There’s Chemistry Between Us – Nucleophiles, Electrophiles and Nucleophilic Substitution

This is Post 2 in a series of posts reviewing and explaining the content of my first-year university chemistry subject, CHEM10004, at the University of Melbourne. For an introduction to this project, go here.

Introduction to Nucleophiles and Electrophiles

A lot of organic reactions are polar: they take place between molecules that are positively and negatively charged. As we saw in the last post, acid/base reactions are also polar, as they involve the formation/breaking of bonds to protons (H+), but most organic reactions are different; they are all about bonds around carbon atoms. Because of this difference, we need to introduce some new terminology: nucleophile and electrophile.

A nucleophile is a molecule that is nucleus-loving – it is attracted to positive charge (low electron density) due to its own abundance of electrons. This abundance of electrons usually manifests as a lone pair or a negative charge, as in HO:-, RO:-, RS:-, :NH3, etc. (where “:” represents a non-bonding, lone pair of electrons).

However, whole molecules do not have to function as nucleophiles: there can be nucleophilic regions of large molecules that come about through polar covalent bonds. For example, a bond between carbon and chlorine leaves a partial negative charge on chlorine through its higher electronegativity, making it act as a nucleophile.

Electrophiles, on the other hand, are electron-loving – they are attracted to negative charge (high electron density) due to their own lack of electrons. Most electrophiles either have a full positive charge or a partial positive charge, such as H+, NO (which has a partial positive charge on the nitrogen) and diatomic halogen molecules like Br2 (which contain an easily polarizable bond, producing an electrophilic end), or are neutral but are missing two electrons from their stable octet, such as BF3 and AlCl3.

Molecules can also have electrophilic regions as well as nucleophilic regions. In fact, they often go hand in hand – when there’s a polar covalent bond in a molecule the atom with the lower electronegativity will become electrophilic (partially positively charged) and the atom with the higher electronegativity will become nucleophilic (partially negatively charged). A prominant example in organic chemistry is the C=O bond: the oxygen steals a lot of the electron density from the pi bond, resulting in an electrophilic carbon and a nucleophilic oxygen. This bond will become very important when we start to look at the reactivity of various organic molecules.

Electrophiles and nucleophiles will react together when the nucleophile gives a pair of electrons to the electrophile and they form a covalent bond between the two molecules. In organic chemistry, the two broad categories of nucleophile/electrophile reactions are defined by the chemical substance forming a bond to carbon – if it’s a nucleophile it will be a nucleophilic reaction, while if it’s an electrophile it will be an electrophilic reaction.

Nucleophilic Substitution

Nucleophilic reactions in organic chemistry involve a nucleophile attacking an electrophilic carbon atom, a carbon atom with a partial positive charge. Carbon atoms in unsubstituted alkyl chains (ie. in saturated hydrocarbons) are neutral and rarely act as electrophiles. This means that for a nucleophilic reaction to take place the carbon atom in question must be bonded to an atom with a higher electronegativity, such as oxygen or a halogen (ie. chlorine, bromine or iodine), giving it a partial positive charge. This positive charge is what will attract the nucleophile and promote a nucleophilic reaction.

The first kind of nucleophilic reaction we’ll look at is nucleophilic substitution, a reaction where a nucleophile is “substituted” for an already-present group on a carbon atom called the leaving group. Here’s an example using hydroxide and bromoethane:

(Note: The arrows between atoms represent two electrons being transferred from one to the other, forming a bond. In the case of bromine, it’s taking the two electrons from its bond to carbon and keeping them as a negative charge.)

In this reaction, hydroxide is the nucleophile, substituting itself for the bromine atom leaving group, which leaves as an anion.

A wide variety of molecules can be formed through nucleophilic substitution, such as ethers:

Here methoxide is the nucleophile, replacing the leaving group chloride, forming methyl propyl ether.

Esters can also be formed by using the conjugate bases of carboxylic acids as nucleophiles:

Here ethanoate is the nucleophile, replacing the leaving group bromide, forming methyl ethanoate.

Other possible nucleophiles that can be used for substitution include :NH3, RC≡C- and N≡C-.

SN1 Reactions

There are two main mechanisms for nucleophilic substitution reactions: SN1 and SN2. Rarely does only one mechanism occur in isolation, though we will find out later on that various reagents favour one or the other.

The first mechanism is SN1. “SN” stands for “Nucleophilic Substitution”, while “1″ refers to the unimolecular rate-limiting step. Rate-limiting step? Every chemical reaction mechanism has a certain rate that it will proceed at, and certain steps within the reaction can be slower than others, so it’s the rate at which these steps occur that limit the rate of the overall mechanism. In SN1 reactions the rate-limiting step (in other words, the slowest step) is a unimolecular reaction where the leaving group leaves the substrate through ionisation.

Here’s an example of an SN1 rate-limiting step:

Tert-butyl iodide is being ionised to form the tert-butyl carbocation and the iodide anion. Note that the carbocation is sp2 hybridised.

Spontaneous ionisation in solution is an equilibrium reaction, but the carbocation is being consumed in the next step of the SN1 reaction, so the equilbrium is constantly being shifted to the right to produce more product. For a lot of substrates the ionisation equilibrium lies mostly to the left (favoring the reactant), meaning that it is a slow reaction even with the constant consumption of carbocations.

After the first step is complete, the carbocation is free to react with any nucleophiles in solution. This step is much faster than the ionisation of the substrate, so it doesn’t affect the overall rate of the reaction. Because of this, the overall rate depends only on the concentration of substrate, providing that the nucleophile is in excess. This contrasts with the SN2 reaction, as we will see.

The reaction with the nucleophile proceeds as you would expect:

Here ammonia is the nucleophile, reacting with the tert-butyl carbocation to form tert-butylamine. (The neutralisation of the amine group is not shown.)

Do you see how the hybridisation of the carbocation changed when the nucleophile was added? The carbocation’s central carbon hybridisation is sp2, which produces a 2D, flat molecule. After the nucleophile bonds to the electrophilic carbon, its hybridisation reverts to sp3, resulting in a 3D molecule.

If the substrate is chiral, this is a very important point, because the nucleophile can attack from either below or above the plane of the 2D carbocation, producing one of two possible stereoisomers. Because chemical reactions typically involve large amounts of molecules and the direction each nucleophile will approach from is essentially random, the outcome of an SN1 reaction will be a racemic (50/50) mixture of the two possible stereoisomers of the product.

Here’s an example of a chiral substrate undergoing an SN1 reaction:

Hydroxide is the nucleophile, reacting with (3S)-3-chloro-2,3- dimethylpentane to form two stereoisomers - (3R)-2,3-dimethylpentan-3-ol and (3S)-2,3- dimethylpentan-3-ol.

For those who don’t know what chirality is, it’s basically the “handedness” of a molecule. Every carbon atom that is bonded to four different groups is considered a chiral center, and any molecule that has at least one chiral center is considered a chiral molecule. To represent the different chiral isomers (known as stereoisomers) in two dimensions, different bonds are used: the dashed bond represents a group that is going into the plane of the screen, and a thick wedge bond represents a group that is coming out of the plane of the screen.

Applying this to the reaction above, the two products are stereoisomers of each other – they’re mirror images. The direction of the nucleophilic attack, either from above or below, determines which stereoisomer will be produced in any single molecular interaction, as I’ve mentioned before.

SN2 Reactions

If the “1″ in SN1 meant it has a unimolecular rate-limiting step, then the “2″ in SN2 must mean it has a bimolecular rate-limiting step, and yes, it’s true. In the SN2 mechanism, the slowest part of the reaction is the addition of the nucleophile to the substrate, which still has the leaving group attached. This bonding creates an unstable trigonal bipyramidal molecule which rapidly loses the leaving group to return to a tetrahedral geometry.

The nucleophilic hydroxide bonds to the center carbon, producing a short-lived intermediate that rapidly loses the chloride leaving group.

It’s the first reaction that’s the slowest, so the rate of the overall reaction is limited by the concentrations of both the substrate and the nucleophile.

When it comes to chirality, SN2 reactions differ significantly to SN1 reactions. As you recall, SN1 reactions produce a racemic mixture of the two possible stereoisomers of the product. SN2 reactions, on the other hand, produce an inversion of configuration – if the substrate was R, the product will be S, and visa versa. This is because the nucleophile always attacks from the back of the molecule, on the other side from where the leaving group is bonded.

Ammonia, the nucleophile in this reaction, attacks the electrophilic carbon from the other side from the bromide leaving group, turning (3R)-3-bromo-3-methylhexane into (3S)-3-methylhexan-3-aminium. (The aminium group has not been neutralised.)

This “back-attack” addition becomes important when we consider the factors affecting the relative contributions of these two substitution mechanisms to various reactions.

Factors Affecting Nucleophilic Substitution

SN1 reactions are more likely to occur as the carbocation intermediate produced by the rate-limiting ionisation step increases in stability. Due to an effect called hyperconjugation, wherein the hydrogen atoms of neighbouring methyl groups share some of their electron density with the empty p-orbital, tertiary carbocations are the most stable and primary carbocations are the least stable.

Hyperconjugation makes tertiary carbocations the most stable, and primary carbocations the least stable.

As such, any SN1 reaction that would produce a primary carbocation as an intermediate will not be favored as the major mechanism, and the reverse is true for tertiary carbocations.

The SN2 mechanism is conversely favoured by primary substituted substrates, with tertiary substrates inhibiting it. The reason for this goes back to the concept of the “back-attack” addition that we observe in SN2 reactions. Because the nucleophile must approach the electrophilic carbon from the other side from the leaving group, it comes into close proximity with the three other groups around that carbon. If they are large groups (eg. anything bigger than a hydrogen atom, such as a methyl group), then they will hinder the nucleophile from reaching the carbon atom to form a bond, raising the energy of the transition state. The phenomenon behind this effect is known as steric strain.

Steric strain prevents nucleotide "back-attack" on carbon atoms with multiple methyl groups around it. Note that any alkyl group could be substituted for the methyl groups shown, to the same effect.

The outcome of these two factors is that tertiary substituted substrates will almost always undergo SN1 reactions exclusively, while primary substituted substrates will almost always undergo SN2 reactions exclusively.

Another factor relating to nucleophilic substitution is the strength of the nucleophile involved in the reaction. Strong nucleophiles (ie. strong bases) are high in energy and therefore allow the reaction to reach its activation energy a lot faster than weak nucleophiles. This is only really important in SN2 reactions, where the nucleophile influences how fast the overall reaction proceeds, and not in SN1 reactions, where the rate-limiting step is the rather slow process of spontaneous ionisation and any nucleophile, weak or strong, will readily react with the carbocation that forms. As such, strong nucleophiles favour the SN2 mechanism.

A general principle that applies to both mechanisms of substitution is that the nucleophile must be a stronger base than the leaving group, and thus good leaving groups are weak bases. We talked about what makes a base weak in the last post, but just to recap:

- a highly electronegative charged/lone pair-ridden atom decreases base strength
- greater amounts of “s” character in the hybridisation of the charged/lone pair-ridden atom decreases base strength
- resonance stability (diffusion of charge across multiple bonds) decreases base strength

This explains why halides are often used as substrate molecules in nucleophilic substitution reactions – the anions they form are weak bases due to the high electronegativity of halogens. The OH2+ group is also a good leaving group, because it leaves as H2O, a stable, weak base.

Solvents also affect substitution reactions. In SN1 reactions, solvents that stabilise the intermediate carbocations lower their energy and increase the speed of the rate-limiting step. Solvents that tend to do this are polar and protic (donate hydrogen ions), such as water. In SN2 reactions, solvents that minimise hydrogen bonding to the nucleophile increase its energy and therefore increase the rate of the overall reaction. Good solvents for this are polar and aprotic (do not donate hydrogen ions), such as acetone. Thus, the major mechanism by which a substitution reaction will proceed can also be influenced by the solvent used.

Summary

Nucleophilic substitution reactions can proceed in two ways, SN1 and SN2, either exclusively one or a mixture of both. SN1 reactions produce a racemic mixture of products, while SN2 reactions produce an inversion of configuration.

Factors that increase the contribution of the SN1 pathway are tertiary, or highly substituted, substrates and polar, protic solvents.

Factors that increase the contribution of the SN2 pathway are primary, or poorly substituted, substrates, polar, aprotic solvents, and strong nucleophiles.

For either mechanism to proceed, the nucleophile must be a stronger base than the leaving group. Halogens are usually the best leaving group for most basic purposes, due to their high electronegativity and low reactivity in solution.

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