Expt #5. Part
2.
Preparation of DEET and VT NMR Study of Amide
C-N Bond Rotation
Relevant textbook readings - Mohrig Chapter
7.2-7.3. Smith Chapter 22.
Literature References
(1) Reaction procedures adapted from
http://chemconnections.org/organic/chem227/deet-procedure-09.html
(accessed Jan 21, 2013).
(2) (a) Jensen, B. L.; Fort, R. C. Jr. J.
Chem. Educ. 2001, 78,
538-540. (b) Gryff-Keller,
A.; Szczeciński, P. Org.
Mag. Res. 1978, 11,
258–261.
Overview - The 3-methylbenzoic
acid prepared in part 1 of expt
5 will be chlorinated using thionyl
chloride and the product formed (m-toluoyl chloride) will be
reacted with diethylamine
hydrochloride and sodium hydroxide to form the
common insect repellant, N,N-diethyltoluamide
(DEET). The product will be characterized by proton
NMR and IR. In Part 3, variable temperature 1H
NMR (VTNMR) will be used to determine the effect of
amide resonance on the rate of C-N bond rotation.
Background
Amides are
easily prepared by treating a carboxylic acid with
thionyl chloride to
form an acyl chloride (eq
1), which can then be reacted with an amine to
form the desired amide (eq
2). The reaction of the acyl chloride with the
amine (eq 2) is
usually very rapid and exothermic so that, in many
cases, the rate must be controlled by cooling or
other means.
![fbx](amideprep.gif)
In the absence
of an added base, it is necessary to use 2.0 equiv of amine for eq 2 because the reaction
produces HCl, which
reacts rapidly with the amine to form an ammonium
salt (eq 3). Although
the reaction is often carried out in this manner
(using excess amine) it can be wasteful
(especially if the amine is valuable) and the
ammonium salt formed presents a product
purification problem depending on how difficult it
is to separate from the product. These
disadvantages can be avoided if a base such as
pyridine or sodium hydroxide is included as an
additional reactant.
![vb](amideprepxsamine.gif)
The Schotten-Baumann reaction
is the variation of this reaction that uses
aqueous sodium hydroxide as the base (eq 4). Water-soluble acyl
chlorides are unsuitable reactants for this
procedure because they will hydrolyze rapidly in
water to form carboxylic acids (thus undoing eq 1). However, most
aromatic acyl chlorides are practically insoluble
in water and, therefore, hydrolyze much more
slowly. The use of NaOH
also makes it possible to use an amine
hydrochloride rather than the free amine (e.g. Et2NH2+
Cl− instead
of Et2NH) because the salt reacts with
base to form the amine in situ. Many
amines are corrosive and malodorous so the use of
an amine salt is often advantageous.
![ds](amideprepSchotten-Baumann.gif)
A disadvantage
of the Schotten-Baumann
reaction is that very efficient mixing is
necessary to provide adequate contact between the
water-insoluble acyl chloride and the amine. To
overcome this we will use a detergent known as
sodium lauryl sulfate. Detergent action helps
disperse the acyl chloride into smaller particle
sizes that increase the reaction rate.
Procedures
Preparation of m-Toluoyl Chloride
Use dry glassware
and wear gloves for these procedures! Thionyl chloride
decomposes violently on contact with water to
produce poisonous gases (HCl
and SO2). Avoid skin contact with
it, keep away from water, and do not breathe
its vapors.
Place 5 mmol m-toluic acid and 6 mmol thionyl chloride in a
4-mL conical vial (14/10 standard taper)
equipped with a magnetic spin vane. Attach a
condenser and gently reflux
(sand bath at ca. 100 °C) with
stirring for 30 minutes or until the evolution
of gases stops. Check for HCl
evolution using litmus paper inserted into the
top of the reflux condenser.
Preparation of Diethylamine Free-Base
Solution
Carry out
this part while the 30-min reflux is going! Add
6.0 mL of 3.0 M NaOH(aq)
to a 25 mL r.b.
flask. Add a stir bar and cool the mixture on an
ice bath. Carefully add 5 mmol
of diethylamine
hydrochloride.
Reaction
of m-Toluoyl
Chloride with Diethylamine
Hydrochloride
Add 0.1 g sodium lauryl sulfate to the free-base
solution. Attach a reflux condenser to the flask
and then use a warm, short-stem Pasteur pipet to
slowly add (through the
top of the condenser) the m-toluoyl
chloride from part A to the stirring NaOH/ Et2NH2+
Cl−
solution. When the addition is complete, heat on
a hot water bath for 15 min.
Work-up
Cool the
reaction mixture to room temperature. Transfer
it to a test tube and extract it with three 3-mL
portions of dichloromethane. Wash the combined
DCM extracts with 5 mL of 5% NaOH followed by 5 mL of
water. Dry over sodium sulfate and then
evaporate the solvent
using the rotary evaporator. Determine the
yield.
Characterization. Obtain the
proton NMR spectrum and, if you have enough
material, also the IR spectrum.
Variable Temperature (VT) NMR. One
group will also be chosen to obtain the spectrum
at varying temperatures. These spectra will be
available to the whole class in the class storage
folder.
Background for VT NMR. We can
use the VT NMR results to learn about amide
resonance and specifically how it affects rotation
of the amide C-N bond.
The energy barrier to rotation about
carbon-carbon single bonds is usually about 3-5
kcal/mol. This low barrier means that these bonds
freely rotate. For instance, the C-C bond of
ethane rotates approximately 1011 times
per second at room temperature. However, rotation
about the the C-N
bond of an amide is much less "free". This is due
to the amide resonance which makes the C-N bond
have appreciable double bond character. In other
words, rotating the C-N bond destroys the pi
overlap between the carbonyl carbon and the
nitrogen resulting in a much higher energy barrier
(Ea) for
bond rotation.
![deet](DEETex1.gif)
The rate of a chemical reaction is
related to the activation energy (Ea) according
to the Arrhenius equation.
k = A × e-Ea/RT
A is the Arrhenius factor and is
approximately 2 x 1013 for the
reaction being considered here. R is the
gas constant = 0.001987 kcal mol-1
K-1 and T is the temperature in
Kelvins.
Nuclear magnetic resonance occurs on a
slow time scale. Therefore, fast reactions are not
discernable by NMR and
the observed spectrum is the average spectrum of
the interconverting molecules. In general, an
averaged spectrum is observed when the rate of the
process is 2π times the frequency
difference (Δν) (2π × Δν) between the peaks being
observed. For example, consider a
hypothetical molecule with two nonequivalent
methyl groups with 1H NMR chemical
shifts of 1.0 and 1.5 ppm on a 300 MHz instrument.
The frequency difference between the two peaks is
150 Hz (0.5 ppm x 300 Hz/ppm). If a chemical
process interconverts these methyl groups
significantly faster than 900 times per second
(900 s-1) (2π × 150 Hz) (Hz =
s-1) then these six protons would show
up as a single peak at 1.25 ppm. In contrast, if
the methyl groups interconvert much slower than
900 times per second then they will show up as two
distinct peaks at 1.0 and 1.5 ppm. When the interconversion rate is
about equal to 2π × Δν the six methyl protons
will appear as a
single broad peak at the average chemical shift
(1.25 ppm).
Increasing the temperature increases
the rate of a reaction according to the Arrhenius
equation (given above). Therefore, in certain
cases it is possible to time a chemical process by
finding the temperature at which averaged spectra
for the interconverting groups are obtained. At
lower temperatures the process is slower and
separate peaks are observed. At higher
temperatures, one sharp peak at the average
chemical shift value is obtained. Thus, the rate
and the Ea
of C-N bond rotation in DEET can be determined by
obtaining the proton NMR over a range of
temperatures.
VT NMR Data Interpretation. Use
the VT spectra to determine the temperature at
which the two ethyl groups of DEET start to become
equivalent, i.e., when the Ha and Hb
signals each coalesce to form one broad peak for
each. At this temperature, the rate of bond
rotation (k) is approximately 2π × Δν. Because the Δν
values are different for Ha and Hb these
peaks are not expected to coalesce at exactly the
same temperature. (Use the lowest temperature
spectrum to determine Δν
values.)
![deet](DEETex2.gif)
Hence, k at this T can be determined
and A and R are known, so we can calculate Ea using the
rearranged Arhennius
equation:
Ea
= ln (A/k) x RT
The value of Ea
so obtained can be compared to literature values
(reference 2).
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