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org/jchemeduc Communication

An Updated Simple SN2 Reaction for the Undergraduate Organic

Laboratory
Kelli S. Khuong,* Fabio Agnelli, and Matthew A. Parker
Cite This: J. Chem. Educ. 2023, 100, 376−379 Read Online

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ABSTRACT: SN2 reactions are of fundamental importance in introductory organic

chemistry courses, and a number of experiments suitable for the first-semester
undergraduate organic lab have been previously reported. Most of these experiments
have used alkyl halides as electrophiles, but alkyl halides are often less than ideal for
reasons of toxicity/volatility and difficulty in TLC visualization. We report an updated
methodology utilizing an alkyl tosylate, rather than a halide, as the electrophile. The
SN2 reaction of 2-naphthol/sodium hydroxide with butyl p-toluenesulfonate is
performed in a single 3 or 4 h lab period and affords a solid product in good yield.
The tosylate electrophile gives students experience with a commonly encountered
leaving group, is easily visualized on TLC, and has an improved safety profile.

KEYWORDS: Second-Year Undergraduate, Organic Chemistry, Laboratory Instruction, Alkylation, Ethers, Reactions, Synthesis,
Thin Layer Chromatography

■ INTRODUCTION
In 2009, Esteb and co-workers published an article titled “A
Simple S N2 Reaction for the Undergraduate Organic
Laboratory” in this Journal.1 That article detailed the successful
implementation of a new SN2 reaction (2-naphthol/sodium
hydroxide with 1-iodobutane) into their first-semester organic
laboratory (Scheme 1).
Scheme 1. SN2 Reaction of 2-Naphthol and 1-Iodobutane
(Original Procedure1)
These were exactly the reasons why we chose to incorporate
this simple SN2 experiment into our own first-semester organic
laboratory. As expected, the SN2 reaction of 2-naphthoxide and
1-iodobutane proceeded smoothly, was well received by the
students, and hit the desired learning objectives.
After performing the experiment as published for two
semesters, we modified the procedure by switching the
electrophile from 1-iodobutane to butyl p-toluenesulfonate
(butyl tosylate). Scheme 2 highlights the leaving group change
in red. We have been very pleased with the results. Our
updates maintain all the fantastic qualities of the original
experiment and add the following advantages: (1) students can
monitor the reaction progress by thin layer chromatography
(TLC), (2) students can gain experience with a different good

Scheme 2. SN2 Reaction of 2-Naphthol and Butyl p-

The authors clearly explained their rationale for developing Toluenesulfonate (Updated Procedure)
this simple SN2 reaction:
(1) the timing of the experiment coincides with students
learning SN2 and SN1 in their corresponding lecture
class,
(2) the procedure is appropriate for a first-semester
laboratory course that is heavily focused on common Received: August 13, 2022
organic lab techniques, Revised: October 27, 2022
(3) the reaction product is a solid that is easily isolated and Published: November 22, 2022
can be analyzed without NMR or IR since spectroscopy
is introduced in the following semester,
(4) the procedure uses relatively benign reagents.
© 2022 The Authors. Published by
American Chemical Society and Division https://doi.org/10.1021/acs.jchemed.2c00794
of Chemical Education, Inc. 376 J. Chem. Educ. 2023, 100, 376−379
Journal of Chemical Education
leaving group (tosylate vs halide), and (3) butyl tosylate is less
volatile and less toxic than 1-iodobutane.
■ BACKGROUND: ALTERNATIVE SN2 EXPERIMENTS
Esteb and co-workers included a thoughtful review of
alternative SN2 experiments in their article,1 and we present
a similar analysis of SN2 experiments that have been published
in this Journal since 2009.
Ether Syntheses
Multiple SN2 experiments employ the Williamson ether
synthesis. As noted in several of these articles, typical ether
syntheses can be difficult because they require long refluxes
and suffer from low yields.
Baar and co-workers report two experiments that use
microwave acceleration. When potassium 2-naphthoxide is
paired with p-bromobenzyl bromide (an electrophile that
contains an both an sp2 carbon and an sp3 carbon attached to a
bromine leaving group), the recrystallized solid product is
isolated in reasonable yields (∼30%).2 In the reaction of 2-
fluorophenol/K2CO3 and 1-bromoethane to form 2-fluoro-
phenetole, students work to optimize the variables of the
reaction (reagent equivalents, reaction time and temperature,
solvent choice), and the percent conversion is quickly
calculated by GC−MS.3
There are three articles that describe ether based SN2
experiments in which the alkyl halide or the alkoxide is varied.
Yearty and co-workers pair 4-bromophenol with one of three
potential alkyl bromides. Students must determine which alkyl
halide was used based on the 1H NMR and FTIR of the ether
product. The reaction requires 1 h reflux or 25 min microwave
heating and is performed during second-semester organic
chemistry.4
Curran and co-workers describe a competition setup in
which a single nucleophile (phenoxide anion from 2,6-
dimethylphenol/NaOH) can react with a mixture of 1-
bromopropane and 2-bromopropane. The reaction is heated
for 40 min, and the crude product is an oil that is analyzed by
1
H NMR and/or GC−MS. Ultimately, first-semester organic
students conclude that the SN2 mechanism is at play.5
Finally, Wharry describes an advanced experiment in which
students untangle mechanism outcomes by performing multi-
ple combinations of alkoxide nucleophiles with alkyl halide
electrophiles. Reactions require 1 h reflux. Then students
compile GC data for the different reactions to draw
conclusions about how the structures of both the nucleophile
and electrophile influence whether the operative mechanism is
substitution or elimination.6
SN2 Experiments That Focus on Stereochemistry
There are two advanced experiments that focus on the
stereospecificity of the SN2 reaction.7 One experiment starts
with phenylalanine, and the other starts with glucopyranosyl
azide.8 In both cases, the product stereochemistry is analyzed
by 1H NMR, in addition to other techniques.
Amine and Phosphine Nucleophiles
A collection of experiments utilize amine and phosphine
nucleophiles for SN2 reactions. The microwave assisted
butylation of theophylline gives students the opportunity to
optimize the alkylation by varying reagent equivalents, reaction
time, and temperature. Reaction outcomes are evaluated by
HPLC, and the experiment is appropriate for first-semester
students.9
377
pubs.acs.org/jchemeduc Communication
Sibbald describes a first-semester SN2 experiment in which
students react triphenylphosphine or tributylphosphine with a
variety of alkyl halides. The reaction requires only 30 min
reflux, no workup, and a single scan 31P NMR spectrum.
Students compile data for product composition (unreacted
phosphine relative to product phosphonium salt) and draw
conclusions about SN2 reactivity as a function of reactant
structure.10
The following experiments all feature a key SN2 reaction as
part of a multistep synthesis, appropriate for a second-semester
or advanced organic laboratory: conversion of lidocaine to the
most bitter substances (denatonium saccharinate and
denatonium benzoate),11 synthesis of R,R-tartrate salt of R-
rasagiline,12 and a student-driven greenification of the synthesis
of lidocaine.13
Other SN2 Options
Mobley reports a first-semester experiment in which students
experimentally determine the rate law of the SN2 reaction of 1-
bromobutane and iodide anion. Reactant and product
concentrations are measured as a function of time by collecting
multiple 1H NMR scans.14
When pentanols undergo competitive nucleophilic sub-
stitution in acidic solution, students can use a combination of
1
H NMR and GC data to identify the reaction mechanism(s)
based on product ratios. Students must address how alcohol
structure, solvent, and nucleophilic strength contribute to the
reaction outcomes and to the likelihood of rearrangement.15
■ HAZARDS
Sodium hydroxide, both as pellets and in ethanolic solution, is
corrosive. 2-Naphthol and butyl p-toluenesulfonate are
considered eye and skin irritants, are toxic, and are harmful
to the environment. Ethanol is flammable. Students should
always wear eye protection and gloves and should work
exclusively in a hood.
■ EXPERIMENT
To a solution of sodium hydroxide in ethanol (0.5 M, 16 mL)
in a 100 mL round-bottom flask was added 2-naphthol (0.85 g,
5.89 mmol), and this was stirred at RT until the 2-naphthol
was dissolved (10 min). Butyl p-toluenesulfonate (butyl
tosylate, 1.12 mL, d = 1.120 g/mL, 5.50 mmol, 0.93 equiv)
was added to the round-bottom flask, and the mixture was
brought to reflux. The reaction was monitored by thin layer
chromatography (TLC, hexane:ethyl acetate 60:40) for 40 to
60 min. After reaction completion, the hot reaction mixture
was poured over crushed ice and allowed to stand until the ice
melted. The tan crystalline solid that precipitated was collected
by vacuum filtration and washed with a 5 mL portion of ice-
cold water. If desired, the product can be recrystallized from
methanol−water and dried until the next laboratory period
before recording the melting point.
■ RESULTS AND DISCUSSION
The results of this experiment were highly reproducible over 3
semesters, with each semester having 10 sections of 12 to 16
students. All students were able to complete the synthesis and
TLC analysis in a single 3 h period (with optional
recrystallization in a single 4 h period).
This experiment is generally performed as one of the last
two experiments in a first-semester organic lab. This is the first
time that our organic students are using TLC to monitor a
https://doi.org/10.1021/acs.jchemed.2c00794
J. Chem. Educ. 2023, 100, 376−379
Journal of Chemical Education
reaction; however, students have already performed TLC
multiple times prior to this experiment. Therefore, student
technique is generally good enough that the TLC data is
relatively easy to interpret.
When Esteb and co-workers utilized 2-naphthol as the
limiting reactant, the 2-naphthol spot did not completely
disappear on the TLC due to its high UV-activity.1 We avoid
that complication by using 2-naphthol as the excess reactant
and butyl tosylate as the limiting reactant. The butyl tosylate
spot does disappear completely upon reaction completion.
Furthermore, this has the added advantage that excess 2-
naphthoxide remains in the aqueous layer during the reaction
workup.
An example student TLC plate is shown below (Figure 1).
At time zero, both 2-naphthol (the excess reactant) and butyl
Figure 1. Example of student TLC data monitoring the SN2 reaction
of 2-naphthol and butyl tosylate.
tosylate (the limiting reactant) are visible. By 20 min, a spot for
the product 2-butoxynaphthalene is visible and the spot for
butyl tosylate has clearly faded. By 40 min, the spot for butyl
tosylate is barely visible. Reaction completion is indicated by
the presence of only two spots, excess 2-naphthol and 2-
butoxynaphthalene. Occasionally, the reaction will be complete
in as little as 20 min or as long as 60 min. Additional examples
of student-reported TLC results are included in the Supporting
Information.
All students obtain the crude product as a tan to off-white
crystalline solid in reasonable amounts (typically 60−85%
crude yield).
It is important that the reaction mixture is poured while still
hot on crushed ice (no water) and allowed to stand still until
all the ice has melted. We found that when the reaction
mixture was poured over ice water and stirred, a colloidal
precipitate formed that was impossible to filter.
We tested product recrystallization and ran melting points
on the crude and recrystallized product. The recrystallized
product is noticeably lighter in color (off-white instead of tan),
but the student-measured melting points (crude 28−34 °C;
recrystallized 30−34 °C) were only slightly closer to the
literature value (33−35 °C).
As detailed in the original article, it is possible to
characterize the product via 1H NMR and IR spectroscopy.1
However, since we do not cover spectroscopy until our
second-semester organic laboratory, we rely on the TLC
interpretation.
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pubs.acs.org/jchemeduc Communication
Overall, this experiment accomplishes the following
objectives. First, students are introduced to various skills for
the first time in their organic lab (reflux and monitoring the
progress of reaction by TLC). Second, students reinforce
techniques and skills they previously learned (recrystallization,
mp, calculating percent yield). Finally, students make
important connections to the material that they are learning
in their corresponding lecture course. As expected, this
experiment improves students’ comfort level with sulfonate
leaving groups, and like Esteb and co-workers,1 we find that
this experiment provides a valuable opportunity to emphasize
both foundational concepts (identifying the electrophile,
identifying the nucleophile, drawing a reasonable curved
arrow mechanism) and more advanced topics related to
nucleophilic substitution (choice of appropriate solvent, role of
the hydroxide ion, possibility of elimination as a competing
pathway).
■ CONCLUSION
Nucleophilic substitution is one of the first and most important
reactions taught in first-semester organic chemistry classes. In
this article, we describe a simple implementation of an SN2
reaction that can be successfully completed in a 3 or 4 h lab
period, relies solely on standard organic chemistry techniques
(TLC, reflux, crystallization, mp), and affords a solid product
in good yields. The electrophile, butyl tosylate, is the limiting
reactant. This not only allows the reaction to be monitored by
TLC but also gives students experience with an important
leaving group. Furthermore, this reagent has an improved
safety profile compared to its halide analogue. Ultimately, this
experiment strengthens the connection between what students
are learning in their lecture and laboratory classes and serves as
a gateway to more complex organic syntheses.
■
*
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available at https://pubs.ac-
s.org/doi/10.1021/acs.jchemed.2c00794.
Student handout, notes for instructors, sample calcu-
lations and TLC data, report questions, and character-
ization of 2-butoxynaphthalene (PDF, DOCX)
■ AUTHOR INFORMATION
Corresponding Author
Kelli S. Khuong − Department of Chemistry and Biochemistry,
University of San Diego, San Diego, California 92110, United
States; orcid.org/0000-0002-1080-1309;
Email: khuong@sandiego.edu
Authors
Fabio Agnelli − Department of Chemistry and Biochemistry,
University of San Diego, San Diego, California 92110,
United States
Matthew A. Parker − Department of Chemistry and
Biochemistry, University of San Diego, San Diego, California
92110, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jchemed.2c00794
Notes
The authors declare no competing financial interest.
https://doi.org/10.1021/acs.jchemed.2c00794
J. Chem. Educ. 2023, 100, 376−379
Journal of Chemical Education pubs.acs.org/jchemeduc Communication

■ ACKNOWLEDGMENTS
The authors would like to thank USD’s organic chemistry team
for helpful discussions in fine-tuning this experiment and the
2019−2021 organic chemistry students in the preparation and
testing of this experiment.

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