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Leaving Groups &
Substrate Effects

Understand how the leaving group ability and substrate structure control whether a nucleophilic substitution follows an \(\text{S}_\text{N}1\) or \(\text{S}_\text{N}2\) pathway.

Organic Chemistry 1

What Is a Leaving Group?

A leaving group is the atom or group that departs from the substrate carbon during a substitution reaction, taking the bonding electrons with it. After departure it exists as a stable, independent species (anion or neutral molecule).

C LG
\(\text{LG}^-\)
 Nu Substrate Departed

Good vs. Poor Leaving Groups

A good leaving group is a weak base: it can stabilize the negative charge after departure. A poor leaving group is a strong base that clings to its bond.

Good Leaving Groups
\(\text{I}^-\), \(\text{Br}^-\), \(\text{Cl}^-\), \(\text{TsO}^-\), \(\text{H}_2\text{O}\): weak bases that stabilize charge via size or resonance.
Poor Leaving Groups
\(\text{OH}^-\), \(\text{NH}_2^-\), \(\text{OR}^-\), \(\text{H}^-\): strong bases that are too unstable as free anions to depart easily.

Ranking Leaving Group Ability

Better leaving group Poor Leaving Groups
\(\text{H}^-\)
\(\text{p}K_\text{a}\) 35
\(\text{OH}^-\)
\(\text{p}K_\text{a}\) 15.7
\(\text{F}^-\)
\(\text{p}K_\text{a}\) 3.2
 Good Leaving Groups
\(\text{TsO}^-\)
\(\text{p}K_\text{a}\) −2.8
\(\text{Cl}^-\)
\(\text{p}K_\text{a}\) −7
\(\text{Br}^-\)
\(\text{p}K_\text{a}\) −9
\(\text{I}^-\)
\(\text{p}K_\text{a}\) −10
 Worst Best

The Substrate: Carbon Classification

The substrate is the organic molecule bearing the leaving group. Its reactivity depends on how many alkyl groups (R) are attached to the carbon bonded to the leaving group.

Methyl
\(\text{CH}_3\text{-LG}\): 0 R groups on the carbon. Least hindered.
\(1^\circ\) (Primary)
\(\text{RCH}_2\text{-LG}\): 1 R group. Slightly more hindered.
\(2^\circ\) (Secondary)
\(\text{R}_2\text{CH-LG}\): 2 R groups. Moderate steric bulk.
\(3^\circ\) (Tertiary)
\(\text{R}_3\text{C-LG}\): 3 R groups. Maximum steric hindrance.

\(\text{S}_\text{N}2\): Prefers Less Substituted Substrates

\(\text{Nu}^-\)
 C H H LG Backside Attack: Inversion of Configuration One concerted step
\(\text{Rate} = k[\text{Nu}][\text{Substrate}]\)
 Bimolecular
\(\text{Methyl} > 1^\circ > 2^\circ\)
\(3^\circ\): No \(\text{S}_\text{N}2\)!

\(\text{S}_\text{N}1\): Prefers More Substituted Substrates

Step 1: LG Departs
\(\text{C}^+\)
 R R R
\(\text{LG}^-\)
 Carbocation (RDS) Step 2: Nu Attacks
\(\text{C}^+\)
 Nu Nu Both faces: Racemization
\(\text{Rate} = k[\text{Substrate}]\) only (Unimolecular)
\(3^\circ > 2^\circ \gg 1^\circ\) (methyl: No \(\text{S}_\text{N}1\)!)
 More alkyl groups stabilize the carbocation via hyperconjugation

\(\text{S}_\text{N}1\) vs. \(\text{S}_\text{N}2\): Side by Side

\(\text{S}_\text{N}2\) \(\text{S}_\text{N}1\)
Rate Law \(k[\text{Nu}][\text{Sub}]\) \(k[\text{Sub}]\)
Steps 1 (concerted) 2 (stepwise)
Substrate \(\text{Methyl} > 1^\circ > 2^\circ\) \(3^\circ > 2^\circ\)
Stereochem Inversion (Walden) Racemization
Nucleophile Strong required Weak is fine
Solvent Polar aprotic Polar protic

Why Steric Hindrance Matters

C H H H Methyl Wide open C H H R Primary Slight block C H R R Secondary Moderate block C R R R Tertiary Fully blocked

Carbocation Stability and \(\text{S}_\text{N}1\)

Stability
\(\text{CH}_3^+\)
 Methyl
\(\text{RCH}_2^+\)
 Primary
\(\text{R}_2\text{CH}^+\)
 Secondary
\(\text{R}_3\text{C}^+\)
 Tertiary

Step-by-Step Decision Process

1
Identify the leaving group. Is it a weak base (good LG)? If not, the reaction will not proceed by substitution.
2
Classify the substrate carbon: methyl, \(1^\circ\), \(2^\circ\), or \(3^\circ\). Count the R groups bonded to the carbon bearing the LG.
3
Methyl or \(1^\circ\)? Strongly favors \(\text{S}_\text{N}2\), especially with a strong nucleophile and polar aprotic solvent.
4
Tertiary (\(3^\circ\))? Exclusively \(\text{S}_\text{N}1\) for substitution (or \(\text{E}1/\text{E}2\) elimination). No \(\text{S}_\text{N}2\) possible.
5
Secondary (\(2^\circ\))? Borderline: check nucleophile strength, solvent, and temperature to determine \(\text{S}_\text{N}1\) vs. \(\text{S}_\text{N}2\).

Example 1: Methyl Bromide

Problem: \(\text{CH}_3\text{Br} + \text{NaOH} \rightarrow\) ? Predict the mechanism and product.

\(\text{CH}_3\)
 methyl Br
\(\text{CH}_3\text{OH}\)
 methanol
\(\text{OH}^-\)
+ \(\text{Br}^-\)

Example 2: Tertiary Substrate

Problem: \((\text{CH}_3)_3\text{CBr} + \text{H}_2\text{O} \rightarrow\) ? Predict the mechanism.

\((\text{CH}_3)_3\text{C-Br}\)
\(3^\circ\) substrate
 slow
\((\text{CH}_3)_3\text{C}^+\)
carbocation
+ \(\text{Br}^-\)
departs fast
\((\text{CH}_3)_3\text{C-OH}\)
t-butanol
\(\text{H}_2\text{O}\) attacks

Example 3: The Secondary Challenge

Problem: 2-bromobutane reacts with \(\text{NaCN}\) in DMSO. What mechanism predominates?

Substrate
\(2^\circ\) carbon: borderline territory. Could be \(\text{S}_\text{N}1\) or \(\text{S}_\text{N}2\).
Nucleophile
\(\text{CN}^-\): strong nucleophile, favors \(\text{S}_\text{N}2\).
Solvent
DMSO: polar aprotic, does not stabilize carbocations, favors \(\text{S}_\text{N}2\).

Solvent Effects on the Mechanism

Polar Aprotic
DMSO, DMF, acetone: do not solvate nucleophiles strongly, leaving them "naked" and reactive. Favors \(\text{S}_\text{N}2\).
Polar Protic
\(\text{H}_2\text{O}\), \(\text{CH}_3\text{OH}\), ethanol: stabilize ions via H-bonding. Help stabilize carbocations and departing LGs. Favors \(\text{S}_\text{N}1\).

Common Mistakes to Avoid

✕ Forcing \(\text{S}_\text{N}2\) on \(3^\circ\)
Tertiary substrates are too sterically hindered for backside attack. Always assign \(\text{S}_\text{N}1\) (or elimination).
✕ Forgetting LG quality
Even a perfect substrate won't react if the leaving group is a strong base like \(\text{OH}^-\) or \(\text{NH}_2^-\). Check the LG first.
✕ Ignoring solvent
A \(2^\circ\) substrate with a weak nucleophile in polar protic solvent = \(\text{S}_\text{N}1\), not \(\text{S}_\text{N}2\). Solvent tips the balance.

Question 1 of 5

Which of the following is the best leaving group?

Question 2 of 5

\((\text{CH}_3)_3\text{CCl}\) reacts with water. Which mechanism is most likely?

Question 3 of 5

What is the expected stereochemical outcome of an \(\text{S}_\text{N}2\) reaction?

Question 4 of 5

A reaction uses \(\text{NaCN}\) (strong nucleophile) in DMSO (polar aprotic). Which substrate would react fastest via \(\text{S}_\text{N}2\)?

Question 5 of 5

Why does a polar protic solvent favor \(\text{S}_\text{N}1\) over \(\text{S}_\text{N}2\)?