Introduction
The reactivity of molecules may be influenced by a large number of factors. It is also difficult for us to confidently say what exactly a molecule’s ‘reactivity’ is: for example, if there are two reactants, and only one of them increases in reactivity, we cannot say that the other increases in reactivity as well, although the reaction appears faster.
Taking the above into consideration, we will list down 10 factors which influence the reactivity of molecules. These are resonance, inductive and field effects, electronegativity, steric hindrance, back, internal and conformation strain, as well as the pressure, temperature and solvent. These 10 factors may be grouped into 3 distinct categories: electrical effects, steric effects, and reaction conditions.
As such, without further ado, let us get started.
1. Resonance Effects
Resonance is one of the most important concepts in organic chemistry, being able to confer reactivity upon many compounds. It is an electrical effect.
When a molecule’s true structure cannot be represented sufficiently by a single structure, but is instead a weighted average of several different structures, resonance is taking place. For example, benzene has five resonance structures (Fig. 1), depending on the locations of the three bonds which are constantly moving around the molecule. Note that some of them are of higher weightage than others as they are more stable.
Fig. 1: Resonance structures of benzene.
This means that the electron density from those bonds would be equally spread across the entire benzene molecule, making all its carbons equivalent.
In most cases, it is likely that resonance would act to stabilize a molecule. When a positive or negative charge exists on a molecule, resonance can act to delocalize this charge over more atoms. This prevents charges from being concentrated at one point, and makes the molecule more stable, lowering the reactivity of a molecule.
It is possible that resonance could destabilize the molecule although this would be slight. If delocalization occurs for a negative charge over an electron-donating group, for example, it would be destabilizing (we will see why next in inductive effects). However, it is likely that such a resonance form would not be as ‘important’ and would be of a lower weightage than the other, more stable molecules.
2. Inductive Effects
Inductive effects are also electrical effects, and its key chemistry is concentrated on two types of molecules: electron-donating groups, and electron-withdrawing groups. As their name suggests, they donate and withdraw electrons, respectively.
How can this affect the reactivity of molecules? There are many examples of this in organic chemistry. Electron-withdrawing groups such as the halogens are able to ‘activate’ a substrate towards nucleophilic substitution.
For example, in the carbonyl group, the oxygen atom withdraws electron density from the carbon atom, making the carbon atom relatively more electrophilic. This makes it susceptible to attacks from other nucleophilic molecules, and thus confers more reactivity upon it. ‘Normal’ carbons, such as in alkanes, do not enjoy this type of reactivity.
Inductive effects are most prominent in the case of benzene rings, and this even affects the position of attack by the electrophile on the aromatic ring. The presence of an electron-donating group increases the reactivity of the ring; at the same time, it also activates the ring toward attack at the 1 and 4 carbons (Fig. 2).
Fig. 2: Inductive effect of electron-donating groups.
Electron-donating and withdrawing groups exist on a spectrum; this means that there exists a stronger electron-donating group and a weaker electron-donating group. Logically, they affect the reactivity differently. An example of a weaker electron-withdrawing group is the halogens.
An important thing to take note of is that inductive effects work through bonds; they cannot reach out through space. Thus, the electron-donating or withdrawing group can only affect the atom it is directly bonded to.
3. Field Effects
Inductive effects are very similar to field effects, and they are often confused or mixed together. Field effects are also a bit of an oddball in organic chemistry, because they have the same idea as inductive effects, except for one key difference.
Field effects also similarly involve electron-donating and withdrawing groups. However, it instead works through space (Fig. 3) instead of bonds (which we had emphasized earlier for inductive effects). This is very important, because it means that as long as an electron-withdrawing or donating group is present on a molecule, both the field and inductive effects will be present (another reason why they are often confused together).
Fig. 3: Field effect of atoms.
The core idea of field effects is that electron-donating and withdrawing groups are able to affect the reactivities of atoms on a molecule other than the atom they are directly bonded to. Furthermore, the distance between the electron-donating and withdrawing groups also matters. The further away an atom from the electron-donating or withdrawing group, the weaker the group’s effect on the atom.
So, how can we prove the field effect? Its effect should not be that obvious because there are often many other factors at play, unlike for the inductive effect. There is evidence for the field effect, stemming from the fact that it is able to affect the acidity of atoms on a molecule.
Two stereoisomers will have varying proximities of the electron-donating or withdrawing group. By comparing the acidities of the two stereoisomers, conclusions can be made about the existence of the field effect: if the acidities are different, it shows us that the field effect indeed exists.
4. Electronegativity
Previously, we discussed two different electrical effects: one which affects atoms near to it and one which affects atoms directly bonded to it. Now, we will discuss the effect that affects only the atom itself: electronegativity (Fig. 4). Electronegativity is one of the simplest topics to grasp and is interlinked with the inductive and field effects.
Fig. 4: Electronegativity of oxygen.
The electronegativity of each atom is a fixed value; in general, atoms get more electronegative as we move up and to the right of the periodic table (excluding the noble gasses). As such, the most electronegative element is fluorine.
When an atom is electronegative, it will want as much electron density as possible (the opposite is electropositivity, where an atom wants as little electron density as possible). This means that when it forms bonds to other molecules, most of the electron density in that bond will be pulled towards the more electronegative atom, making the bond polar.
So how does this give an atom more reactivity? Well, a more electronegative atom would tend to be surrounded by more electron density, giving it a partial negative charge and more reactivity as it can now attack positively charged sites. Because of this, nucleophilic atoms tend to be more electronegative (halogens and OH-).
However, from another point of view, it is also possible for electronegativity to make an atom more stable. We do not see metal atoms bearing negative charges because they are not electronegative enough; metal atoms would be too unstable to bear negative charges, and therefore electron density.
For halogens, however, they may exist as free, negatively charged atoms, as in the case of Cl- and Br-, because they are electronegative and able to bear the negative charge well.
5. Steric Hindrance
The first type of steric effect we will introduce is steric hindrance. It can affect the reactivity of a molecule greatly, but is also useful to some extent. But before we look into that, we have to first understand what steric hindrance itself is first.
When a substituent or atom hinders another atom from undergoing reaction by physically blocking it, that is known as steric hindrance (Fig. 5). Usually, it will occur either when large atoms or bulky groups are present on the molecule, although it is usually the latter.
Fig. 5: Illustration of steric hindrance.
What qualifies as a large atom or a large group? There is no clear definition for either. In general, when the atom or group is large enough to cause observable effects to the rates of a reaction, it can be considered large atoms or bulky groups. An example of a bulky group is the tert-butyl group.
When one tert-butyl group is present and bonded to a small atom (such as carbon), it either slows down or completely prevents a reaction from occurring, thus we can say that it is a bulky group. In conclusion, steric hindrance makes a molecules less reactive.
However, steric hindrance can also be very useful in certain cases. One of these cases can be seen in LDA, lithium diisopropyl amide, which is a base. The structure of LDA is shown below in Fig. . Notice that the two large isopropyl groups sterically hinder the basic nitrogen, and thus we can consider the nitrogen sterically hindered.
Since the base is sterically hindered, it can only approach acids that are not sterically hindered. As such, if there are two acidic sites on a molecule, with only one sterically hindered, LDA may be employed to selectively remove one of the protons. This gives LDA much utility although it is sterically hindered.
6. Back Strain
Back strain is another type of steric effect, but it is instead caused by strain in a molecule’s structure, thus distinguishing strain from hindrance as discussed earlier.
Let us explain back strain with an example. In the first step of the SN1 reaction, a carbon atom loses one hydrogen atom to form a carbocation. We should also note that the SN1 reaction usually occurs only to form tertiary carbocations, and never to form a primary carbocation. Why is this so?
In the chemical literature this phenomenon is attributed to a variety of reasons; however, back strain should be at least one of those reasons. In a molecule with a tertiary carbon, the central carbon atom is bonded to three methyl (CH3) groups as well as a single hydrogen (that is later removed to form the carbocation).
The primary and tertiary carbon both assume a tetrahedral structure. In each of these structures, the substituents are relatively close to each other, at a 109.5o angle. This is no problem for primary carbons, because hydrogen atoms are very small and there is no strain.
For the tertiary carbon, however, the methyl groups are relatively larger and thus strain, known as back strain, is present when they are put into that angle with one another. So, how does this increase the reactivity of the tertiary carbon (towards SN1 reactions)?
Well, in the first step of the SN1 reaction, a hydrogen is lost from the tertiary carbon. This causes the geometry about the carbon to change (due to different hybridization), resulting in a larger 120o angle (trigonal planar) instead. This would decrease the strain between methyl groups and is thus energetically favored. For the primary carbon, there is no increase or decrease in strain and the reactivity is not increased.
7. Internal Strain
This special type of strain, internal strain, is present in cyclic compounds. Most prominently we can compare the solvolysis rates of different membered cyclic compounds. 1-chloro-1-methylcyclopentane is observed to have very fast solvolysis rates, but this is not so for its six-membered counterpart, 1-chloro-1-methylcyclohexane.
Usually, we would expect both five and six-membered rings to possess stability, so what is the cause of the difference here? Well, we can tell that five-membered rings should be more reactive than six-membered rings, because the rate of solvolysis is faster.
This means that there must be some factor that causes five-membered rings to have higher reactivity. The answer lies in internal strain. For the five-membered ring, there exists steric interactions between the methyl group of the 1-carbon and the hydrogens of the 2 or 5-carbons, because of the presence of a large chlorine atom.
When solvolysis occurs, removing the chlorine atom from the cyclic compound, it is much more favored for the strained five-membered ring. The same strain does not exist for the six-membered ring, where bond angles are larger.
8. Conformational Strain
Conformation strain is rather similar to internal strain, but it does not necessarily refer to cyclic compounds. To visualise this type of strain better, it is helpful to employ Newman projections (Fig. 6). In the Newman projection, carbons are represented as overlapping, three-dimensional spheres.
Fig. 6: Example of a Newman projection.
Rotation is possible about a single bond. As such, this allows for the presence of different ‘isomers’, known as conformations. Logically, a molecule would choose to assume the most stable conformation.
For a molecule like butane (we are focussing on the bond between the center two carbons), it is important that the molecule is not rotated such that the methyl groups bonded to each of the center carbons are overlapped with each other. In such a case, the conformation is known as synperiplanar and it is of the highest energy (and thus the most reactive). The lowest energy conformation is antiperiplanar, where the methyl groups are directly opposite one another.
In certain cases, it is possible for a molecule to prefer higher energy conformations than lower energy conformations, usually because of chemical reasons rather than structural. This will then increase their reactivity as compared to other, similar molecules, which have the lower energy conformations. Thus we can say that conformational strain affects reactivity.
9. Pressure
For atoms to react, they must collide with one another with sufficient activation energy. To increase the rate of reaction, we may increase the pressure, so that there are more particles in a smaller space. This would increase the frequency of collisions and along with it the more likely are particles to collide with sufficient activation energies, thereby making the reaction faster.
However, this is not always the case. For some reactions, an increase in the pressure leads to a decrease in the reaction rate. There are four types of reactions which increase in reaction rate with an increase in pressure. These are synthesis reactions, pericyclic reactions, reactions with dipolar transition states (meaning that both positive and negative charges are present in the transition state) and reactions with steric hindrance.
The comparison between the rates of a reaction at different pressures is not easy because a rate law does not include pressures. Instead, a separate equation to calculate the volume of activation (Fig. .) is used, as that equation does indeed take into account the pressures of each reaction.
Fig. 7: Equation for the volume of activation as seen in the Gold Book.
If the volume of activation of the reaction is negative, the rate of the reaction will increase as the pressure increases. However, if the volume of activation of the reaction is positive, the rate of the reaction will decrease as the pressure increases.
The temperature is also related to the rate of the reaction. When the temperature increases, the rate of the reaction increases as the average kinetic energy of particles increases, making particles more likely to collide with the correct activation energy.
10. Solvent
For solvents it is a little more unclear what factors are involved. The type of solvent matters, as does the presence of the solvent itself. Nonpolar molecules react poorly in polar solvents. This is because nonpolar molecules dissolve slowly in polar solvents, and being in solution is required before reaction can occur.
In some cases nonpolar molecules may actually react faster in polar solvents, although this is rare. If the polar solvent is water, and the nonpolar molecule is hydrophobic, it will cause association to occur, bringing the reactant molecules closer together. This will then increase the rate of the reaction.
Traditionally, reactions are carried out in the presence of solvent. However, solventless reactions also exist, where the media is dry. Dry media reactions, which are carried out under microwaves, can speed up the reaction rate. This is a physical method, and thus physical concerns exist as usual: the affordability, the lack of control.
It is not possible to quench (stop) dry media reactions because quenching is performed using cool water, but this does not work in dry media. Furthermore, the dry media, which is either viscous or solid, may be difficult to handle.
There are, however, also many notable benefits of solventless reactions, one of which is that sequential reactions can occur as there is no need to change solvents to prevent unwanted side reactions between the reactants and the solvents.