the first step, the carbon-halogen bond breaks heterolytically, with the halogen retaining the previously shared pair of electrons. In the second step, the nucleophile reacts rapidly with the carbocation that was formed in the first step.

Mechanism of the SN1 reaction

From the observation that the rate of an SN1 reaction depends only on the concentration of the alkyl halide, we know that the first step is the slow and rate-determining step. Because the nucleophile is not involved in the rate-determining step, its concentration has no effect on the rate of the reaction.

How does the reaction mechanism that we have just seen account for the three pieces of experimental evidence? First, because the alkyl halide is the only species that participates in the rate-limiting step, the mechanism agrees with the observation that the rate of the reaction depends on the concentration of the alkyl halide and does not depend on the concentration of the nucleophile.

Second, a carbocation is formed in the slow step of an SN1 reaction. Because a tertiary carbocation is more stable and therefore easier to form than a secondary carbocation, which in turn is more stable and easier to form than a primary carbocation, tertiary alkyl halides are more reactive than secondary alkyl halides, which are more reactive than primary alkyl halides in an SN1 reaction. Thus, the reactivity order agrees with the observation that the rate of an SN1 reaction decreases as the methyl groups of tert-butyl bromide are successively replaced by hydrogens.

The relative reactivities of alkyl halides in an SN1 reaction are

 

3° alkyl halide > 2° alkyl halide > 1o alkyl halide

The positively charged carbon of the carbocation intermediate is sp2 hybridized, and the three bonds connected to an sp2 hybridized carbon are in the same plane. In the second step of the SN1 reaction, the nucleophile can approach the carbocation from either side of the plane.

If the nucleophile attacks the carbon from the side from which the leaving group departed, the product will have the same relative configuration as the reacting alkyl halide. If, however, the nucleophile attacks the opposite side of the carbon, the product will have the inverted configuration compared with the alkyl halide. We can now understand the third piece of experimental evidence for the mechanism of the SN1 reaction. The SN1 reaction of an alkyl halide in which the leaving group is attached to a chirality centre leads to the formation of two stereoisomers: attack of the nucleophile on one side of the planar carbocation forms one stereoisomer, and attack on the other side produces the other stereoisomer.

3.7 LEAVING GROUP IN SN1 REACTION

Because the rate-determining step of an SN1 reaction is dissociation of the alkyl halide to form a carbocation, two factors affect the rate of an SN1 reaction: the ease with which the leaving group dissociates from the carbon and the stability of the carbocation that is formed. We saw that tertiary alkyl halides are more reactive than secondary alkyl halides, which are more reactive than primary alkyl halides. This is because the more substituted the carbocation is, the more stable it is, and therefore the easier it is to form. But what about a series of alkyl halides with different leaving groups that dissociate to form the same carbocation? The answer is the same for the SN1 reaction as for the SN2 reaction. The weaker the base, the less tightly it is bonded to the carbon and the easier it is to break the carbon–halogen bond. So an alkyl iodide is the most reactive and an alkyl fluoride is the least reactive of the alkyl halides in both SN1 and SN2 reactions.

The relative reactivities of alkyl halides in an SN1 reaction are RI > RBr > RCl > RF

3.8 NUCLEOPHILE IN SN1 REACTION

The nucleophile traps the carbocation that is formed in the rate-determining step of the SN1 reaction. Because the nucleophile comes into play after the rate-determining step, the reactivity of the nucleophile has no effect on the rate of the SN1 reaction. In some SN1 reactions, the solvent is the nucleophile. Water serves as both the nucleophile and the solvent. When the solvent is the nucleophile, the reaction is called a solvolysis reaction.

3.9 CARBOCATION REARRANGEMENTS

A carbocation intermediate is formed in an SN1 reaction. We know that a carbocation will rearrange if it becomes more stable as a result of the rearrangement. If the carbocation formed in an SN1 reaction can rearrange, SN1 and SN2 reactions can produce different constitutional isomers as products, because carbocation is not formed in an SN2 reaction, and thus rearrangement of the carbon skeleton cannot occur. For example, the product obtained when 2-bromo-3-methylbutane undergoes an SN1 reaction is different from the product obtained when it undergoes an SN2 reaction. When the reaction is carried out under conditions that favour an SN1 reaction, the initially formed secondary carbocation undergoes a 1, 2-hydride shift, rearranging to a more stable tertiary carbocation.

The product obtained from the reaction of 3-bromo-2,2-dimethylbutane with a nucleophile also depends on the conditions under which the reaction is carried out. The carbocation formed under conditions that favour an SN1 reaction undergoes a 1, 2 -methyl shift. Because a carbocation is not formed under conditions that favour an SN2 reaction, the carbon skeleton does not rearrange.

3.10 STEREOCHEMISTRY OF SN2 AND SN1 REACTIONS

The substitution product obtained from the reaction of 2-bromobutane with hydroxide ion has a chirality centre. Therefore, it can exist as a pair of enantiomers.

We cannot specify the configuration of the product formed from the reaction of 2-bromobutane with hydroxide ion, unless we know the configuration of the alkyl and whether the reaction is an SN2 or an SN1 reaction. For example, in the SN2 reaction of (S)-2-bromobutane with hydroxide ion, the incoming hydroxide ion attacks the chirality centre on the side opposite to where the bromine is bonded. This results in a product whose configuration is inverted compared to the configuration of the reactant. An SN2 reaction takes place with inversion of configuration.

In the SN1 reaction of (S)-2-bromobutane with water, two substitution products are formed: one product has the same relative configuration as the reactant, and the other has the inverted configuration. In an SN1 reaction, the leaving group leaves before the nucleophile attacks. This means that the nucleophile is free to attack either side of the planar carbocation. If it attacks the side from which the bromide ion left, the product will have the same relative configuration as the reactant. If it attacks the opposite side, the product will have the inverted configuration.

Although you might expect that equal amounts of both products should be formed in an SN1 reaction, a greater amount of the product with the inverted configuration is obtained in most cases. Typically, 50% to 70% of the product of an SN1 reaction is the inverted product. If the reaction leads to equal amounts of the two stereoisomers, the reaction is said to take place with complete racemization. When more of the inverted product is formed, the reaction is said to take place with partial racemization.

Saul Winstein was the first to explain why extra inverted product is formed. He postulated that dissociation of the alkyl halide initially results in the formation of an intimate ion pair. In an intimate ion pair, the bond between the carbon and the leaving group has broken, but the cation and anion remain next to each other. This species then forms an ion pair in which one or more solvent molecules have come between the cation and the anion. This is called a solvent-separated ion pair. Further separation between the two results in the dissociated ions.

The nucleophile can attack any of these four species. If the nucleophile attacks only the completely dissociated carbocation, the product will be completely racemized. If the nucleophile attacks the carbocation of the intimate ion pair or the solvent-separated ion pair, the leaving group will be in a position to partially block the approach of the nucleophile to that side of the carbocation. As a result, more of the product with the inverted configuration will be obtained. (If the nucleophile attacks the undissociated molecule, it will be an SN2 reaction and all of the product will have the inverted configuration).

The attack by potassium acetate on the trans-tosylate gives exclusively the cis-cyclohexyl acetate. No trans-isomer is formed. Thus, a 100% inversion of the configuration has taken place. The SN2 mechanism is casually also referred to as an umbrella mechanism. The nucleophile enters in the direction of the umbrella handle and displaces the leaving group, which was originally lying above the tip of the umbrella.

The difference between the products obtained from an SN1 reaction and from an SN2 reaction is a little easier to visualize in the case of cyclic compounds. When cis-1-bromo-4-methylcyclohexane undergoes an SN2 reaction, only the trans product is obtained, because the carbon bonded to the leaving group is attacked by the nucleophile only on its back. When, however, cis-1-bromo-4-methylcyclohexane undergoes an SN1 reaction, both the cis and the trans products are formed because the nucleophile can approach the carbocation intermediate from either side.

When optically pure R-2-bromooctane is treated with a water/ethanol mixture (solvolysis), a contact ion-pair with bromide ion is formed. The contact ion-pair in contrast to free carbenium ion is chiral. Starting from enantiomerically pure R-2-bromooctane, the contact ion-pair first produced is also a pure enantiomer. In this ion-pair, the adjacent bromide ion partially protects one side of the carbenium ion-pair from the attack of the nucleophile. Consequently, the nucleophile preferentially attacks from the side that lies opposite the bromide ion. It was actually found that 83% of the solvolysis product was formed with inversion of configuration and 17% with retention. This result is equivalent to the occurrence of 66% inversion of configuration and 34% racemization. We can generalize that when in an SN1 reaction the nucleophile attacks the contact ion-pair, the retention proceeds with partial inversion of configuration.

Stereochemistry of an SN1 reaction that takes place via a contact ion-pair

On the other hand, when in an SN1 reaction the nucleophile attacks the carbenium ion after it has separated from the leaving group, the reaction takes place with complete racemization. This is the case with more stable and longer lived carbenium ions. For example, during the solvolysis of R-phenethyl bromide in a water/ethanol mixture, α-methyl benzyl cation is produced in the rate-determining step.

Stereochemistry of an SN1 reaction that takes place via a solvent-separated ion-pair

The bromide ion in the above example moves so far away from the α-methyl benzyl cation intermediate that it allows the solvent to attack both sides of the carbenium ion with equal probability. The electrostatic attraction between oppositely charged particles holds the carbenium ion and bromide ion together at a distance large enough for the solvent molecules to fit in between.

3.11 ROLE OF SOLVENT IN SN2 AND SN1 REACTIONS

The solvent in which the nucleophilic substitution reaction is carried out also has an influence on whether an SN2 or an SN1 reaction will predominate. Before we can understand how a particular solvent favours one reaction over another, we must understand how solvents stabilize organic molecules.

The dielectric constant of a solvent is a measure of how well the solvent can insulate opposite charges from one another. Solvent molecules insulate charges by clustering around a charge, so that the negative poles of the solvent molecules surround positive charges and the positive poles of the solvent molecules surround negative charges. Remember that the interaction between a solvent and an ion or molecule dissolved in that solvent is called solvation. When an ion interacts with a polar solvent, the charge is no longer localized solely on the ion but is spread out to the surrounding solvent molecules. Spreading out the charge stabilizes the charged species.

Polar solvents have high dielectric constants and thus are very good at insulating (solvating) charges. Nonpolar solvents have low dielectric constants and are poor insulators. Recall that protic solvents contain hydrogen that is bonded to oxygen or nitrogen; in other words, they are hydrogen atom donors; for example, water, methanol, ethanol, acetic acid and aqueous acetone. The common polar-aprotic solvents are acetone, acetonitrile, dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) and N,N’-dimethyl-N,N’-propylene urea (DMPU). Unfortunately, DMPU and hexamethyl phosphoric acid triamide (HMPA is a carcinogen) do not solvate.

Iodomethane is attacked by chloride ion. Changing the solvent from methanol to DMF is found to result in a million-fold (106) increase in the rate of the reaction. The reason for this amazing difference is believed to be that in MeOH the chloride ion, Cl is surrounded by molecules of solvent methanol, which are attached to it by hydrogen bonds. Before the Cl ion is in a position to attack methyl iodide, this solvation envelope of methanol molecules has to be stripped away: to achieve this, energy has to be expended. This need for energy input makes the overall reaction more difficult, and hence slower. Thus, polar solvents solvate the anionic nucleophiles and slow the reaction down. A nonpolar solvent destabilizes the starting materials more than it destabilizes the transition state and speeds up the reaction.

Stabilization of charges by solvent interaction plays an important role in organic reactions. For example, the first step in an SN1 reaction is dissociation of the carbon-halogen bond of the alkyl halide to form a carbocation and a halide ion. Energy is required to break the bond; but, with no bonds being formed, where does this energy come from? If the reaction is carried out in a polar solvent, the ions that are produced as products are solvated. The energy associated with a single ion–dipole interaction is small, but the additive effect of all the ion–dipole interactions involved in stabilizing a charged species by the solvent represents a great deal of energy. These ion–dipole interactions provide much of the energy necessary for dissociation of the carbon–halogen bond. So, in an SN1 reaction, the alkyl halide does not fall apart spontaneously, but solvent molecules pull it apart. An SN1 reaction, therefore, can take place in a polar solvent but not in a nonpolar solvent. This reaction also cannot take place in the gas phase, where there are no solvent molecules and, consequently, no solvation effects.

If an SN2 reaction has neutral starting materials and an ionic product, then a polar solvent is better, for example, formation of phosphonium salt.

3.12 SOLVATION EFFECT

The tremendous amount of energy that is provided by solvation can be appreciated by considering the energy required to break the crystal lattice of sodium chloride. In the absence of a solvent, sodium chloride must be heated to more than 800°C to overcome the forces that hold the oppositely charged ions together. However, we are all aware that sodium chloride (table salt) readily dissolves in water at room temperature. Solvation of the Na+ and Cl ions by water provides the energy necessary for the ions to a part.

3.13 EFFECT OF SOLVENT ON RATE OF REACTION

The rate of a reaction depends on the difference between the energy of the reactants and the energy of the transition state in the rate-limiting step of the reaction. We can therefore predict how changing the polarity of the solvent will affect the rate of a reaction. We do this simply by looking at the charge on the reactants and on the reagent in the transition state of the rate-limiting step to determine which of these species will be more stabilized by a polar solvent. The greater the charge on the solvated molecule, the stronger it will interact with a polar solvent and the more the charge will be stabilized.

Therefore, if the charge on the reactants is greater than the charge on the rate-determining transition state, a polar solvent will interact more strongly with the reactants than with the transition state. As a result, a polar solvent will stabilize reactants more than it will stabilize the transition state, increasing the difference in energy between the reactants and the transition state. Therefore, increasing the polarity of the solvent will decrease the rate of the reaction.

In contrast, if the charge on the rate-determining transition state is greater than the charge on the reactants, a polar solvent will interact more strongly with the transition state than with the reactants, stabilizing the transition state more than it stabilizes reactants. Therefore, increasing the polarity of the solvent will decrease difference in energy (ΔG#) between the reactants and the transition state, which decreases the rate of the reaction.

3.13.1 Effect of solvent on Rate of SN1 Reaction

Now let us see how increasing the polarity of the solvent affects the rate of an SN1 reaction of an alkyl halide. The alkyl halide is the only reactant in the rate-determining step. It is a neutral molecule with a small dipole moment. The rate-determining transition state has a greater charge because, as the carbon–halogen bond breaks, the carbon becomes more positive and the halogen becomes more negative. As the charge is greater in the rate-determining transition state, increasing the polarity of the solvent will increase the rate of the SN1 reaction.

 

Effect of the polarity of the solvent on the rate of reaction of tert-butyl bromide in a SN1 reaction

  Solvent Relative rate
  100% water 1200
  80% water / 20% ethanol 400
  50% water / 50% ethanol 60
  20% water / 80% ethanol 10
  100% ethanol 1

As long as the compound is undergoing an SN1 reaction, increasing the polarity of the solvent will increase the rate of the SN1 reaction, because the polar solvent will stabilize the dispersed charge on the transition state more than it will stabilize the relatively neutral reactant. If, however, the compound undergoing an SN1 reaction is charged, increasing the polarity of the solvent will decrease the rate of the reaction, because the more polar solvent stabilizes the full charge on the reactant to a greater extent than it will stabilize dispersed charge on the transition state.

It is important to note that the use of polar solvents is a necessary but not a sufficient condition for the feasibility of SN1 substitutions or for the preference of the SN1 over the SN2 mechanism. Thus, in the reaction of Me3C-Br with OH, changing the solvent from ethanol to the more polar increases the rate of the reaction approximately 30,000-fold due to stabilization of both the ions by the polar solvent.

3.13.2 Effect of Solvent on Rate of SN2 Reaction

The way in which an increase in the polarity of the solvent affects the rate of a reaction depends on whether the reactants are charged or neutral, just as in an SN1 reaction.

Most SN2 reactions of alkyl halides involve a neutral alkyl halide and a charged nucleophile. Increasing the polarity of a solvent will have a strong stabilization effect on the negatively charged nucleophile. The transition state also has a negative charge, but the charge is dispersed over two atoms. This means that the interactions between the solvent and the transition state are not as strong as interactions between the solvent and the fully charged nucleophile. Consequently, the polar solvent stabilizes the nucleophile more than it stabilizes the transition state; so, increasing the polarity of the solvent will decrease the rate of the reaction.

If, however, the SN2 reaction involves an alkyl halide and a neutral nucleophile, the charge on the transition state will be larger than the charge on the neutral reactants; so, increasing the polarity of the solvent will increase the rate of the substitution reaction.

We can now summarize that changing the polarity of a solvent will increase the rate of a substitution reaction, regardless of the mechanism of the reaction. If the one or reactants in the rate-limiting step are charged, increasing the polarity of the solvent will decrease the rate of the reaction. If the reactants are not charged, increasing the polarity of the solvent will increase the rate of the reaction.

In considering the solvation of charged species by a polar solvent, we have been discussing polar solvents, such as water or alcohols that are hydrogen bond donors (polar protic solvents). There are also polar solvents such as dimethylformamide (DMF) and dimethylsulfoxide (DMSO) that are not hydrogen donors (polar aprotic solvents).

Ideally, one would like to carry out an SN2 reaction with a negatively charged nucleophile in a nonpolar solvent, since the charge on the reactants is greater than the charge on the transition state. However, a negatively charged nucleophile will not dissolve in a nonpolar solvent. Therefore, a polar aprotic solvent is used. Polar aprotic solvents have atoms with nonbonding electrons that can stabilize positive (DMSO can solvate a cation) charges; they are Lewis bases. But, because aprotic solvents are not hydrogen bond donors, they are less effective than polar protic solvents in stabilizing negative charges. Thus, the rate of an SN2 reaction involving a negatively charged nucleophile will be greater in a polar aprotic solvent than in a polar protic solvent. Thus, a polar aprotic solvent is the solvent of choice for an SN2 reaction in which the nucleophile is negatively charged, whereas a polar protic solvent is used if the nucleophile is a neutral molecule.

We have now seen that when an alkyl halide can undergo both SN2 and SN1 reactions, the SN2 reaction will be favoured by a high concentration of a good (negatively charged) nucleophile in a polar aprotic solvent, whereas the SN1 reaction will be favoured by a poor (neutral) nucleophile in a polar protic solvent.

3.14 BENZYLIC, ALLYLIC, VINYLIC AND ARYL HALIDES

To this point, we have limited our discussion of substitution reactions to methyl halides and primary, secondary and tertiary alkyl halides. But what about benzylic, allylic, vinylic and aryl halides? Let us first consider benzylic and allylic halides. Benzylic and allylic halides readily undergo SN2 reactions unless they are tertiary. Tertiary benzylic and allylic halides, like other tertiary halides, are unreactive in SN2 reactions because of steric hindrance.

Benzylic and allylic halides also undergo SN1 reactions because of the stability of their carbocations. We have seen that primary alkyl halides (such as CH3CH2Br and CH3CH2CH2Br) cannot undergo SN1 reactions because their carbocations are too unstable. Primary benzylic and primary allylic halides, however, readily undergo SN1 reactions because their carbocations have about the same stability as secondary carbocations, as they are stabilized by resonance.

Vinylic halides and aryl halides do not undergo SN2 or SN1 reactions. They do not undergo an SN2 reaction because as the nucleophile approaches the back of the sp2 carbon, it is repelled by the π electron cloud of the double bond or the aromatic ring.

There are two reasons why vinylic halides and aryl halides do not undergo SN1 reactions. First, vinylic and aryl cations are even more unstable than primary carbocations, and it is apparent that primary alkyl halides do not undergo SN1 reactions because of the unstability of their carbocations. The instability of vinylic and aryl cations is the result of the positive charge being on an sp carbon. Because sp carbons are more electronegative than sp2 carbons, which carry the positive charge of alkyl carbocations, sp carbons are more resistant to becoming positively charged. Second, we have seen that sp2 carbons form stronger bonds than do sp3 carbons. As a result, it is harder to break the carbon–halogen bond when the halogen is bonded to an sp2 carbon.

An exceptionally stable cation, that is, triphenylmethyl cation (trityl cation), is used to form ether with a primary alcohol group by an SN1 reaction.

Apocamphyl chloride is inert to hydroxide ion, because inversion of configuration is impossible. Moreover, steric hindrance from the back of the C-Cl bond prohibits SN2 reaction. The corresponding carbenium ion in SN1, if formed, will not be planar. If a tertiary cation cannot become planar, it is not formed. The bridgehead carbon atoms cannot assume planarity and, therefore, do not become the seats of carbocations. However, the larger bicyclic systems undergo a slow SN1 reaction in the bridgehead position. Thus the bridgehead 1-bicyclo[3.2.2] nonyl cation is stable enough to be kept as a solution in SbF5-SO2ClF, below −50°C.

3.15 COMPETITION BETWEEN SN2 AND SN1 REACTIONS

It is important to remember that the ‘2’ in SN2 and the ‘1’ in SN1 refer to the molecularity of the rate-determining step; the rate-determining step of an SN2 reaction is bimolecular, the rate-determining step of an SN1 reaction is unimolecular. These numbers do not refer to the number of steps in the mechanism: the SN2 reaction proceeds by a one-step mechanism, whereas the SN1 reaction proceeds by a two-step mechanism with a carbocation intermediate.

We have seen that methyl halides and primary alkyl halides undergo only SN2 reactions because methyl cations and primary carbocations, which would be formed in an SN1 reaction, are too unstable to be formed. Tertiary alkyl halides undergo only SN1 reactions because steric hindrance makes them very unreactive in an SN2 reaction. Secondary alkyl halides as well as benzylic and allylic halides (unless they are tertiary) can undergo both SN1 and SN2 reactions because they form relatively stable carbocations, and the amount of steric hindrance associated with these alkyl halides is not very great. Vinylic and aryl halides do not undergo either SN1 or SN2 reactions. When an alkyl halide can undergo both SN1 and SN2 reactions, both reactions take place simultaneously. The conditions under which the reaction is carried out determine which of the reactions predominates.

What conditions favour an SN1 reaction? What conditions favour an SN2 reaction? These are important questions to synthetic chemists because an SN2 reaction results in the formation of a single substitution product, whereas an SN1 reaction can form two substitution products if the leaving group is bonded to a chirality centre. An SN1 reaction is further complicated by carbocation rearrangements. In other words, an SN2 reaction is a synthetic chemist’s friend, but an SN1 reaction can be a synthetic chemist’s nightmare.

The conditions that determine whether the predominant reaction will be an SN2 reaction or an SN1 reaction are the concentration of the nucleophile, the reactivity of the nucleophile and the solvent in which the reaction is carried out. To understand how the concentration of the nucleophile and the reactivity of the nucleophile determine whether an SN2 or an SN1 reaction predominates, we must first examine the rate laws for the two reactions. The rate constants have been given subscripts that indicate the reaction order.

   Rate law for the SN2 reaction: rate = k2 [alkyl halide] [nucleophile]
   Rate law for the SN1 reaction: rate = k1 [alkyl halide]

The rate law for the reaction of an alkyl halide that can undergo both SN2 and SN1 reactions simultaneously is the sum of the individual rate laws.

rate = k2[alkyl halide][nucleophile] + k1 [alkyl halide]

It is apparent that an increase in the concentration of the nucleophile increases the rate of an SN2 reaction, but has no effect on the rate of an SN1 reaction. Therefore, when both reactions occur simultaneously, increasing the concentration of the nucleophile increases the fraction of the reaction that takes place by an SN2 pathway. In contrast, decreasing the concentration of the nucleophile decreases the fraction of the reaction that takes place by an SN2 pathway.

The slow (and only) step of an SN2 reaction is the attack of the nucleophile on the alkyl halide. Increasing the reactivity of the nucleophile increases the rate of an SN2 reaction by increasing the value of the rate constant (k2), because more reactive nucleophiles are better able to displace the leaving group. The slow step of an SN1 reaction is the dissociation of the alkyl halide. In a second step, the carbocation formed in the slow step rapidly reacts with any nucleophile present in the reaction mixture. Increasing the rate of the fast step does not affect the rate of the prior slow, carbocation-forming step. This means that increasing the reactivity of the nucleophile has no effect on the rate of an SN1 reaction. A good nucleophile, therefore, favours an SN2 reaction over an SN1 reaction. A poor nucleophile favours an SN1 reaction, not by increasing the rate of the SN1 reaction itself but by decreasing the rate of the competing SN2 reaction.

  • An SN2 reaction is favoured by a high concentration of a good nucleophile.
  • An SN1 reaction is favoured by a low concentration of a good nucleophile or by a poor nucleophile.

Structural variations for the SN1 and SN2 reactions

  Type of electrophilic carbon atom SN1 reaction SN2 reaction
  methyl (CH3–X) no very good
  primary alkyl (RCH2–X) no good
  secondary alkyl (R2CH–X) yes yes
  tertiary alkyl (R3C–X) very good no
  allylic (CH2=CH–CH2–X) yes good
  benzylic (ArCH2–X) yes good
  α-carbonyl (RCO–CH2–X) no excellent
  α-alkoxy(RO–CH2–X) excellent good
  α-amino(R2N–CH2–X) excellent good

In other words, a poor nucleophile is used to encourage an SN1 reaction, and a good nucleophile is used to encourage an SN2 reaction.

The last five types listed in Table will also be primary, secondary, or tertiary. If they are primary, they will favour SN2 more, but if they are tertiary they will all react by the SN1 mechanism, except the tertiary α-carbonyl compounds, which will still react by SN2 mechanism. If they are secondary, they might react by either mechanism.

3.16 MIXED SN1 AND SN2 MECHANISM

Nucleophilic substitutions on primary carbon atoms tend to proceed by the SN2 mechanism; those on tertiary carbon atoms tend to proceed by the SN1 mechanism and those on secondary carbon atoms often contribute border-line cases. At least two broad theories have been devised to explain these phenomena.

  1. One theory holds that intermediate behaviour is caused by a mechanism that is neither pure SN1 nor pure SN2, but some in-between type.
  2. There is no intermediate mechanism at all, and borderline behaviour is caused by simultaneous operation, in the same flask, of both SN1 and SN2 mechanisms; that is, some molecules react by the SN1 mechanism and others react by the SN2 mechanism.

According to Sneen, all SN1 and SN2 reactions can be accommodated by one basic mechanism — the ion-pair mechanism.

The difference between the SN1 and SN2 mechanisms is that in the former case the formation of the ion-pair (k1) is rate-determining, whereas in the SN2 mechanism its destruction (k2) is rate-determining. Border-line behaviour is found where the rates of the formation and destruction of the ion-pair are of the same magnitude.

Addition of azide ions increases the rate of the ionization (by the salt effect), but decreases the rate of the hydrolysis.

If there are two steps in a single mechanism, the slower of the two determines the overall rate of the reaction. If there are two different mechanisms available under the reaction conditions, only the faster of the two actually occurs.

3.17 NEIGHBOURING GROUP PARTICIPATION

It has been observed that nucleophilic substitution occurs with inversion or with racemization of configuration. However, most of the reactions occur with complete retention of configuration at the attacked carbon atom. One factor that leads to retention of configuration is neighbouring group participation. For an SN reaction to take place with neighbouring group participation, a neighbouring group not only must be present, but it must be sufficiently reactive. The attack of the neighbouring group must take place faster than the attack by the external nucleophile. The first bit of evidence regarding neighbouring group participation is the faster increase in rate than expected and the retention of configuration at a chiral carbon.

The nucleophilic electron-pairs of the neighbouring group can be nonbonding, or they can be in a π bond or, in special cases, in a σ-bond. They displace the leaving group only when this produces a three- or five-member cyclic intermediate. Ring closure rates of different rings are in the order five-member ~ three-member > six-member >> other ring sizes.

Neighbouring groups can accelerate substitution reactions. The mechanism by which they speed up the reactions is known as neighbouring group participation, and involves two successive inversions of configuration, the net result being retention of configuration. The important neighbouring groups are sulfides, esters, carboxylates, ethers, halides and amines. The important characteristic that they have in common is an electron-rich heteroatom with a lone pair that can be used to form the cyclic intermediate.

The sulphur-containing dichloride ‘mustard gas,’ a high-boiling liquid used in World War I as a combat gas in the form of an aerosol, hydrolyzes much more rapidly to give HCl and a diol than its sulphur-free analogue, 1, 5-dichloropentane. The reason for the higher rate of hydrolysis of mustard gas is a neighbouring group effect, which is due to the availability of a free electron-pair in a nonbonding orbital on the sulphur atom.

β-Chlorosulphide, C2H5SCH2CH2Cl, is hydrolyzed in aqueous dioxan 10,000 times faster than its ether analogue, C2H5OCH2CH2Cl, and thus can be ascribed to neighbouring group participation by the sulphur atom.

In 1,2-disubstituted cyclohexane derivatives, neighbouring group participation occurs only if the groups are anti to each other, that is, if they are diaxial. A ring flip may be necessary to have such an arrangement. (a,a)-trans-2-chlorocyclohexanol when treated with sodium hydroxide, gives cyclohexene oxide, whereas (a,e)-cis-2-chlorocyclohexanol does not react with NaOH to give the corresponding oxide.

Acetolysis of cis and trans isomers of 2-acetoxycyclohexyl tosylate gives the same product.

The trans-isomer reacts (about 700 times faster than the cis-isomer) via neighbouring group participation by involving symmetrical achiral acetoxonium ion, which can be attacked by the acetate ion at either of the two equivalent carbons. Overall, it has been observed that the retention of stereochemistry is possible only if there are two sequential SN2 reactions taking place. Neighbouring group participation is impossible in the cis-isomer, and the substitution, which goes simply by the intermolecular SN2 displacement of OTs by AcOH, means the overall inversion of configuration.

Enantiomerically pure (S)-2-bromopropanoic acid reacts with concentrated NaOH to give (R)-lactic acid, whereas (S)-lactic acid is obtained if the reaction is carried out using Ag2O with low concentration of sodium hydroxide. SN reactions that go with retention of stereochemistry proceed through two successive inversions with neighbouring group participation. In this example, the neighbouring group is carboxylate; the silver oxide is important because it encourages the ionization of the starting material by acting as a halogen-selective Lewis acid. A three-member ring intermediate forms, which then gets opened by hydroxide ion in a second SN2 step.

Among the norbornyl derivatives, the anti-tosylate (C) on acetolysis reacts 1011 times faster than its saturated analogue (A), while B has 104 times reactivity compared to A.

The faster rate of acetolysis of anti-tosylate C, compared to A, proves the removal of the tosyl group with strong anchimeric assistance by the double bond. The resulting non-classical carbocation, that is, bridged ion can only react with acetate ion from the side opposite to the neighbouring group, with retention of configuration. In the syn-isomer B the rate is slower because the double bond is not properly situated for participation.

II reacts 1014 times faster than I because the developing p-orbital of the carbocation in II is orthogonal to the participating bond of the cyclopropane ring.

A more distant OMe group from the leaving group, that is, 4-methoxy alkyl sulfonate reacts with alcohols 4000 times faster than the n-butyl sulphonate.

The OH group in trans-2-hydroxycyclopentyl arenesulphonates acts as a neighbouring group when the leaving group is tosylate, but not when the leaving group is nosylate (p-NO2.C6H4SO2O, -ONs); apparently because the nosylate group leaves so fast that it does not require assistance. Neighbouring group lends anchimeric assistance only when there is sufficient demand for it.

Aryl participation is more common than simple alkene participation. Again π-electrons are involved, but the reaction is now electrophilic aromatic substitution with a delocalized intermediate, often termed as a phenonium ion. Phenonium ion is so symmetrical that it can be attacked on either atom in the three-member ring to give the same product.

PhC(CH3)2-CH2Cl undergoes solvolytic rearrangement thousands of times faster than neopentyl chloride because the rate-determining step in the former case involves the formation of delocalized (‘bridged’) phenonium ion. The rate of the reaction is increased by the presence of electron-releasing groups in the aromatic ring and retarded by electron-withdrawing groups.

Secondary alkyl chloride with good nucleophile (Et2N) can participate to make an aziridinium intermediate that is attacked by HO in SN2 mode to give an amino alcohol. CH2 carbon has less steric crowing than the CHMe carbon. Intramolecular reactions, including participation, that give three-, five-, or six-member rings are usually faster than intermolecular reactions.

Tetramethylene chlorohydrin in H2O is converted into THF about 103 times faster than ethylene chlorohydrin to ethylene oxide.

During the acetolysis of exo- and endo-norbornyl brosylates, it is found that the solvolysis of exo-isomer is 350 times faster than that of endo-isomer. Both the isomers give only the exo-acetate: optically pure exo-brosylate gives a 100% racemic product while an optically pure endo-brosylate gives 93% racemic exo-acetate. The C6—C1 bond is situated to the rear of the ionizable group; the σ electrons attack the carbon bearing the ionizable group, thus facilitating the ionization. This leads to non-classical carbenium ion that reacts with acetic acid to yield the racemic mixture of acetates. No such anchimeric assistance is available to the endo-isomer, which undergoes slow acetolysis through classical carbenium ions.

3.18 SUMMARY

Substitution processes are diverse both in scope and in mechanism. Substitution at carbon atoms by nucleophiles-electron-rich reagents is promoted by electron-withdrawing groups attached to the carbon atom being attacked. Kinetic evidence suggests that nucleophilic substitution at a saturated carbon atom proceeds by one or other of two different pathways: (1) a simple one-step collision between the nucleophile and the molecule being attacked; this is known as the SN2 pathway-Substitution Nucleophilic in which 2 species are involved in the kinetic rate equation; (2) slow loss of the leaving group from the carbon atom being attacked; this is known as the SN1 pathway, as only 1 species is involved in the kinetic rate equation; it is followed by rapid, non rate-limiting attack of the nucleophile in a second step.

Consideration is then given to the influence of structure (in the molecule being attacked), of the solvent, of the leaving group and of the entering group (the nucleophile) in the course of these two pathways.

PROBLEMS
  1. (a) Most nucleophiles are anions but some anions are not nucleophiles. A particular example is BF4. Explain the inertness of BF4 as a nucleophile.

    (b) Thiocyanate (SCN) and cyanate (OCN) each give two products when allowed to react with allyl bromide. In the former case, one product predominates highly. Show the products in each reaction, and account for this predominance.

  2. Offer explanations for the following observations:
    1. An alcohol reacts with a halide ion only in the presence of a strong base.
    2. CH3OCH2Cl reacts with iodide ion in acetone several thousand times faster than CH3Cl.
    3. Trans–2–chlorocyclohexanol easily reacts with base, while the cis-isomer does not react.
    4. Allylic chloride reacts faster than n-propyl chloride in an SN2 reaction.
    5. CF3COOH is a stronger acid than CCl3COOH, indicating that fluorine is more electronegative than chlorine, but C6H5F is less reactive than C6H5Cl in solvolysis.
    6. Phenacyl chloride reacts more than 12000 times as fast as 2-phenylethyl chloride with KI in acetone.
    7. Quinuclidine reacts faster than triethylamine with isopropyl iodide in an SN2 reaction.
    8. Allyl chloride undergoes substitution by SN1 mechanism, whereas n-propyl chloride reacts by SN2 mechanism.
    9. Chlorobenzene and vinyl chloride are inert towards nucleophilic substitution reactions.
    10. (+)–4–Bromo-2-pentene form a racemic product on treatment with sodium iodide.
    11. The alkyl halide shown below does not undergo substitution reaction.
  3. 3-Bromo-3-methyl-1-butene forms two substitution products when it is added to a solution of sodium acetate in acetic acid.
    1. Give the structures of the substitution products.
    2. Which is the kinetically controlled product?
    3. Which is the thermodynamically controlled product?
  4. Propose a suitable mechanism for each of the following reactions:
  5. Starting with cyclohexane, how could the following compounds be prepared?
    1. Cyclohexyl bromide
    2. 3-Methylcyclohexene
    3. 3-Cyclohexanol
  6. Rank the following compounds in order of decreasing nucleophilicity:
    1. CH3COO, CH3CH2S, CH3CH2O in methanol
    2. RO or RS in DMF
    3. C6H5O and C6H11O in DMSO
    4. H2O and NH3 in methanol
    5. Br, Cl, I in methanol
    6. Br, Cl, I in acetone
  7. Predict the product(s) and write the mechanism for each of the following reactions:
  8. Which is the better nucleophile in methanol?
    1. H2O or HO
    2. H2O or H2S
    3. I or Br
    4. NH3 or NH2
    5. HO or SH
    6. Cl or Br
    7. RO or SH
    8. Phenol or ethanol
  9. (a) State the kinetic and stereochemical differences between SN1 and SN2 reactions. Why is benzyl chloride more reactive than ethyl chloride in both reactions?

    (b) Write the single specific structure of an optically active compound with two stereogenic centres, which gives an optically inactive compound when treated with AgNO3.

    (c) Give two examples that show the alkylation of ambient nucleophiles in two different ways.

OBJECTIVE TYPE QUESTIONS
  1. The halogen compound most reactive with water is
    1. t-butyl chloride
    2. chlorobenzene
    3. acetyl chloride
    4. n-butyl chloride
  2. In order for a reagent to behave as a nucleophile it must possess
    1. an overall positive charge
    2. an overall negative charge
    3. an unpaired electron
    4. an unshared pair of electrons
  3. The list Br2, OH, HCl(gas), NH3 contains
    1. all nucleophiles
    2. one nucleophile and three electrophiles
    3. two nucleophiles and two electrophiles
    4. three nucleophiles and one electrophile
  4. Which of the following series contains only nucleophiles?
    1. NH3, H2O, CN, I
    2. AlCl3, NH3, H2O, I
    3. AlCl3, BF3, H2O, NH3
    4. AlCl3, BF3, NO2+, NH3
  5. An example of nucleophilic displacment is the reaction of
    1. benzene with bromine
    2. bromoethane with aqueous sodium hydroxide
    3. chlorine with ethane
    4. an aldehyde with potassium dichromate
  6. A tertiary carbenium ion is more stable than either a secondary or primary carbenium ion because:
    1. it carries three positive charges
    2. it carries three negative charges
    3. it is trigonal planar
    4. it possesses three electron-donating groups
  7. An SN2 reaction involves:
    1. a two-step process.
    2. a radical intermediate.
    3. a carbenium ion intermediate.
    4. a one-step, synchronous process.
  8. One of the completions A to E is incorrect. Choose the option corresponding to the incorrect completion. In an SN2 reaction between (D)-2-bromooctane and hydroxyl ions,
    1. the rate of the reaction is independent of the concentration of hydroxyl ions.
    2. the product is (L)-2-octanol.
    3. if (D)-2-bromooctane is replaced by (2)-2-chlorooctane the reaction rate is decreased.
    4. the rate of reaction is increased if the (D)-2-bromooctane is replaced by 1-bromooctane.
    5. a change of solvent from acetone to a mixture of acetone and water does not change the rate of reaction significantly.
  9. Which of the following alkyl halides undergoes an SN1 reaction the fastest?
    1. CH3Cl
    2. C2H5Cl
    3. (CH3)2CHCl
    4. (CH3)3CCl
  10. Which of the following reactions would you expect to occur mainly by an SN2 mechanism?
  11. Which of the following bases is most likely to promote SN1 reactions rather than SN2 reactions?
    1. OH
    2. OEt
    3. H2O
    4. PhO
  12. CH3.CHO + NH2.NH2 —> CH3.CH=N-NH2 Classify the above reaction as
    1. nucleophilic substitution
    2. elimination
    3. condensation
    4. electrophilic addition
    5. electrophilic substitution
  13. In SN1 reactions the order of reactivity of halides is
    1. primary allyl > 3° > 2° > 1o
    2. 3° > primary allyl > 2° > 1o
    3. 1o > 2° > 3° > primary allyl
    4. 1o > 2° > primary allyl > 3°
    5. primary allyl > 1o > 2° > 3°
  14. If the above reaction was strictly SN2, the organic product(s) would be

    1. A only
    2. A and B
    3. A, B and C
    4. B only
    5. C only
  15. Which one of the following compounds is the most reactive towards SN2 displacement?
    1. CH3.CH2.CH2.CH2.Cl
    2. (CH3)3CCl
    3. CH3.CH(CH2.CH3)Cl
    4. (CH3)2CH.CH2Cl
  16. If the above reaction was strictly SN1, the organic product(s) would be

    1. A only
    2. A and B
    3. A, B and C
    4. B only
    5. C only
  17. Select the false statement concerning nucleophilic substitution at an aliphatic trigonal carbon atom.
    1. Substitution does not occur when the carbon atom is doubly bonded to a nitrogen atom.
    2. Some nucleophilic substitutions at a carbonyl carbon are catalyzed by nucleophiles.
    3. Simple SN2 mechanisms are rarely found in carbonyl substrates.
    4. The attack of a nucleophile on a carbonyl group may result in substitution or addition.
    5. Substitutions occurring by the tetrahedral mechanism are frequently speeded up by the addition of acid.
  18. Which statement is the most likely to be correct concerning the given SN1 reaction?

    1. The reaction proceeds with partial racemization.
    2. The stereochemistry of the halide is not inverted.
    3. The carbenium ion Ph.CH2.CH2+ is involved.
    4. The carbenium ion is attacked in each side to the same degree.
    5. The rate of reaction is dependent on [OH].
  19. One of the following compounds readily undergoes SN1 reactions owing to the stability of its carbenium ion. Is it
    1. CH3Cl
    2. CH2=CHCl
    3. CH3.CH2.CH2Cl
    4. CH2=CH.CH2Cl
  20. t-Butyl bromide reacts with hydroxide ion by a first-order process with the rate proportional to [t-Bu Br]. One rationale for this is that
    1. the intermediate t-butyl radical is stabilized by solvation.
    2. the product t-butanol is thermodynamically stable.
    3. in this case a stereochemical inversion is favourable.
    4. formation of a very stable intermediate t-butyl carbenium ion is facile.
  21. Under certain conditions an important side reaction in the conversion of t-butyl bromide to t-butanol with OH ions is
    1. formation of isobutene by elimination
    2. formation of hexamethylethane by Wurtz coupling.
    3. isomerization of t-butyl bromide
    4. stereochemical inversion of the t-butyl bromide
  22. What would be the product from the photochemical monochlorination of propane at room temperature?
    1. 1-chloropropane
    2. 2-chloropropane
    3. an approximately equal mixture of 1-chloropropane and 2-chloropropane
    4. a mixture of 75% 1-chloropropane and 25% 2-chloropropane
  23. An alkane is most likely to react with
    1. a free radical.
    2. a nucleophile.
    3. an acid.
    4. a base.
    5. an electrophile.
  24. Which of these organic halides most readily undergoes unimolecular solvolysis?
    1. CH3.CHCl
    2. CH2=CH.CH2Br
    3. Ph.CH2.CH2Br
    4. CH2=CH.CH2.CH2.Br
  25. The typical reaction of alkyl halides is
    1. electrophilic substitution
    2. nucleophilic substitution
    3. electrophilic addition
    4. nucleophilic addition