Difficulty: Intermediate | Prerequisites: Part 1 of these notes (S_N1 vs S_N2 Fundamentals), Chapter 5 substitution from alcohols, basic stereochemistry (R/S assignments).
Knowing that a reaction is S_N1 or S_N2 is only half the job. You also need to draw the mechanism step by step, predict the correct product (including stereochemistry and any rearrangements), and sketch the energy diagram that goes with it. This is where the exam separates students who memorised the rules from those who understand what is happening at the molecular level. This set of notes walks through worked examples from the CHEM 2301 Week 10 problem set, covering S_N2 product prediction, "no reaction" recognition, tosylation, S_N1 with carbocation rearrangement, and energy diagrams for multi-step mechanisms.
S_N2 is one step (backside attack, inversion). S_N1 is two steps (leaving group departs to form a carbocation, then the nucleophile attacks from either face). S_N1 carbocations can rearrange via hydride or alkyl shifts to reach greater stability, which changes the product's carbon skeleton. Energy diagrams for S_N1 show two transition-state humps with a carbocation intermediate valley between them.
Transition state
A fleeting, highest-energy arrangement of atoms along the reaction pathway. It cannot be isolated. In S_N2, the single transition state has partial bonds to both the nucleophile and the leaving group. In S_N1, there are two transition states: one for leaving-group departure and one for nucleophilic attack. Think of it as the top of the hill the reaction must climb over.
Intermediate
A species that forms between two transition states. Unlike a transition state, an intermediate sits in an energy valley and has a finite (though often short) lifetime. The carbocation in S_N1 is the classic example.
Activation energy (E_a)
The energy difference between the reactants (or intermediate) and the next transition state. A higher E_a means a slower step. The rate-determining step has the largest E_a.
Energy diagram (reaction coordinate diagram)
A plot of potential energy (y-axis) against reaction progress (x-axis). It shows reactants, products, transition states (peaks), and intermediates (valleys). For an exothermic reaction, the products sit lower than the reactants.
Carbocation rearrangement
A shift of a hydrogen (hydride shift) or an alkyl group (alkyl shift, including ring expansion) from an adjacent carbon to the carbocation centre, producing a more stable carbocation. This changes the carbon skeleton of the product.
1,2-Hydride shift
A hydrogen atom with its bonding electrons migrates from a carbon adjacent to the carbocation to the carbocation carbon itself. The result is that the positive charge moves one carbon over. In simple terms, a nearby H hops across to stabilise the positive charge.
1,2-Alkyl shift (ring expansion)
An alkyl group (or a C-C bond within a ring) migrates to the carbocation centre. When this happens inside a ring, the ring expands by one carbon. This is how a five-membered ring can become a six-membered ring during S_N1.
Walden inversion
The complete inversion of stereochemistry at the electrophilic carbon during S_N2. If the starting material is (R), the product is (S), and vice versa.
Racemisation
Formation of equal (or near-equal) amounts of both enantiomers. This occurs in S_N1 because the planar carbocation intermediate can be attacked from either face.
Example A: Alkyl chloride + NaSR (thiolate)
A secondary alkyl chloride bearing a cyclopentane ring is treated with sodium thiolate (NaSR). Cl⁻ is a good leaving group, the thiolate is a strong, charged nucleophile, and the substrate is accessible to backside attack. This proceeds via S_N2. The product is the thioether, with inversion of configuration at the electrophilic carbon.
Key reasoning: strong nucleophile + secondary substrate + good leaving group = S_N2.
Example B: Alcohol + NaCl in DMSO
A primary alcohol is treated with NaCl in DMSO. No reaction occurs. The hydroxyl group (-OH) is a poor leaving group. DMSO is aprotic, so there is no acid to protonate the -OH into water (which would be a viable leaving group). Cl⁻ is a reasonable nucleophile, but it has nothing to displace.
Key reasoning: poor leaving group under these conditions = no reaction, regardless of nucleophile strength.
Example C: Alcohol + TsCl + pyridine (tosylation)
A secondary alcohol is treated with tosyl chloride (TsCl) in the presence of pyridine. The TsCl reacts with the -OH group to form a tosylate ester (-OTs). Pyridine acts as a base to mop up the HCl produced. The result is that the poor leaving group -OH is converted into the excellent leaving group -OTs. The C-O bond at the stereogenic centre is not broken during tosylation, so the configuration at carbon is retained.
Key reasoning: tosylation is an activation step. The substitution itself happens in a separate reaction using the tosylate as substrate.
The Week 10 problem set features two important S_N1 examples. Here is the step-by-step logic for each.
Example 1: Secondary alkyl chloride + methanol (with ring expansion)
Starting material: a secondary alkyl chloride on a cyclopentane ring. The nucleophile is methanol (CH₃OH), a weak, neutral nucleophile.
Step 1, leaving-group departure: Cl⁻ leaves, forming a secondary carbocation on the ring.
Step 2, 1,2-alkyl shift (ring expansion): A C-C bond adjacent to the carbocation migrates so that the five-membered ring expands to a six-membered ring. The carbocation is now tertiary, which is more stable. This is the rearrangement that changes the carbon skeleton.
Step 3, nucleophilic capture: Methanol (the weak nucleophile) attacks the tertiary carbocation from either face of the now-planar cation.
Step 4, deprotonation: Another molecule of methanol (acting as a base) removes the proton from the oxonium ion, yielding the final methyl ether product.
The clue in the problem was the change in carbon skeleton: the starting material had a five-membered ring, but the product had a six-membered ring. A skeleton change signals a carbocation rearrangement, which only happens in S_N1.
Two products form (both methyl ethers on the expanded ring) because the planar carbocation can be attacked from either face.
Example 2: Tertiary alkyl bromide + NaCl in protic solvent
Starting material: a tertiary alkyl bromide. NaCl provides Cl⁻ as the nucleophile, and the solvent is polar protic (e.g. water).
Step 1, leaving-group departure: Br⁻ leaves, forming a stable tertiary carbocation.
Step 2, nucleophilic capture: Cl⁻ attacks the carbocation to form the tertiary alkyl chloride.
Byproduct: NaBr.
No rearrangement occurs here because the carbocation is already tertiary (the most stable class for simple alkyl systems). The starting structure could also be drawn with a 1,2-alkyl shift to show an alternate pathway, but the tertiary carbocation does not need to rearrange.
The protic solvent stabilises both the carbocation intermediate and the departing bromide through hydrogen bonding, supporting the S_N1 pathway.
Drawing an energy diagram is a standard exam question. Here is how to construct one for the S_N1 reaction of a tertiary alkyl bromide with NaCl (exothermic overall).
Axes
Y-axis: potential energy
X-axis: reaction coordinate (reaction progress)
Shape: two humps with a valley
S_N1 has two steps, so the diagram has two transition-state peaks separated by an intermediate valley.
Reactants sit at an initial energy level on the left.
Transition state 1 (highest point): This is the rate-determining step, leaving-group departure. The Br-C bond is partially broken, with partial negative charge (delta minus) developing on Br and partial positive charge (delta plus) developing on the carbon. Draw this as the taller of the two peaks.
Intermediate (valley): The carbocation intermediate sits in a local energy minimum between the two peaks. It is higher in energy than either reactants or products, but lower than either transition state.
Transition state 2 (second, shorter peak): The nucleophile (Cl⁻) attacks the carbocation. The transition state has partial bonds to both Cl and the carbon, with partial charges on each. This peak is shorter than the first because the step has a smaller activation energy.
Products sit lower than reactants (exothermic).
Activation energies to label
E_a(1): the energy difference from reactants to transition state 1. This is the larger activation energy and corresponds to the rate-determining step.
E_a(2): the energy difference from the intermediate to transition state 2. This is smaller.
Transition-state structures to draw
TS1 (forming carbocation): Show the C-Br bond partially broken with dashed lines, delta minus on Br, delta plus on C, enclosed in square brackets with a double-dagger symbol.
TS2 (nucleophile attacks): Show Cl partially bonded to C with dashed lines, delta minus on Cl, delta plus on C, again in square brackets with a double-dagger.
Comparison: S_N2 energy diagram
For contrast, S_N2 has only one step and therefore one transition-state peak with no intermediate valley. The single transition state shows the nucleophile and leaving group both partially bonded to the central carbon (pentacoordinate). This is simpler to draw but worth knowing so you do not confuse the two.
S_N2 reactions are used in pharmaceutical synthesis to introduce specific functional groups with precise stereochemical control. The predictable inversion of configuration makes S_N2 a reliable tool for building single-enantiomer drugs.
Tosylation followed by nucleophilic substitution is a common two-step sequence in medicinal chemistry when the starting material is an alcohol. The same logic applies in industrial synthesis of agrochemicals and specialty chemicals.
Carbocation rearrangements (S_N1 pathway) explain why certain terpene biosynthesis pathways produce ring-expanded natural products. Understanding these shifts helps biochemists trace how complex molecules like steroids and terpenes are assembled in living organisms.
Students draw S_N1 energy diagrams with only one hump. S_N1 has two steps, so there must be two transition-state peaks with an intermediate valley between them.
Students place the intermediate higher than the transition states. The intermediate is a local minimum (valley), not a peak. It is higher than reactants or products, but lower than either transition state.
Students forget to label E_a for each step separately. Each step has its own activation energy, measured from the starting point of that step (reactants for step 1, intermediate for step 2) to the top of its transition state.
Students assume all carbocations rearrange. Rearrangement only occurs when a more stable carbocation can form. A tertiary carbocation already at maximum stability for simple alkyl systems will not rearrange.
Students draw the transition-state structure for S_N1 as if it were S_N2. In S_N1 TS1, only the leaving group is partially bonded to carbon (it is departing). The nucleophile is not present in TS1.
⚠️ Drawing a full stepwise mechanism with curved arrows is a core exam skill. Every arrow must start from an electron source (lone pair or bond) and point to where those electrons go.
⚠️ If the carbon skeleton changes between starting material and product, the mechanism is S_N1 with a carbocation rearrangement. This is a common exam clue.
⚠️ Energy diagrams are tested both as sketches (draw and label) and as interpretation questions (identify the rate-determining step, explain why one step is faster). Know both directions.
⚠️ Transition-state structures in brackets with the double-dagger symbol are frequently required. Show partial bonds (dashed lines) and partial charges (delta plus, delta minus).
⚠️ For S_N1 in protic solvents, remember to justify your solvent choice: protic solvents stabilise ionic intermediates through hydrogen bonding.
True or False: An S_N1 energy diagram has one transition-state peak. (False, it has two, one per step.)
Fill in the blank: The rate-determining step of S_N1 is ______ departure. (Leaving-group.)
True or False: A 1,2-hydride shift moves a hydrogen from the carbocation carbon to an adjacent carbon. (False, it moves a hydrogen from an adjacent carbon to the carbocation carbon.)
Fill in the blank: If the carbon skeleton of the product differs from that of the starting material, the mechanism is ______ with a carbocation rearrangement. (S_N1.)
True or False: In an S_N1 energy diagram for an exothermic reaction, the products are drawn at a higher energy level than the reactants. (False, products are lower for an exothermic reaction.)
Q: A secondary alkyl chloride on a five-membered ring reacts with methanol. The products are methyl ethers on a six-membered ring. Draw or describe the mechanism and explain the ring expansion.
A: This is S_N1. Cl⁻ departs to form a secondary carbocation. A 1,2-alkyl shift (migration of a ring C-C bond) expands the five-membered ring to a six-membered ring, generating a more stable tertiary carbocation. Methanol attacks the carbocation from either face, and a deprotonation step yields the methyl ether. The ring expansion is the evidence for a carbocation rearrangement.
Q: Sketch an energy diagram for the S_N1 reaction of a tertiary alkyl bromide with Cl⁻ in water. Assume the reaction is exothermic. Label all key features.
A: Draw two humps. The y-axis is potential energy, x-axis is reaction coordinate. Reactants on the left, products lower on the right (exothermic). The first, taller peak is TS1 (leaving-group departure, rate-determining). The valley between peaks is the carbocation intermediate. The second, shorter peak is TS2 (nucleophilic attack). Label E_a(1) from reactants to TS1 and E_a(2) from intermediate to TS2. Draw the TS structures in brackets: TS1 has a partial C-Br bond breaking (delta minus on Br, delta plus on C); TS2 has a partial C-Cl bond forming (delta minus on Cl, delta plus on C).
Q: Why does the problem set say "no reaction" when an alcohol is treated with NaCl in DMSO?
A: -OH is a poor leaving group. In DMSO (aprotic, no acid), there is nothing to protonate the -OH into water or to convert it into a better leaving group. Cl⁻ cannot displace -OH regardless of its nucleophilic strength.
Q: What is the purpose of pyridine in the reaction of an alcohol with TsCl?
A: Pyridine is a base. It absorbs the HCl released during tosylation, driving the reaction forward and preventing acidic side reactions. It does not act as the nucleophile.
Energy diagrams appear again with elimination reactions (E1 and E2) and later with addition reactions to alkenes. The same principles apply: count the steps, draw that many humps, identify the rate-determining step as the highest barrier.
Carbocation rearrangements are not limited to substitution. They also occur in E1 eliminations and in certain addition reactions (e.g. Markovnikov additions involving carbocation intermediates). Once you learn to spot a rearrangement here, you will recognise it everywhere.
The tosylation technique connects to synthesis planning later in the course. Whenever a retrosynthesis calls for replacing -OH with another group via substitution, tosylation is typically the enabling step.
Related Terms / Search Tags
SN1 mechanism, SN2 mechanism, energy diagram, reaction coordinate diagram, transition state, intermediate, activation energy, carbocation rearrangement, hydride shift, alkyl shift, ring expansion, Walden inversion, racemisation, tosylation, TsCl, pyridine, leaving group, no reaction, stereochemistry, curved arrow mechanism, rate-determining step, exothermic, endothermic, CHEM 2301, organic chemistry 1, University of Minnesota, substitution reactions alkyl halides