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Nucleophilic Substitution Reactions

General Features

One of the most common reactions of alkyl halides and related substances is nucleophilic substitution (or displacement). The carbon-halogen (C-X) bond in an alkyl halide is polarised, with a partial positive charge on the carbon and a partial negative charge on the halogen. Thus the carbon atom is susceptible to attack by a nucleophile (a reagent that brings a pair of electrons) and the halogen leaves as the halide ion (X-), taking on the two electrons from the C-X bond. The nucleophile is usually neutral or negatively charged and some examples are HO-, H2O, MeOH, EtO-, RS-. A general equation for a nucleophilic substitution by a nucleophile Y is shown below.

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When the nucleophile is also used as the solvent for the reaction, the substitution reaction is called a solvolysis. This is a term which is used widely in mechanistic studies, especially in the older literature.

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Nucleophilic substitution reactions (II) can be compared to a Brønsted-Lowry acid-base equilibrium (I):

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The equilibria of these reactions generally lies far to the right. In the Brønsted reaction, hydroxide ion displaces bromide ion from HBr. In the organic reaction, hydroxide ion displaces bromide ion from ethyl bromide. Thus, by analogy, the equilibrium in nucleophilic substitution reactions favours the release of the weaker base. We can now see why the reverse reaction is disfavoured, i.e. iodide ion does not displace hydroxide ion. We say that hydroxide ion is a good nucleophile and iodide ion is a good leaving group. Nucleophilicity and leaving group ability can often be estimated by comparing pKa values of the species concerned.

 

The SN2 Reaction

Kinetics

Nucleophilic substitution reactions follow different rate laws, depending on the exact mechanism. The rate law for an SN2 reaction is: Rate = k [RX] [Nuc]

where k is the rate constant, RX is the alkyl halide and Nuc is the nucleophile.

Mechanism

The reaction rate is therefore second order overall. This also tells us that the reaction is bimolecular, i.e. two species are involved in the rate-determining step. If the kinetics are determined experimentally, it is possible to propose a mechanism which is consistent with the data:

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This proposed mechanism for the SN2 reaction raises an interesting question: If the substitution occurs at a chiral carbon, does the reaction proceed with retention, inversion or loss of stereochemistry? The answer to this question lies in the direction of attack of the incoming nucleophile. Attack on the same side as the halogen would result in retention of stereochemistry. Attack from the opposite side to the halogen would result in inversion of stereochemistry. A mixture of these two possibilities would lead to loss of stereochemical integrity at the chiral carbon. Experimentally, it is found that a purely SN2 reaction at a chiral carbon proceeds with inversion of stereochemistry.

In 1896, German chemist Paul Walden reported the conversion of enantiopure (+)-(R)-malic acid into the enantiomer (-)-(S)-malic acid, although he did not know at which step inversion was occurring. In the 1920s Kenyon and Philips investigated a similar process with 1-phenyl-2-propanol:

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From this and several other such cycles, Kenyon and Phillips concluded that the nucleophilic substitution reaction of primary and secondary alkyl halides and tosylates always proceeds with inversion of stereochemistry. In the cycle above inversion takes place in the nucleophilic substitution of tosylate ion by acetate ion.
 

The SN1 Reaction

The SN2 reaction is favoured by basic nucleophiles such as hydroxide ion and disfavoured by protic solvents such as alcohols and water. The reaction also depends on the nature of the substrate: primary substrates react rapidly, secondary substrates react more slowly and tertiary substrates are almost inert to SN2 reaction. In protic media with non-basic nucleophiles under neutral or acidic conditions, tertiary substrates can be orders of magnitude more reactive than their primary or secondary counterparts. The SN2 mechanism clearly cannot account for this and it can be concluded that a different mechanism can operate under these circumstances. This mechanism is called SN1 which denotes Substitution by a Nucleophile, Unimolecular. That is, only one species is involved in the rate-determining step.
 

Kinetics

The SN1 reaction is first order and the rate varies only as the concentration of the alkyl halide: Rate = k [RX]

The rate of reaction is found to be independent with respect to the concentration of the nucleophile. In other words, the nucleophile does not take part in the rate-determining step.
 

Mechanism

Any proposed mechanism for the reaction must therefore have the alkyl halide undergoing some change without the aid of the nucleophile. The first step must therefore be cleavage of the C-X bond to form a carbocation, followed by reaction with the nucleophile to give the substitution product.

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This mechanism is clearly different from the SN2 pathway above and the stereochemical outcome should also differ. Carbocations are sp2 hybridised, planar species - at first glance it would appear that the nucleophile, Y- could attack from either face of the carbocation, with an equal probability. We would predict that this should lead to complete racemisation, if the starting alkyl halide were optically pure. In practice, complete racemisation is rarely observed and usually, a minor excess (up to ~20%) of inversion is observed. One explanation for this was provided by Winstein, an eminent physical organic chemist. It was proposed that an ion-pair, between the carbocation and the leaving group X- is present, which partly blocks attack of the nucleophile from one face. Thus, inversion slightly dominates.
 

Factors which Influence the Reaction Pathway

SN2

  • Steric Effects: The transition state in the SN2 reaction involves partial bonding between the nucleophile and the substrate. The bulkier the substrate, the more difficult it is for the transition state to be reached. The reactivity order is 1o > 2o > 3o.
  • The Nucleophile: By definition, a nucleophile must have an unshared pair of electrons, whether it is charged or neutral. Nucleophilicity follows approximately basicity, so pKa values can be used. Nucleophilicity usually increases going down a group in the periodic table. The reactivity order of the more common nucleophiles is: CN- > I- > MeO- > HO- > Cl- > H2O.
  • The Leaving Group: The leaving group is normally ejected with a negative charge. Therefore the best leaving groups are those which can best stabilise a negative charge. Weak bases (TsO-, I-, Br-) are generally good leaving groups, whereas strong bases (F-, HO-, RO-) are generally poor leaving groups.
  • The Solvent: Polar aprotic solvents are best for SN2 reactions. These include acetonitrile (CH3CN), dimethyl sulphoxide (Me2SO) and N,N-dimethylformamide (Me2NCHO). Protic solvents tend to form a 'cage' around the nucleophile, decreasing its reactivity.

SN1

  • The Substrate: Substrates which can form relatively stable carbocation intermediates favour SN1 reactions. The order of stability of carbocations is: 3o > 2o > benzyl > allyl > 1o.
  • The Nucleophile: The nucleophile is not involved in the rate-determining step in an SN1 reaction but the SN1 pathway is more likely to be followed if the nucleophile is poor, e.g. H2O.
  • The Leaving Group: The leaving group is also involved in the rate-determining step for an SN1 reaction, so the same reactivity order as for SN2 is followed.
  • The Solvent: The solvent can have an effect on the rate of the SN1 reaction, but for different reasons. Solvent effects arise from stabilisation of the transition state and not the reactants themselves. The rate of SN1 reaction is increased in a polar solvent such as water or aqueous ethanol.

The problems in this section concentrate on the common substitution pathways. If some of the nucleophiles or electrophiles look unfamiliar, use the chemistry that you know to work out a realistic mechanism and remember, you are looking for a substitution (displacement) reaction overall.

 

 

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Page author : Dr Mary Masson