Source: Chemistry 225 Exam 2, University of Michigan
Difficulty: Intermediate | Prerequisites: Stereochemistry (R/S assignments, Fischer projections), Lewis acid-base theory, and basic organic functional groups.
Nucleophilic substitution is one of the two central reaction families in Organic Chemistry II (the other being elimination). These reactions describe how a nucleophile replaces a leaving group on a carbon, and they divide into two mechanisms (SN1 and SN2) with very different requirements for substrate structure, nucleophile strength, solvent, and stereochemical outcome. Understanding when each mechanism operates, and what happens to the stereocentre during the reaction, is essential for the entire second half of the course. This material builds directly on the stereochemistry you have already studied: you need to assign configurations before and after reactions to determine whether inversion or retention occurred.
SN1 and SN2 are two mechanisms by which a nucleophile replaces a leaving group on carbon. SN2 is a one-step, backside-attack process that inverts stereochemistry and works best on unhindered (primary/methyl) substrates with strong nucleophiles in polar aprotic solvents. SN1 is a two-step process through a carbocation intermediate, leading to racemisation, favoured by tertiary substrates, weak nucleophiles, and polar protic solvents.
SN2 (Substitution, Nucleophilic, Bimolecular)
A one-step mechanism in which the nucleophile attacks the electrophilic carbon at the same time the leaving group departs. The rate depends on the concentration of both the substrate and the nucleophile: rate = k[substrate][nucleophile].
In simple terms, this means the nucleophile shoves the leaving group out from the back side in a single, concerted step.
SN1 (Substitution, Nucleophilic, Unimolecular)
A two-step mechanism. First, the leaving group departs to form a carbocation. 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 on its own, leaving a flat, positively charged carbon that the nucleophile then approaches from either face.
Nucleophile
A Lewis base that donates an electron pair to an electrophilic (electron-poor) carbon. Strong nucleophiles include HO-, CN-, N3-, RS-, and halides in polar aprotic solvents.
In simple terms, this means the "attacking" species that brings electrons to form a new bond.
Leaving Group
The group that departs with the bonding electrons during substitution. Good leaving groups are weak bases (stable after departure). Examples: Cl-, Br-, I-, TsO- (tosylate), H2O.
Think of it as the group that is comfortable leaving because it can stabilise the negative charge it takes with it.
Tosylate (OTs)
A sulfonate ester leaving group, formed by treating an alcohol with tosyl chloride (TsCl) and a base such as pyridine. Converts the poor leaving group -OH into the excellent leaving group -OTs without changing the configuration at the carbon bearing the oxygen.
In simple terms, this means you swap the -OH for an -OTs, which is far easier for a nucleophile to displace.
Inversion of Configuration (Walden Inversion)
The stereochemical outcome of an SN2 reaction: the configuration at the carbon under attack flips from R to S (or S to R). This happens because the nucleophile attacks from the back side, opposite to the leaving group.
Think of it as an umbrella flipping inside out in the wind.
Retention of Configuration
The configuration stays the same. This occurs when the bond to the stereocentre is not broken (e.g. tosylation of an alcohol: the C-O bond to the oxygen is not broken, so the carbon's configuration is preserved).
Racemisation
Loss of optical purity. In SN1, the planar carbocation intermediate can be attacked from either face, giving roughly equal amounts of R and S products (a racemic mixture).
HOMO (Highest Occupied Molecular Orbital)
The highest-energy orbital that contains electrons. In nucleophilic substitution, the nucleophile's HOMO donates electrons into the substrate's LUMO. The HOMO of the nucleophile is typically a lone pair (e.g. sp3 on nitrogen in N3-).
In simple terms, this means the orbital on the attacking species that provides the electrons for the new bond.
LUMO (Lowest Unoccupied Molecular Orbital)
The lowest-energy empty orbital on the substrate. In SN2, this is the sigma-antibonding orbital (sigma*) of the C-leaving group bond. The nucleophile's electrons flow into this orbital, which weakens and eventually breaks the C-LG bond.
Backside Attack
The nucleophile approaches the electrophilic carbon from the side directly opposite the leaving group (180 degrees). This geometry is required for SN2 because the nucleophile must overlap with the sigma* orbital of the C-LG bond.
Polar Aprotic Solvent
A solvent that is polar (dissolves ionic compounds) but does not have an O-H or N-H bond, so it cannot hydrogen-bond to and stabilise anions. Examples: acetone, DMF, DMSO, acetonitrile. These solvents leave nucleophilic anions "naked" and reactive, favouring SN2.
Polar Protic Solvent
A solvent with O-H or N-H bonds that can hydrogen-bond to anions, stabilising them and reducing their nucleophilicity. Examples: water, ethanol, methanol, acetic acid. Polar protic solvents favour SN1 by stabilising the carbocation intermediate and the departing leaving group.
One step, concerted: nucleophile attacks and leaving group departs simultaneously.
Rate = k[substrate][nucleophile]. Both concentrations matter.
Stereochemistry: always inversion of configuration (Walden inversion). The nucleophile attacks from the back side (180 degrees from the leaving group).
Substrate requirements: works best on methyl and primary substrates. Secondary substrates can undergo SN2 but more slowly. Tertiary substrates essentially do not undergo SN2, because the three bulky groups block backside attack.
The transition state has five groups around the central carbon (trigonal bipyramidal geometry), with the nucleophile entering and the leaving group departing on opposite sides.
Key factors favouring SN2:
Strong, unhindered nucleophile (e.g. CN-, N3-, CH3O-, RS-)
Polar aprotic solvent (acetone, DMF, DMSO) that does not solvate the nucleophile heavily
Good leaving group (I- > Br- > Cl- > F- for halides; OTs is excellent)
Unhindered substrate (methyl > primary > secondary; tertiary blocked)
Two steps. Step 1 (rate-determining): the leaving group departs to form a carbocation. Step 2: the nucleophile attacks the carbocation.
Rate = k[substrate]. Only the substrate concentration affects the rate; the nucleophile is not involved in the slow step.
Stereochemistry: the carbocation is sp2-hybridised (planar). The nucleophile can attack from either face, giving a mixture of retention and inversion. A purely SN1 process gives racemisation (50/50 R and S), though in practice there is often a slight excess of inversion.
Substrate requirements: works best on tertiary substrates, which form the most stable carbocations. Secondary substrates can go SN1 under the right conditions. Primary and methyl substrates do not form stable carbocations and essentially never undergo SN1.
Key factors favouring SN1:
Tertiary (or benzylic/allylic) substrate that forms a stable carbocation
Weak nucleophile (e.g. H2O, ROH) or no strong nucleophile present
Polar protic solvent (water, ethanol) that stabilises the carbocation and the departing leaving group through solvation
Good leaving group (same ranking as SN2)
Nucleophile strength (for SN2):
Negatively charged species are stronger nucleophiles than their neutral counterparts (HO- is stronger than H2O).
Within the same row of the periodic table, nucleophilicity increases with basicity: NH2- > HO- > F-.
Down a column in polar protic solvents, nucleophilicity increases with size (larger atoms are less tightly solvated): I- > Br- > Cl- > F-. In polar aprotic solvents this trend can reverse, because solvation no longer dominates.
Steric hindrance decreases nucleophilicity: CH3O- is a better nucleophile than (CH3)3CO-.
Solvent effects:
Polar aprotic solvents (acetone, DMF, DMSO): do not hydrogen-bond to nucleophilic anions. Nucleophiles remain "naked" and highly reactive. Favours SN2.
Polar protic solvents (H2O, EtOH, MeOH): hydrogen-bond to anions, reducing their nucleophilicity. Stabilise cations through solvation. Favours SN1.
Leaving group ability:
Good leaving groups are weak bases (stable anions). Ranking: I- > Br- > Cl- >> F- for halides.
Tosylate (OTs-) is an excellent leaving group, comparable to or better than bromide.
Hydroxide (HO-) and methoxide (CH3O-) are terrible leaving groups because they are strong bases. This is why alcohols cannot directly undergo SN2: you must first convert -OH to -OTs, -OMs, or protonate it to make water the leaving group.
Methyl and primary substrates: fast SN2, essentially no SN1.
Secondary substrates: can go either SN2 or SN1 depending on nucleophile and solvent. Strong nucleophile + polar aprotic solvent pushes SN2. Weak nucleophile + polar protic solvent pushes SN1.
Tertiary substrates: SN1 only. The three bulky groups block backside attack entirely, making SN2 impossible. Strong nucleophiles with tertiary substrates give elimination (E2), not substitution.
Benzylic substrates (carbon attached to an aromatic ring): can undergo SN2 (primary benzylic) or SN1 (secondary/tertiary benzylic, because the carbocation is stabilised by resonance with the ring). Benzyl chloride with CH3ONa in acetone reacts rapidly by SN2.
Vinyl and aryl substrates: essentially unreactive toward both SN1 and SN2. The sp2 carbon is not accessible for backside attack (SN2), and vinyl/aryl cations are too unstable for SN1.
Exam application: when asked which substrate reacts fastest with a given nucleophile, consider both the mechanism and the substrate's ability to participate. CH3ONa in acetone is a strong nucleophile in a polar aprotic solvent, pointing to SN2. Among the choices, benzyl chloride (primary benzylic, unhindered) reacts fastest. Cyclohexyl chloride (secondary, bulky) is slower. Phenyl and vinyl chlorides do not react at all.
The orbital picture of an SN2 reaction:
The nucleophile's HOMO (its highest occupied molecular orbital, typically a lone pair) donates electron density into the substrate's LUMO.
The substrate's LUMO is the sigma-antibonding orbital (sigma*) of the C-leaving group bond.
When the nucleophile's electrons fill the sigma* orbital, the C-LG bond weakens and breaks.
For the reaction NaN3 + CH3CH2Cl, the HOMO is the lone pair on nitrogen in N3-. This is an sp3 orbital on the terminal nitrogen that carries the negative charge. The electrons flow from this orbital into the sigma* of the C-Cl bond (the LUMO), displacing chloride.
Common exam question: "What is the HOMO in this reaction?" The answer is the nucleophile's lone pair orbital, not the sigma bond being broken. The sigma bond of C-Cl is a filled bonding orbital; the relevant empty orbital (LUMO) is its antibonding counterpart.
Forming a tosylate:
Treat an alcohol with TsCl (tosyl chloride) and a base (typically pyridine).
This replaces the -OH with -OTs.
The reaction occurs at the oxygen, not at the carbon stereocentre. The C-O bond is not broken. Therefore, the configuration at the stereocentre is retained.
Example: (S)-2-butanol + TsCl/pyridine gives (S)-2-butyl tosylate. The S configuration is preserved because the carbon's bonds were not disturbed.
Fischer projection of the tosylate: replace -OH with -OTs in the same position. Everything else stays the same.
Sequential SN2 reactions on a tosylate:
Step 1: (S)-2-butyl tosylate + NaBr (SN2, backside attack) gives (R)-2-bromobutane. Inversion of configuration.
Step 2: (R)-2-bromobutane + NaSCH2CH3 (SN2, backside attack) gives (S)-2-(ethylthio)butane. Inversion again.
Each SN2 step inverts configuration. Two successive inversions return you to the original configuration. But if asked about each step individually, each one is an inversion.
Tertiary substrates and tosylates:
2-Methyl-2-butanol + TsCl/pyridine gives the corresponding tertiary tosylate (retention at the carbon, since the C-O bond is not broken).
Tertiary tosylate + NaBr: this can still proceed (likely through SN1 or possibly a concerted pathway), though slowly. The product is the tertiary bromide.
Tertiary bromide + NaSCH2CH3: no reaction. NaSCH2CH3 is a strong nucleophile, but a tertiary substrate cannot undergo SN2 (backside attack is blocked), and SN1 is not favoured with a strong nucleophile in a polar aprotic-like setting. Strong nucleophiles with tertiary substrates typically give elimination (E2) rather than substitution.
To obtain a substitution product from a tertiary substrate, you would need to change to conditions that favour SN1: use a weak nucleophile in a polar protic solvent, or change the substrate to a less hindered one.
When a molecule has both a nucleophilic group (-OH after deprotonation) and a leaving group (-Cl, -Br) on the same chain, an intramolecular SN2 reaction can occur. The oxygen attacks the carbon bearing the halide from within the same molecule, forming a cyclic ether.
Ring size matters:
3-membered rings (epoxides): formed when the -OH and -Cl are on adjacent carbons or 1,2 apart. Fast intramolecular reaction despite the ring strain, because the geometry is favourable.
5-membered rings (tetrahydrofurans): formed when the -OH and -Cl are 1,4 apart. Five-membered rings are the most thermodynamically and kinetically favourable ring size.
6-membered rings (tetrahydropyrans): formed when the -OH and -Cl are 1,5 apart. Also quite favourable.
Exam example: a chloroalcohol (Cl on one end, OH on the other, with a double bond in between) can cyclise to give both a six-membered and a five-membered cyclic ether. The mechanism involves deprotonation of the -OH (by base or by the reaction conditions), followed by intramolecular backside attack on the C-Cl. Different ring sizes arise if the oxygen can attack different carbons along the chain, particularly if there is an alkene that allows for two possible closure points.
The key principle: intramolecular reactions are often faster than the equivalent intermolecular reaction because the nucleophile and electrophile are already tethered together, making the effective concentration very high.
Students often think that SN2 can occur on tertiary substrates if you use a strong enough nucleophile. It cannot. The steric bulk around a tertiary carbon completely blocks backside attack. A strong nucleophile with a tertiary substrate gives elimination (E2), not substitution.
Students frequently confuse the stereochemical outcome of tosylation with that of SN2. Tosylation retains configuration (the C-O bond at the stereocentre is not broken). SN2 inverts configuration (the C-LG bond at the stereocentre is broken with backside attack). These are different steps with opposite stereochemical results.
A common error is identifying the sigma bonding orbital of C-Cl as the HOMO in an SN2 reaction. The HOMO is on the nucleophile (its lone pair). The sigma* antibonding orbital of C-Cl is the LUMO.
Students sometimes assume that -OH is a good leaving group. It is not. Hydroxide is a strong base and a poor leaving group. You must convert it to a tosylate, mesylate, or protonate it before it can leave.
⚠️ Predicting SN1 vs SN2 is the single most important skill for this section. Every factor matters: substrate structure, nucleophile strength, solvent, and leaving group. Learn the decision framework, not just individual rules.
⚠️ Tracking stereochemistry through multiple reaction steps is heavily tested. Each SN2 step inverts; tosylation retains. If you lose track of configuration at any step, the rest of the problem collapses.
⚠️ The HOMO/LUMO question is a favourite. Remember: HOMO = nucleophile's lone pair; LUMO = sigma* of C-LG bond.
⚠️ Leaving group ability (especially why -OH is poor and -OTs is excellent) comes up in both multiple-choice and free-response.
⚠️ Tertiary substrates with strong nucleophiles: the exam tests whether you know that SN2 is impossible here and that strong base/nucleophile conditions give E2 elimination instead.
True or False: SN2 reactions give retention of configuration at the stereocentre.
Fill in the blank: The rate law for an SN1 reaction is rate = k[______].
True or False: Tosylation of an alcohol with TsCl/pyridine inverts the configuration at the carbon bearing the -OH.
Fill in the blank: In an SN2 reaction, the nucleophile's HOMO interacts with the ______ of the C-leaving group bond.
True or False: Vinyl chloride readily undergoes SN2 reactions with strong nucleophiles.
Answers: 1. False (SN2 gives inversion). 2. Substrate. 3. False (tosylation retains configuration; the C-O bond at the stereocentre is not broken). 4. Sigma-antibonding orbital (sigma*/LUMO). 5. False (vinyl substrates are essentially unreactive toward SN1 and SN2).
Q: (S)-2-Butanol is treated with TsCl/pyridine, then the resulting tosylate is treated with NaBr. What is the configuration of the product?
A: (R)-2-bromobutane. Tosylation retains S configuration. SN2 with NaBr inverts S to R.
Q: 1-Bromo-1-methylcyclohexane is treated with four different reagents: NaOH/DMF, ethanol, methylamine, and NaCN/acetone. Which reacts fastest?
A: Ethanol. The substrate is tertiary, so SN2 is impossible. The reaction must go by SN1. Ethanol is a weak nucleophile and a polar protic solvent, which are ideal SN1 conditions. NaOH/DMF and NaCN/acetone are strong nucleophiles that would promote E2 elimination on a tertiary substrate rather than substitution.
Q: Four substrates (cyclohexyl-Br, cyclohexyl-OCH3, cyclohexyl-OTs, cyclohexyl-OH) are mixed with NaCl in toluene. Which is least reactive?
A: Cyclohexyl-OH. Hydroxide is a very poor leaving group (strong base), so the alcohol will not undergo substitution under these conditions. OCH3 is also a poor leaving group for the same reason. Among poor leaving groups, -OH and -OCH3 are both bad, but -OH is generally considered worse because at least methoxide departure could be slightly assisted in some contexts. The key point: -OTs and -Br are good leaving groups; -OCH3 and -OH are not.
Q: A chloroalcohol cyclises to form both a six-membered and a five-membered cyclic ether. What type of mechanism explains this?
A: Intramolecular SN2. The deprotonated oxygen (alkoxide) acts as the nucleophile and attacks the carbon bearing the chlorine within the same molecule. Different ring sizes arise because the oxygen can attack different electrophilic carbons, particularly when an alkene in the chain provides two possible closure points.
Q: Why does the reaction of a tertiary tosylate with NaSCH2CH3 give "no reaction"?
A: NaSCH2CH3 is a strong nucleophile. A tertiary substrate cannot undergo SN2 (steric blockage). Under these conditions (strong nucleophile, likely a polar aprotic or moderately polar solvent), E2 elimination would compete, but SN1 substitution by the thiolate is not favoured. The exam's answer is "no reaction" for substitution; to get a substitution product, you would need to switch to SN1-friendly conditions (weak nucleophile, polar protic solvent) or use a less hindered substrate.
This connects directly to stereochemistry: every SN2 reaction inverts a stereocentre, so you need confident R/S assignment skills (covered in the companion notes) to track what happens at each step.
Nucleophilic substitution is the foundation for elimination reactions (E1 and E2), which compete with SN1 and SN2 respectively. Understanding when substitution wins vs when elimination wins is the next major topic in Organic Chemistry II.
In biochemistry, enzyme-catalysed substitution reactions (e.g. methyltransferases using SAM) follow SN2-like mechanisms with inversion. Drug metabolism often involves nucleophilic attack on electrophilic centres, and knowing whether the mechanism is SN1 or SN2 helps predict the products.
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