Source: Carey, Organic Chemistry, 11th ed., Chapters 5-7
Tags: alcohols, alkyl halides, reaction mechanisms, nucleophilic substitution, SN1, SN2, elimination, E1, E2, Zaitsev rule, leaving groups, nucleophiles, bases, CHEM 2301 UMN
Difficulty: Intermediate to Advanced | Prerequisites: Chapters 1-4 and 14 study notes (bonding, hybridisation, stereochemistry, conformational analysis)
Big picture: This is where organic chemistry transitions from "what does a molecule look like?" to "what does it do?" Chapters 5-7 introduce the four core reaction mechanisms of the course: SN1, SN2, E1, and E2. These govern how alkyl halides and alcohols react with nucleophiles and bases, and nearly every reaction you encounter in the second half of the course builds on these four pathways. Getting comfortable with curved-arrow notation, energy diagrams, and the factors that favour one mechanism over another is the single most important thing you can do for the rest of CHEM 2301.
Chapter 5 introduces alcohols and alkyl halides as the first functional groups that undergo interesting reactions, and teaches the basics of reaction mechanisms (curved arrows, transition states, intermediates, energy diagrams). Chapter 6 covers nucleophilic substitution in detail: SN2 (one-step, backside attack, inversion of configuration) and SN1 (two-step via carbocation, racemisation). Chapter 7 introduces elimination reactions: E2 (one-step, antiperiplanar geometry required, Zaitsev or Hofmann product) and E1 (two-step via carbocation, Zaitsev product favoured), plus how to predict when substitution versus elimination will dominate.
Alkyl halide
An organic compound in which a halogen atom (F, Cl, Br, or I) is bonded to an sp3 carbon. Classified as primary (1 degree), secondary (2 degree), or tertiary (3 degree) depending on the substitution of the carbon bearing the halogen.
Alcohol
An organic compound containing a hydroxyl (-OH) group bonded to an sp3 carbon. Classified as 1 degree, 2 degree, or 3 degree by the same logic as alkyl halides.
Leaving group
An atom or group of atoms that departs with a pair of electrons during a reaction. Good leaving groups are weak bases (stable after departure). Halide ions (I-, Br-, Cl-) and water (from protonated alcohols) are common leaving groups.
Nucleophile
A species that donates an electron pair to an electrophilic atom, typically carbon. In simple terms, it is the electron-rich attacker. Nucleophilicity is a kinetic property (how fast the species attacks).
Electrophile
A species that accepts an electron pair. The carbon bearing the leaving group in an alkyl halide is the electrophile.
Curved-arrow notation (electron-pushing)
A formalism where curved arrows show the movement of electron pairs in a reaction mechanism. The arrow starts at the electron source and points to where the electrons go.
Transition state
The highest-energy point along a reaction pathway. It represents a fleeting arrangement of atoms that cannot be isolated. Drawn in square brackets with a double-dagger symbol.
Intermediate
A species formed during a multi-step reaction that is higher in energy than reactants or products but sits in an energy well (a local minimum). Unlike a transition state, an intermediate has a finite lifetime.
Reaction coordinate diagram (energy diagram)
A plot of energy versus reaction progress. Shows activation energy barriers, transition states, and any intermediates. The difference in energy between reactants and products indicates whether the reaction is exothermic or endothermic.
Carbocation
A positively charged carbon with only six electrons (an empty p orbital). Stability order: 3 degree > 2 degree > 1 degree > methyl. Carbocations are key intermediates in SN1 and E1 mechanisms.
Carbocation rearrangement
A 1,2-shift of a hydrogen atom (hydride shift) or an alkyl group (methyl shift or alkyl shift) that converts a less stable carbocation into a more stable one. Rearrangements are common in reactions that proceed through carbocation intermediates.
Alkyl halides: named as haloalkanes. The halogen is a substituent prefix (fluoro-, chloro-, bromo-, iodo-) on the parent alkane chain.
Alcohols: the -OH group defines the parent chain. The suffix changes from -e to -ol (e.g. ethanol, 2-propanol). The chain is numbered to give -OH the lowest locant.
The C-X bond in alkyl halides is polarised: carbon is delta-positive, halogen is delta-negative.
The C-O bond in alcohols is also polar, but -OH is a poor leaving group. Protonation converts -OH to -OH2+ (water), which is an excellent leaving group.
Carbon-halogen bond strengths decrease down the periodic table: C-F > C-Cl > C-Br > C-I. Reactivity goes the opposite way (C-I reacts most readily).
Use curved arrows to show electron pair movement. The tail of the arrow sits on the electrons; the head points to where they go.
A full-headed arrow indicates movement of two electrons. A half-headed (fishhook) arrow indicates movement of one electron (used in radical reactions, Ch. 10).
Every mechanism step must conserve charge and maintain proper valence.
Nucleophilic substitution
A reaction in which a nucleophile replaces a leaving group on an electrophilic carbon. The two mechanisms are SN2 and SN1.
SN2 (substitution, nucleophilic, bimolecular)
A one-step mechanism in which the nucleophile attacks the electrophilic carbon from the back side (180 degrees opposite the leaving group) 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].
Backside attack
The requirement in SN2 that the nucleophile approaches from the side opposite the leaving group. This produces inversion of configuration at the reacting carbon (Walden inversion).
Walden inversion
The stereochemical outcome of an SN2 reaction: the configuration at the carbon centre is inverted, like an umbrella flipping inside out.
SN1 (substitution, nucleophilic, unimolecular)
A two-step mechanism. Step 1 (rate-determining): the leaving group departs to form a carbocation intermediate. Step 2: the nucleophile attacks the carbocation. Rate = k[substrate] only; the nucleophile does not appear in the rate law.
Racemisation
The formation of equal amounts of both enantiomers at a chirality centre. In SN1 reactions, the planar carbocation can be attacked from either face, leading to racemisation (or near-racemisation).
Solvolysis
An SN1 reaction in which the solvent acts as the nucleophile. Example: tert-butyl bromide in water/ethanol produces tert-butyl alcohol or tert-butyl ethyl ether.
One step, concerted: bond formation and bond breaking happen simultaneously.
Stereochemistry: complete inversion at the reacting carbon.
The rate is second-order: rate = k[nucleophile][substrate].
Factors favouring SN2:
Substrate: methyl > primary > secondary. Tertiary substrates do not undergo SN2 (too much steric hindrance at the reacting carbon).
Nucleophile: strong, unhindered nucleophiles are best (e.g. CN-, I-, RS-, HO-, CH3O-).
Leaving group: good leaving groups accelerate the reaction (I- > Br- > Cl- >> F-). Tosylate (OTs) and mesylate (OMs) are also excellent leaving groups.
Solvent: polar aprotic solvents (DMSO, DMF, acetone) favour SN2. They dissolve ionic nucleophiles without stabilising them through hydrogen bonding, keeping the nucleophile reactive.
Two steps:
Step 1 (slow, rate-determining): ionisation of the C-X bond to form a carbocation and a halide ion.
Step 2 (fast): nucleophilic attack on the carbocation.
Stereochemistry: racemisation (or close to it) at the reacting carbon, because the carbocation intermediate is planar and can be attacked from either face. In practice, there is sometimes a slight excess of inversion because the leaving group partially blocks one face as it departs (ion-pair effect).
The rate is first-order: rate = k[substrate].
Factors favouring SN1:
Substrate: tertiary > secondary. Primary and methyl substrates do not undergo SN1 (their carbocations are too unstable).
Nucleophile: does not affect the rate. Weak nucleophiles (water, alcohols) are sufficient because the carbocation is already formed before the nucleophile arrives.
Leaving group: good leaving groups still help (the rate-determining step is departure of the leaving group).
Solvent: polar protic solvents (water, alcohols, acetic acid) favour SN1. They stabilise the carbocation intermediate through solvation.
If the initial carbocation is secondary, check whether a 1,2-hydride shift or 1,2-methyl shift can produce a more stable (tertiary) carbocation.
The rearranged carbocation is then attacked by the nucleophile, giving a product whose carbon skeleton differs from the starting material.
Rearrangements are possible only in SN1 (and E1), never in SN2 (and E2), because SN2 has no carbocation intermediate.
Elimination reaction
A reaction in which atoms or groups are removed from adjacent carbons to form a pi bond (typically a C=C double bond). The two main mechanisms are E2 and E1.
E2 (elimination, bimolecular)
A one-step mechanism in which a base removes a proton from the carbon adjacent (beta) to the leaving group at the same time as the leaving group departs and a pi bond forms. Rate = k[substrate][base].
Antiperiplanar geometry
The spatial requirement for E2: the H being removed and the leaving group must be on opposite sides of the C-C bond being broken (180 degree dihedral angle). In cyclohexane systems, this means both the H and the leaving group must be axial and trans to each other.
Zaitsev's rule (Saytzeff's rule)
The more substituted alkene is the major product of an elimination reaction. In simple terms, the double bond forms toward the side with more alkyl groups. This product is thermodynamically more stable.
Hofmann product
The less substituted alkene, which becomes the major product when a bulky base is used (because steric hindrance prevents the base from reaching the more substituted beta-hydrogen).
E1 (elimination, unimolecular)
A two-step mechanism. Step 1 (rate-determining): the leaving group departs to form a carbocation. Step 2: a base (often solvent) removes a proton from a carbon adjacent to the carbocation, forming the alkene. Rate = k[substrate].
Beta-hydrogen (beta-H)
A hydrogen atom on the carbon adjacent to the carbon bearing the leaving group. Elimination requires at least one beta-hydrogen.
Regioselectivity
The preference for a reaction to form one constitutional isomer over another. In elimination, regioselectivity refers to which alkene isomer (more or less substituted) predominates.
One step, concerted: base removes beta-H while the leaving group departs and the C=C forms.
The base, beta-H, the two carbons, and the leaving group must all be in the same plane (antiperiplanar).
Stereochemistry:
In acyclic systems, the anti arrangement is preferred but other conformations may also react.
In cyclohexane rings, the leaving group and the beta-H must both be axial and trans-diaxial. Draw the chair and check which hydrogens satisfy this requirement.
Regioselectivity: Zaitsev product (more substituted alkene) is major with most bases. Hofmann product (less substituted alkene) is major with bulky bases like potassium tert-butoxide (KOtBu).
Factors favouring E2:
Strong, non-nucleophilic bases (NaOH, NaOEt, KOtBu, DBU, LDA)
Higher temperature (elimination is generally favoured over substitution at elevated temperature)
Tertiary substrates strongly favour elimination over substitution with base.
Two steps: identical first step to SN1 (carbocation formation), followed by loss of a proton.
Regioselectivity: Zaitsev product is major (loss of the proton that gives the more substituted alkene).
E1 competes directly with SN1. Both proceed through the same carbocation intermediate. Which product dominates depends on the reaction conditions:
Higher temperature favours E1 over SN1.
Weaker nucleophiles/bases tend to give more SN1.
This is the central problem of Chapters 5-7 and a major exam topic. The decision tree:
Substrate class:
Methyl and primary: SN2 dominates (E2 possible with strong base and heat).
Secondary: competition among all four. Strong nucleophile/weak base favours SN2. Strong base/weak nucleophile favours E2. Weak nucleophile + polar protic solvent favours SN1/E1.
Tertiary: no SN2 possible. Strong base favours E2. Weak nucleophile in polar protic solvent favours SN1/E1.
Nature of the reagent:
Strong nucleophile (especially if uncharged or small): SN2
Strong, bulky base: E2 (Hofmann product)
Strong base (not bulky): E2 (Zaitsev product)
Weak nucleophile/weak base (solvent): SN1/E1 (usually mixtures)
Solvent:
Polar aprotic: favours SN2
Polar protic: favours SN1/E1
Temperature:
Higher temperature: favours elimination (E1 or E2) over substitution
SN2 rate law
rate = k[nucleophile][substrate]
SN1 rate law
rate = k[substrate]
E2 rate law
rate = k[base][substrate]
E1 rate law
rate = k[substrate]
Carbocation stability order
3 degree > 2 degree > 1 degree > methyl (benzylic and allylic carbocations are stabilised by resonance)
Nucleophilicity trend (in polar aprotic solvent)
Nucleophilicity roughly parallels basicity for atoms in the same row of the periodic table. For halides in polar protic solvents, the order reverses: I- > Br- > Cl- > F- (because smaller, more solvated ions are less nucleophilic).
SN2 reactions are workhorses of pharmaceutical synthesis. Forming a new C-N or C-O bond by displacing a halide is one of the most common steps in building drug molecules. The requirement for inversion at the reacting centre is exploited to set specific stereochemistry in chiral drugs.
Elimination reactions are how alkenes are manufactured industrially. Dehydration of ethanol to ethylene (an E1-type process) is a multi-million-tonne-per-year industrial process used to make polyethylene plastic.
Students often assume SN2 and SN1 are the only two options and forget about elimination entirely. On most exam problems involving a base and an alkyl halide, you must consider all four pathways.
A common error is predicting SN2 at a tertiary carbon. Tertiary centres are too sterically hindered for backside attack. If you see a tertiary substrate, SN2 is off the table.
Students frequently confuse nucleophilicity with basicity. They are related but not identical. A good nucleophile attacks carbon well (kinetic property); a strong base removes protons well (thermodynamic property). Some species are good nucleophiles but weak bases (e.g. I-, RS-), and some are strong bases but poor nucleophiles (e.g. KOtBu, LDA).
In cyclohexane-based E2 problems, students often forget that the leaving group and beta-H must both be axial and trans-diaxial. Drawing the correct chair conformation is essential.
⚠️ The SN1/SN2/E1/E2 decision is the most important skill tested on Exam III. Be able to look at a substrate, a reagent, and a solvent and predict which mechanism operates, what the product is, and what the stereochemistry is.
⚠️ Draw complete curved-arrow mechanisms for each of the four pathways. Know how many steps each has and what the intermediates (if any) look like.
⚠️ Stereochemistry of SN2 (inversion) and SN1 (racemisation) is tested frequently. If the starting material is chiral, you must specify the configuration of the product.
⚠️ Carbocation rearrangements are a favourite exam topic. If a reaction goes through a carbocation (SN1 or E1), always check for possible 1,2-hydride or 1,2-methyl shifts.
⚠️ For E2 on cyclohexane rings, draw the chair, identify the trans-diaxial beta-hydrogens, and determine which elimination product forms.
True or False: SN2 reactions proceed with retention of configuration.
Fill in the blank: The rate-determining step of an SN1 reaction is ______.
True or False: E2 reactions always give the Zaitsev product.
Fill in the blank: A tertiary alkyl halide treated with a strong base in a polar aprotic solvent will most likely undergo an ______ reaction.
True or False: Carbocation rearrangements can occur in SN2 reactions.
Answers: 1. False (SN2 gives inversion, Walden inversion). 2. Formation of the carbocation (ionisation of the C-X bond). 3. False (bulky bases like KOtBu favour the Hofmann product). 4. E2. 5. False (SN2 has no carbocation intermediate).
Q: Predict the product(s) and mechanism when (R)-2-bromobutane is treated with NaOCH3 in DMSO.
A: NaOCH3 is a strong nucleophile and strong base. DMSO is a polar aprotic solvent (favours SN2). The substrate is secondary, so both SN2 and E2 are possible, but the polar aprotic solvent and good nucleophile favour SN2. The major product is (S)-2-methoxybutane (inversion of configuration).
Q: Predict the product(s) and mechanism when 2-bromo-2-methylpropane is dissolved in ethanol at room temperature.
A: The substrate is tertiary (no SN2 possible). Ethanol is a polar protic solvent and a weak nucleophile/weak base. These conditions favour SN1/E1. The major substitution product is 2-methyl-2-ethoxypropane (tert-butyl ethyl ether). Some 2-methylpropene (elimination product) will also form.
Q: For the E2 elimination of trans-1-bromo-4-tert-butylcyclohexane, draw the chair conformation and predict the product.
A: The tert-butyl group locks the ring with tert-butyl equatorial. In the trans isomer, bromine is therefore axial. The beta-hydrogens that are trans-diaxial to bromine can undergo E2 elimination. The product is 4-tert-butylcyclohexene.
Q: Why does 2-bromo-3-methylbutane give 2-methyl-2-butene as a significant product with SN1/E1 conditions, even though the double bond is not between C2 and C3 of the original skeleton?
A: The initial carbocation at C2 is secondary. A 1,2-hydride shift from C3 to C2 produces a more stable tertiary carbocation at C3. Loss of a proton from this rearranged carbocation gives 2-methyl-2-butene (the Zaitsev product from the rearranged cation).
These four mechanisms reappear constantly. Addition reactions of alkenes (Ch. 8) are the reverse of elimination. Alkynes (Ch. 9) undergo analogous substitution and elimination chemistry at sp carbons. Free radical reactions (Ch. 10) offer an alternative to ionic mechanisms. Understanding when carbocations form (and when they do not) is essential for predicting products in every remaining chapter.
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