Synthesis: Structure Determines Reactivity
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You should be comfortable identifying functional groups and distinguishing between constitutional and stereoisomers, as covered earlier in this unit.
Why this matters
In organic synthesis, the specific 3D arrangement of atoms dictates which reactions are possible and how fast they occur.
Understanding that structure determines reactivity allows chemists to predict the outcome of a reaction without trial and error. For instance, a nucleophile cannot attack a carbon atom if a bulky group physically blocks the path, or if the electronic distribution of the molecule makes that carbon electron-rich rather than electron-poor. This lecture connects the static structural features you have learned—connectivity, chirality, and geometry—to the dynamic process of chemical change. By mastering this link, you move from memorising reaction types to understanding the underlying logic of molecular behaviour, which is the core skill of the organic chemist.
The Logic of Molecular Interaction
Imagine trying to shake hands with someone who is wearing a very thick, bulky glove. Even if you both want to shake hands, the physical bulk of the glove prevents your hands from touching. In organic chemistry, molecules interact in a similar way. A reaction is not just a matter of two molecules being present in the same solution; it is a precise physical and electronic event. The "structure" of a molecule refers to the exact positions of its atoms in three-dimensional space and the distribution of electrons around those atoms. This structure acts as both a gatekeeper and a guide. It determines which parts of the molecule are accessible to other reagents and which parts are electronically "ready" to form new bonds.
Consider a simple carbon atom in a chain. If that carbon is part of a double bond, the electrons are held in a flat, planar arrangement, making it susceptible to attack from above or below the plane. If that same carbon is part of a single bond in a saturated chain, the electrons are arranged in a tetrahedral geometry, creating a different set of accessible angles. Furthermore, if the carbon is attached to four different groups, it becomes chiral. This chirality means that the molecule has a specific "handedness." A reagent approaching this chiral centre will experience a different steric environment depending on which side it approaches from. Therefore, the structure does not just describe the molecule; it actively directs the reaction pathway. This is why two molecules with the same atoms but different arrangements (isomers) can react completely differently. One might react rapidly, while the other is inert, or one might produce a specific product while the other produces a different one. This principle is the foundation of selective synthesis.
Steric Hindrance and Accessibility
Steric hindrance is the physical blocking of a reactive site by other atoms or groups within the same molecule. In many reactions, particularly nucleophilic substitutions, the reagent must approach the target atom closely enough to form a new bond. If the target atom is surrounded by large groups, this approach is hindered. For example, consider the reaction of a nucleophile with an alkyl halide. If the halide is attached to a primary carbon (one attached to only one other carbon), the carbon is relatively exposed, and the reaction proceeds easily. However, if the halide is attached to a tertiary carbon (attached to three other carbons), the carbon is buried within a cluster of alkyl groups. The nucleophile cannot easily reach the backside of the carbon atom required for an SN2 reaction. This is a direct consequence of the molecule's structure: the connectivity of the carbon skeleton creates a physical barrier. The result is that tertiary alkyl halides often undergo elimination reactions instead of substitution, because the elimination pathway does not require the same degree of close approach to the carbon centre. This demonstrates how the shape of the molecule dictates the type of reaction that is feasible.
Another example is found in aromatic systems. Benzene rings are planar, but if large groups are attached to the ring, they can twist out of the plane or create a "shield" around specific positions. This can prevent electrophiles from attacking certain carbons on the ring, leading to regioselectivity. The structure of the substituent groups determines which positions are electronically activated and sterically accessible. Thus, when designing a synthesis, chemists must consider not just the functional group present, but the entire molecular framework that surrounds it.
Electronic Effects and Reactivity
While steric effects are about physical space, electronic effects are about the distribution of charge. The structure of a molecule determines where electrons are concentrated or depleted. Functional groups influence the electron density of nearby atoms through inductive effects and resonance. For instance, a carbonyl group (C=O) is polar, with the oxygen being electron-rich and the carbon being electron-poor. This makes the carbonyl carbon susceptible to attack by nucleophiles. However, if the carbonyl is part of an ester, the adjacent oxygen donates electron density via resonance, reducing the positive character of the carbon. This makes esters less reactive towards nucleophilic attack than aldehydes or ketones. The difference in reactivity is entirely due to the structural difference: the presence of the additional oxygen atom in the ester changes the electronic landscape of the carbonyl carbon. This is a clear case where structure determines the rate and ease of reaction.
Electronic effects also play a crucial role in acidity and basicity, as discussed in the previous lecture. The stability of the conjugate base determines the strength of an acid. If the structure of the molecule allows the negative charge to be delocalised over several atoms (resonance stabilisation), the acid is stronger. For example, carboxylic acids are stronger than alcohols because the negative charge on the carboxylate ion is shared between two oxygen atoms, whereas the charge on an alkoxide ion is localised on a single oxygen. This structural feature—resonance—directly influences the chemical behaviour of the molecule. Understanding these electronic effects allows chemists to predict which protons are most acidic and which sites are most basic, guiding the choice of reagents in synthesis.
Stereochemical Consequences
The three-dimensional arrangement of atoms, or stereochemistry, has profound effects on reactivity. As established earlier in this unit, enantiomers are non-superimposable mirror images. While they have identical physical properties in an achiral environment, they can react differently with chiral reagents or catalysts. This is because the transition state for the reaction will have a different steric and electronic environment depending on which enantiomer is reacting. For example, in biological systems, enzymes are chiral and highly specific. They will often react with only one enantiomer of a substrate, ignoring the other. This is because the active site of the enzyme is shaped to fit only one specific 3D arrangement of atoms. If the wrong enantiomer is presented, it cannot fit into the active site, and no reaction occurs. This is a dramatic example of structure determining reactivity, where the 3D shape is the key to the reaction's success.
Even in non-biological settings, stereochemistry affects the outcome of reactions. In addition reactions to double bonds, the reagent can approach from either face of the double bond. If the molecule is achiral, both faces are equivalent, and a racemic mixture of products is formed. However, if the molecule is chiral, the two faces are diastereotopic and have different steric environments. One face may be more hindered than the other, leading to preferential attack on the less hindered face. This results in diastereoselectivity, where one stereoisomer is formed in greater amounts than the other. This selectivity is a direct consequence of the molecule's existing stereochemistry. By understanding the 3D structure of the starting material, chemists can predict and control the stereochemical outcome of the reaction, which is essential for the synthesis of complex molecules like pharmaceuticals.
The results
Structural and stereoisomerism
Isomers are distinct compounds sharing an identical molecular formula. Constitutional (structural) isomers differ in atomic connectivity — which atom is bonded to which — and subdivide into chain isomers (different carbon-skeleton branching), positional isomers (a functional group at a different position on the same skeleton), and functional-group isomers (an entirely different functional group). Stereoisomers share both formula and connectivity, differing only in three-dimensional spatial arrangement: geometric (cis/trans) isomers, from restricted rotation about a double bond or ring, and optical isomers (enantiomers), from chirality (treated fully in chirality-optical-activity).
Chirality and optical activity
A chiral molecule is non-superimposable on its own mirror image — most commonly because it contains a carbon bonded to four different substituents (a stereocentre). The two mirror-image forms (enantiomers) share identical ordinary physical properties (melting point, boiling point, density) but rotate the plane of plane-polarised light by equal magnitude in opposite directions, a measurable property called optical activity; a \(50{:}50\) mixture of both enantiomers (a racemic mixture) shows zero net rotation, since the two contributions cancel exactly.
A common misconception is that steric hindrance is the only factor determining reactivity. In reality, electronic effects often dominate. For example, a sterically hindered carbonyl might still be more reactive than a less hindered one if it is more electron-poor. Always consider both steric and electronic factors when predicting reactivity. C
Worked example
Problem. With concentrated HCl, 2-methylpropan-2-ol (tert-butanol) gives its chloride within minutes at room temperature, while butan-1-ol hardly reacts without a catalyst such as ZnCl2. Explain the difference, and estimate the rate ratio at 298 K if the activation energy for the tertiary alcohol is 12.5 kJ mol-1 lower (same pre-exponential factor).
- Both alcohols are first protonated on oxygen, turning –OH into the good leaving group –OH2+.
- The tertiary oxonium ion loses water to give a tertiary carbocation, stabilised by three alkyl groups (inductive donation and hyperconjugation): an SN1 pathway with a fairly low barrier.
- A primary carbocation is far too unstable to form, so butan-1-ol must react by SN2, with Cl− attacking the carbon from the back; Cl− is a weak nucleophile in this strongly acidic, aqueous medium, so the reaction is slow.
- Arrhenius ratio for a 12.5 kJ mol-1 lower barrier: \(\dfrac{k_{\text{tert}}}{k_{\text{prim}}} = \exp\!\left(\dfrac{12\,500}{8.314 \times 298}\right) = e^{5.045}\).
- So \(k_{\text{tert}}/k_{\text{prim}} \approx 155\): even a modest difference in barrier height gives a two-orders-of-magnitude difference in rate, and the real difference between these two alcohols is larger still.
Units check. \(\Delta E_a\) in J mol-1 divided by \(RT\) in J mol-1 is dimensionless, so the rate ratio is a pure number.
Three quick tests
- Why does a tertiary alkyl halide undergo elimination rather than substitution with a bulky base?
Answer
The bulky base cannot access the backside of the carbon for SN2, and the steric hindrance favours the E2 pathway where the base abstracts a proton from a less hindered beta-carbon. - How does the presence of a nitro group on a benzene ring affect the reactivity of the ring towards electrophilic substitution?
Answer
The nitro group is electron-withdrawing, which deactivates the ring towards electrophilic substitution by reducing the electron density on the ring carbons. - Why do enantiomers react at different rates with a chiral catalyst?
Answer
The chiral catalyst creates a diastereomeric transition state for each enantiomer, which have different energies due to steric and electronic interactions, leading to different activation energies and thus different rates.
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Every lecture and every result in this unit, with prerequisites and threads.
Lecture notes checked line by line by the editor; every number in the worked example was recomputed.