CHEM 231: Organic Form and Function
Laboratory 2
Nucleophilic Substitution1
Specific Practical Goals
 to explore the effects of reactant structure on nucleophilic substitution
 to determine the rate law for an organic reaction
Background
The chemistry of molecules can be predicted in large part by the functional groups they contain.
Groupings of atoms that can easily accommodate extra electron density will often depart from a
substrate, removing a shared pair of electrons in the process. Such functionalities are aptly called
leaving groups (abbr. LG). As a general rule of thumb, the stronger its conjugate acid, the better the
leaving group. For example, we expect chloride (Cl-) to be a good leaving group, since its conjugate
acid (HCl) is a strong acid; by the same token, hydroxide (HO-) is a poor leaving group, as its
conjugate acid (H2O) is a weak acid.
Bonds between carbon atoms and leaving groups are usually polarized, with the carbon center bearing
a slight positive character. Consequently, these sites tend to exhibit electrostatic attraction toward
molecules with high electron density; therefore, they are labeled electrophilic centers, and molecules
with leaving groups are often called electrophiles.
On the flip side of the coin, molecules with electron density to spare are attracted to these electrondeficient centers, so they have been dubbed nucleophiles (abbr. Nu). This nucleophilic electron
density is almost always housed in the form of a lone pair, and nucleophiles can be anionic or neutral.
Generally speaking, nucleophilicity decreases with increasing electronegativity (left to right trend) and
increases with increasing polarizability (up to down trend).
When nucleophiles encounter electrophiles, the lone pair of the nucleophile can form a bond with the
electrophilic center at the expense of the bond between the carbon and leaving group, as shown in
equation 1. This overall process is known as nucleophilic substitution.
Nu:
+
R3C
LG
Nu
CR3
+
(1)
:LG
Nucleophilic substitution can occur through at least two different pathways. In the first, the
nucleophile directly displaces the leaving group in a concerted (one-step) mechanism, as shown in
equation 2. Since both the nucleophile and the electrophile are engaged in the transition state, the
rate law reflects both species. Thus, it is known as bimolecular nucleophilic substitution, or SN2.
Consequently, this reaction exhibits second-order kinetics.
Nu: + R3C
LG
Nu
R3
C LG
Nu
CR3 + :LG
rate = k[Nu][R3C-LG]
(2)
The other frequently encountered mechanism occurs in two steps, as shown in equation 3. Here the
first step is departure of the leaving group, also called ionization. This step produces a very reactive
carbocation intermediate, which is rapidly captured by the nucleophile to provide the observed
product. Since the first step is usually much slower than the second, it is the rate-limiting step—and
since the transition state for this step involves only the electrophile, the rate law reflects only the one
species. Not surprisingly, such a reaction is called unimolecular nucleophilic substitution, or SN1, and
it displays first-order kinetics.
R3C
1
LG
R3C
LG
- LG
slow
R3C
Nu:
fast
Nu
CR3
rate = k[R3C-LG]
Adapted from Microscale and Miniscale Organic Chemistry Laboratory Experiments by Schoffstall, Gaddis, and Druelinger
(3)
In many cases, the ultimate product outcome is the same: a leaving group has been replaced by a
nucleophile. To get a handle on the mechanism, therefore, kinetic studies usually must be carried out.
Careful quantitative analysis can be used to generate an expression for the rate law, but even
qualitative data can provide clues to the mechanism. For example, tertiary electrophilic centers tend
to react readily through the SN1 pathway, since their carbocations are relatively stable, yet the SN2
route for these substrates is practically shut down because of crowding around the reactive site. In
this investigation you will gather both quantitative and qualitative rate data for a chemical system.
The Model Reaction
Alkyl bromides (and chlorides) are known to undergo substitution reactions in the presence of sodium
iodide in acetone medium, as shown in equation 4, a process known as the Finkelstein reaction. The
choice of acetone as a solvent is significant, since sodium iodide is freely soluble in acetone, but
sodium bromide and sodium chloride are practically insoluble. This striking solubility difference
provides a convenient way to separate the inorganic by-products from the desired organic compound.
It also represents a simple visual method for observing the progress of the reaction—formation of the
sodium bromide precipitate is evidence that the reaction has occurred.
R3C Br
+
NaI
acetone
R3C
I
+
NaBr
(4)
In this investigation you will use the appearance of precipitate as an indicator for reaction progress.
Even though precipitation will occur before the reaction is finished, if you are careful and consistent,
the cloud point will serve as a reliable benchmark for comparing multiple reactions.
Safety Considerations
You must abide by all laboratory safety rules
Alkyl halides are toxic. All manipulations should be carried out in the fume hood with gloves. Avoid
cross-contamination of environmental surfaces (pens, benchtops, etc.).
Procedural Overview
1.
Structural Investigations. For each of the following reactions, dispense 1.0 mL of sodium iodide
solution into a clean, dry, labeled culture tube (multiple tubes can be prepared at once). Using
an Eppendorf pipet, add 200 L of the electrophile (note the time of addition!), and thoroughly
mix by vortexing. The "endpoint" of the reaction is taken to be the first sign of cloudiness. The
reactions may be run in parallel.
Experimental conditions: 1.0 mL 15% sodium iodide solution + 200 L electrophile
Electrophiles
a. 1-bromobutane (standard reaction)
b. 2-bromobutane
c. 2-bromo-2-methylpropane
d. 1-bromo-2,2-dimethylpropane
e. 1-chlorobutane
2.
Rate Law Investigation. You may want to run each experiment individually, so that the start time
and time to precipitation can be measured precisely. Please pay careful attention to the reagents
used, as there are different combinations in each run. As a general procedure, first dispense 1.0
mL of "Reagent A" into the culture tube; then add 100 L of "Reagent B" by Eppendorf pipet and
rapidly mix.
Experimental conditions: 1.0 mL "Reagent A" + 100 L "Reagent B"
run
1
2
3
4
3.
Reagent A (1.0 mL)
15% sodium iodide
1.0 M 1-bromobutane
Dispose of all solutions in the waste container provided.
Reagent B (100 L)
1.0 M 1-bromobutane
2.0 M 1-bromobutane
7.5% sodium iodide
15% sodium iodide