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Experiment ‐ A Self‐Assembled “Molecular Container”
Reading:
Bruice, P. Y. “Organic Chemistry,” 8th Ed., Pearson, 2015, pg. 817‐819, 876‐878, 886‐888.
Yamanaka, M.; Shivanyuk, A.; Rebek, J. Jr. “Kinetics and Thermodynamics of Hexameric Capsule
Formation.” J. Am. Chem. Soc., 2004, 126, 2939‐2943.
https://www.nobelprize.org/nobel_prizes/chemistry/laureates/1987/
https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2016/
Introduction
Supramolecular chemistry is a quickly growing field that is interested in the interactions between
molecules. The field was recognized by the Nobel Prize in 1987 for work by Cram, Lehn, and Pederson, on
crown ethers and cryptands,
and again in 2016 for the
work of Sauvage, Stoddart,
and Feringa, on molecular
machines (Figure 1b). In
general,
the
field
is
dominated
by
weak
interactions that can hold
molecules together, but that
are weak enough to be
reversible. In some cases this
even extends to so‐called
dynamic
covalent
interactions, which are
formally covalent bonds that
are reversibly formed. The
dominate
interactions,
though,
are
hydrogen
bonding, cation‐π, and π‐π
interactions.
Another important area of research are molecular containers. These can be fully covalent, or they
can be formed by self‐assembly (use of non‐covalent interactions that self‐recognize and come together).
Resorcinarenes are one type of molecular that can be used to form molecular containers via self‐assembly.
Resorcinarenes can be synthesized by a polycondensation reaction between resorcinol (1,3‐
dihydroxybenzene) and aldehydes. They can form many different sized rings, but one of the most
thermodynamically favorable is a tetramer, called resorcin[4]arene. Resorcin[4]arenes are able to form
hexameric complexes in wet organic solvents through a series of hydrogen bonds (Figure 2). The hexamer
resembles a snubbed cube where resorcinarene units make up the six faces with water molecules holding
the hexamer together at the eight vertices. Monomeric resorcinarenes are generally insoluble in dry
chloroform, but the
hexamers are soluble.
The hexamers can only
form when water or
alcohol is present,
because the hydrogen
bonding requires a
number of ROH groups
that
bridge
the
resorcinarene OH’s.
The good news is that
although water and
CDCl3 are immiscible, the small amount of water that will dissolve in CDCl3 is more than enough to
promote hexamer formation.
The hexamer does not exist as an empty sphere, rather it is filled with smaller molecules: Nature
abhors a vacuum! Whenever a molecule with a cavity is filled with other molecules, these smaller
molecules are called
guests. The corresponding
larger structure is then
considered a host, and the
two together are called a
host:guest
complex.
When no other molecules
are present, the hexamer
is filled with solvent
molecules (when formed
in chloroform, the capsule
holds six solvent molecules); however other small molecules can also be encapsulated by displacing some
or all of the solvent (Figure 3). This is similar in principle to how enzymes are able to encapsulate their
substrates to perform the chemistry necessary for life!
Background
You’ve just begun an internship at a non‐profit organization that is interested in studying the
interactions between self‐assembled hosts and potential guest molecules, and wants to develop efficient
ways of detecting common environmental contaminants. One common contaminant of interest are the
tetraalkylammonium salts. Your task is to prepare a resorcin[4]arene from resorcinol and dodecanal. After
this has been prepared, you will sample the ability of the hexamer (that will self‐assemble in wet CDCl3)
to bind two different tetraalkylammonium cations by NMR (Spectra provided on Blackboard). If one of
the salts binds inside of the hexameric capsule, the chemical environment will be different. As a result,
the chemical shift of free guest will be different than that of the bound guest. If the guest exchanges
quickly on the NMR timescale (i.e., meaning the exchange is faster than the measurement), then there
will be one peak for the guest, but the chemical shift will be a weighted average between the chemical
shift of the free and bound guest. If the exchange is slow on the NMR timescale (i.e., meaning the
exchange is slower than the measurement), which is what you are expecting, then you should see two
distinct sets of peaks for the guest, one free and one encapsulated.
Prelab Questions (write in notebook)
1) Based on the Material Safety Data Sheets (MSDS) for the compounds, which of the compounds in this
experiment is the most hazardous, and why?
2) Finish filling in the reagent table with all pertinent information.
Name
n‐Dodecanal
Resorcinol
Ethanol (95%)
Conc. HCl
Product
Mol.‐eq.
1.0
1.0
‐
‐
MW
‐
mmol
4.6
4.6
‐
‐
Density/Conc.
Amount
‐
‐
‐
‐
3 mL
750 µL
3) The mechanism of the condensation is a little long, but you can write the mechanism for one of the
steps, shown below:
4) Why is this called a condensation? What type of reaction does this mechanism remind you of?
Experiment
1. Synthesis of Resorcin[4]arene
First, add resorcinol to a 10 mL round bottom flask with a stir bar, then add 3 mL ethanol and dissolve 4.6
mmol of resorcinol. While the flask is being stirred, add the 750 µL concentrated HCl, followed by 4.6
mmol of dodecanal. Attach a reflux condenser, and stir the reaction at 80 ºC for 1 h. After cooling there
should be a yellow precipitate that can be filtered using your Hirsch funnel, followed by rinsing with a
small amount of cool water. Once the product is thoroughly dried, recrystallize the resorcin[4]arene using
95% ethanol.
2. Characterization
With the recrystallized product in hand, your first goal will be to determine the yield. Your next goal will
be to determine the purity. For this step you will use melting point analysis, as well as IR. The melting
point for this compound is going to be more broad than usual – why? In the IR you can assess the purity
in part by observing which key peak is missing?
3. Guest Binding
You will be/have been given three 1H NMR spectra. Spectrum 1 is of the resorcinarene product only.
Notice many of the peaks are broadened – why might this be? Spectrum 2 is of the resorcinarene product
and tetramethylammonium bromide. What is different, if anything? Spectrum 3 is of the resorcinarene
product and tetrahexylammonium bromide. What is different, and why?
4. Clean‐up
Your materials will need to be disposed of in the regular wash acetone waste.
Postlab Questions
1) Using your assigned 1H NMR spectrum of the resorcinarene hexamer (sample 1) – you should be able
to identify the OH peaks. Why are the OH peaks so broad??
2) In sample 3, identify the peaks for bound tetrahexylammonium salt inside your host molecule. Identify
the peaks for free tetrahexylammonium salt outside your host molecule. Which peak belongs to the
bound CH3 groups, and why does it show up in this region of the spectrum?
3) Why does one guest bind, while the other does not?
4) Look at the peak for Hc in Sample 3 (~ δ 4.0 – 4.5). There are TWO resonances for Hc, as opposed to ONE
in sample 1. Explain why.
5) There is another molecule that behaves this way, called a pyrogalloarene (see above). It requires
no water for assembly – why?
PerkinElmer Spectrum Version 10.4.00
Friday, April 13, 2018 10:24 AM
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Teaching 1661
Sample 1661 By Teaching Date Friday, April 13 2018