Difficulty: Intermediate to Advanced | Prerequisites: IUPAC nomenclature, stereochemistry (R/S), conformational analysis
Nucleophilic substitution reactions replace a leaving group on a carbon with a nucleophile. The two mechanisms, SN2 (one-step, backside attack) and SN1 (two-step, via carbocation), differ in their rate laws, stereochemical outcomes and preferred conditions. This set of notes also covers the practical synthesis skills tested on the exam: choosing reagents and solvents, tosylation to convert a poor leaving group into a good one, and the Williamson ether synthesis.
SN2 (bimolecular nucleophilic substitution)
A one-step mechanism in which the nucleophile attacks the electrophilic carbon at the same time as the leaving group departs. The rate depends on the concentration of both the substrate and the nucleophile: rate = k[substrate][nucleophile].
In simple terms, everything happens at once, in one concerted step.
SN1 (unimolecular nucleophilic substitution)
A two-step mechanism. First, the leaving group departs to form a carbocation intermediate. Then the nucleophile attacks the carbocation. The rate depends only on the substrate concentration: rate = k[substrate].
Think of it as the leaving group walking away first, leaving behind a flat, positively charged carbon that the nucleophile then attacks from either side.
Nucleophile
A species with a lone pair or pi electrons that attacks an electrophilic carbon. Strong nucleophiles (e.g. NaOH, NaSCH₃, NaCN) favour SN2. Weak nucleophiles (e.g. H₂O, CH₃OH) favour SN1.
Leaving group
The group that departs with the bonding electrons. Good leaving groups are stable after they leave: halides (I⁻ > Br⁻ > Cl⁻ >> F⁻), tosylate (OTs), water (after protonation of OH).
Carbocation
A positively charged carbon intermediate formed in SN1 reactions. Stability order: 3° > 2° > 1° > methyl, due to hyperconjugation and inductive effects. More stable carbocations form more readily, so SN1 is favoured at tertiary carbons.
Walden inversion (backside attack)
In SN2, the nucleophile attacks from the side opposite the leaving group, causing the configuration at the carbon to invert (R becomes S, or vice versa).
Racemisation
In SN1, the planar carbocation can be attacked from either face, producing a roughly equal mixture of both configurations (a racemic product).
Polar protic solvent
A solvent that can donate hydrogen bonds (e.g. water, methanol, ethanol). Polar protic solvents stabilise carbocations and favour SN1. They slow down SN2 by solvating the nucleophile.
Polar aprotic solvent
A solvent that dissolves ions but cannot donate hydrogen bonds (e.g. acetone, DMF, DMSO). Polar aprotic solvents leave the nucleophile "naked" and reactive, favouring SN2.
Tosylate (OTs)
The p-toluenesulfonyl group, introduced by treating an alcohol with tosyl chloride (TsCl) and a base such as pyridine. Converting -OH to -OTs turns a poor leaving group into an excellent one, without changing the configuration at the carbon (no bond to the stereogenic centre is broken).
Williamson ether synthesis
A reaction in which an alkoxide ion (formed by treating an alcohol with NaH or another strong base) attacks an alkyl halide or tosylate via SN2, producing an ether. Because it proceeds by SN2, primary substrates work best.
NaH (sodium hydride)
A strong, non-nucleophilic base. It deprotonates an alcohol to form an alkoxide but does not act as a nucleophile itself. Used to generate the alkoxide in the Williamson ether synthesis.
One concerted step: the nucleophile attacks the carbon from the back side (180° from the leaving group) at the same time as the leaving group departs.
Rate law: rate = k[substrate][nucleophile]. Both concentrations matter.
Stereochemistry: complete inversion of configuration at the carbon under attack (Walden inversion).
Substrate preference: methyl > primary > secondary. Tertiary substrates essentially do not undergo SN2 because of steric hindrance around the carbon.
Leaving group quality matters: better leaving group = faster reaction (I⁻ > Br⁻ > Cl⁻).
Favoured by strong nucleophiles and polar aprotic solvents (acetone, DMF, DMSO).
Two steps: (1) the leaving group departs to form a carbocation, (2) the nucleophile attacks the carbocation.
Rate law: rate = k[substrate]. Only the substrate concentration affects the rate. Doubling the nucleophile concentration has no effect on the rate.
Stereochemistry: the carbocation is sp² (planar), so the nucleophile can attack from either face. The product is a roughly racemic mixture (some preference for inversion due to ion pairing is possible, but the exam typically treats it as racemisation).
Substrate preference: tertiary > secondary >> primary. The more stable the carbocation intermediate, the faster the reaction.
Favoured by weak nucleophiles (H₂O, ROH) and polar protic solvents (water, methanol), which stabilise the carbocation and the departing anion.
Exam example (Q III-A): comparing a primary alkyl chloride vs a primary alkyl bromide reacting with ethanol. Bromide is a better leaving group than chloride, so the bromide reacts faster. However, with a weak nucleophile like ethanol and a substrate that could be benzylic or allylic, SN1 may also be relevant.
Exam example (Q III-B): best nucleophile for 3-methyl-3-chloroheptane (a tertiary substrate). This will react by SN1 regardless. H₂O vs NaOH: NaOH is a strong nucleophile/base, but a tertiary substrate undergoing SN1 does not benefit from a strong nucleophile (and NaOH may cause elimination instead). H₂O is sufficient for the SN1 substitution, but consider that NaOH could push toward elimination. On exam terms, H₂O is the better nucleophile for substitution here.
Exam example (Q III-C): best solvent for an SN2 reaction (ammonia reacting with a secondary alkyl bromide). Acetone (polar aprotic) is better than methanol (polar protic) because it does not solvate and slow down the nucleophile.
For SN2: rate = k[RX][Nu]. If you double [RX] and halve [Nu], the rate stays the same (2 x 0.5 = 1, no change).
For SN1: rate = k[RX]. The nucleophile concentration does not appear. Doubling [RX] doubles the rate.
Exam example (Q10): an SN2 reaction with NaSCH₃ and a primary alkyl bromide. Doubling the halide and halving the nucleophile: rate = k(2[RX])(0.5[Nu]) = k[RX][Nu]. The rate stays the same (answer C).
SN2 with a chiral substrate: one product, inverted configuration.
SN1 with a chiral substrate: mixture of both configurations (racemic or close to it). If the starting material is a single enantiomer, expect both enantiomers of the product.
Exam example (Q12): a secondary alkyl chloride reacting with methanol. If the substrate is tertiary or gives a stable carbocation, SN1 dominates, and you get both retention and inversion products (both ether diastereomers/enantiomers). If the substrate is secondary and reacting with a weak nucleophile, SN1 is likely, giving a mixture.
Exam example (Q III-D): a secondary allylic chloride reacting with MeOH. The carbocation intermediate can be stabilised by resonance (allylic system), placing positive charge on multiple carbons. The nucleophile can then attack at each of those carbons, giving multiple substitution products.
When drawing the mechanism: (1) show loss of Cl⁻ to form the allylic carbocation, (2) draw all resonance structures, (3) show MeOH attacking each electrophilic carbon, (4) show loss of a proton (deprotonation by Cl⁻ or another MeOH) to give each neutral ether product.
Alcohols are poor substrates for substitution because HO⁻ is a terrible leaving group. Two strategies fix this:
Tosylation: treat the alcohol with TsCl/pyridine to convert -OH to -OTs (an excellent leaving group). This does not break the C-O bond at the stereogenic centre, so configuration is retained.
Williamson ether synthesis: use NaH to deprotonate the alcohol, forming an alkoxide (RO⁻). The alkoxide then acts as a nucleophile in an SN2 reaction with an alkyl halide or tosylate to form an ether.
Exam example (Problem IV): cyclopentanol is treated with TsCl/pyridine to give cyclopentyl tosylate. Separately, the same alcohol is treated with NaH to form the cyclopentyl alkoxide. The alkoxide can then react with an electrophile via SN2. When the tosylate is treated with NaOCH₃ in DMF (a polar aprotic solvent), SN2 gives inversion: the methoxy group replaces the tosylate with inverted configuration.
Exam example (Problem II-D): a drug molecule has multiple hydroxyl groups. To selectively modify just one, consider sterics and electronics. Primary alcohols react faster than secondary or tertiary alcohols in SN2-type reactions. A hindered (sterically crowded) alcohol may not react at all under mild conditions.
Reagent choice matters: acetic anhydride or acetyl chloride with pyridine to form an ester. The least hindered OH reacts preferentially.
Students often think that SN1 reactions are "faster" than SN2 because they involve a more substituted substrate. Speed depends on conditions. Under polar aprotic conditions with a strong nucleophile, SN2 on a primary substrate can be very fast.
A common error is applying the SN2 rate law to an SN1 reaction. If the exam says "what happens to the rate when you change nucleophile concentration" and the substrate is tertiary, the answer is nothing, because the nucleophile does not appear in the SN1 rate law.
Students confuse the roles of NaH and NaOH. NaH is a base only (deprotonates the alcohol). NaOH is both a base and a nucleophile. For Williamson ether synthesis you use NaH to make the alkoxide cleanly, without competing nucleophilic attack.
Tosylation is often confused with substitution. TsCl/pyridine converts -OH to -OTs in a single step without breaking the C-O bond at a stereocentre. No inversion occurs at this stage. Inversion (or racemisation) happens later, when the tosylate undergoes SN2 (or SN1).
⚠️ Rate-law questions are nearly guaranteed. Know the SN1 and SN2 rate expressions cold and be ready to calculate what happens when concentrations change.
⚠️ "Draw the mechanism" questions (like Q III-D) require arrows, intermediates and all products. For SN1, show the carbocation, its resonance structures and nucleophilic attack at each electrophilic carbon. For SN2, show the single concerted step with a clear backside attack arrow.
⚠️ Solvent choice questions test whether you know polar protic vs polar aprotic. Polar aprotic = SN2 friendly. Polar protic = SN1 friendly.
⚠️ Multi-step synthesis (Problem IV) asks you to connect tosylation, alkoxide formation and Williamson ether synthesis in sequence. Practise working through these reaction maps, filling in reagents or products at each step.
True or False: In an SN2 reaction, the rate depends only on the concentration of the substrate. (False. SN2 rate = k[substrate][nucleophile]. Both matter.)
Fill in the blank: SN2 produces ___ of configuration at the carbon, while SN1 produces ___. (inversion; racemisation)
True or False: Polar protic solvents favour SN2. (False. Polar protic solvents favour SN1. Polar aprotic solvents favour SN2.)
Fill in the blank: TsCl/pyridine converts an alcohol to a ___, which is a good leaving group. (tosylate, OTs)
True or False: NaH is a strong nucleophile. (False. NaH is a strong, non-nucleophilic base. It deprotonates; it does not attack carbon.)
Q: An SN2 reaction has rate = k[RX][Nu]. The halide concentration is doubled and the nucleophile concentration is halved. What happens to the rate?
A: New rate = k(2[RX])(0.5[Nu]) = k[RX][Nu]. The rate stays the same.
Q: A secondary alkyl chloride reacts with methanol. What is the likely mechanism and what stereochemical outcome do you expect?
A: Methanol is a weak nucleophile and a polar protic solvent. These conditions favour SN1. The carbocation intermediate is planar, so methanol attacks from both faces, giving a mixture of retention and inversion products (approximately racemic).
Q: Which is the better solvent for an SN2 reaction between NH₃ and a secondary alkyl bromide: acetone or methanol?
A: Acetone. It is a polar aprotic solvent, which does not solvate the nucleophile and leaves it free to attack the substrate. Methanol (polar protic) would slow the nucleophile by hydrogen-bonding to it.
Q: Cyclopentanol is treated with TsCl/pyridine, then the product is treated with NaOCH₃ in DMF. What is the final product and its stereochemistry?
A: TsCl/pyridine converts the alcohol to cyclopentyl tosylate with retention of configuration (no bond to the stereocentre is broken). NaOCH₃ in DMF (a strong nucleophile in a polar aprotic solvent) then performs SN2 on the tosylate, giving cyclopentyl methyl ether with inversion of configuration relative to the original alcohol.
Q: A secondary allylic chloride reacts with MeOH. Draw the mechanism accounting for all products.
A: Step 1, ionisation: the chloride departs, forming an allylic carbocation. Step 2, resonance: draw both resonance contributors showing the positive charge on the two carbons of the allylic system. Step 3, nucleophilic attack: MeOH attacks each positively charged carbon in separate pathways. Step 4, deprotonation: loss of H⁺ gives the two (or more) neutral ether products. Each attack gives a different regiochemical product.
Substitution reactions connect directly to elimination reactions (E1, E2), which compete under many of the same conditions. Strong bases with hindered substrates favour elimination over substitution. Chem 225 typically tests your ability to predict whether a given set of conditions leads to substitution, elimination or a mixture of both.
The stereochemical concepts here (inversion, racemisation) build on the R/S assignment skills from stereochemistry. If you struggle with SN2 stereochemistry questions, revisit CIP priorities and three-dimensional drawing conventions first.
Tosylation and ether synthesis reappear in more advanced synthesis problems later in the course, often as steps in multi-step sequences.
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