A convenient laboratory synthesis of deuterium-labelled trimethyl tetradecyl ammonium sulphate

Article abstract of DOI:10.1002/jlcr.1035

A convenient and practical laboratory synthesis of deuterium-labelled trimethyl tetradecyl ammonium sulphate is reported. Copyright

Full text of DOI:10.1002/jlcr.1035

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 147–151.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1035
Research Article
A convenient laboratory synthesis of deuterium-labelled
trimethyl tetradecyl ammonium sulphate
Sameer Chavda, Gregory S. Coumbarides, Marco Dingjan, Jason Eames*
and Ali Zarbakhsh
School of Biological and Chemical Sciences, Queen Mary, University of London,
London E1 4NS, UK
Summary
A convenient and practical laboratory synthesis of deuterium-labelled trimethyl
tetradecyl ammonium sulphate is reported. Copyright # 2005 John Wiley & Sons, Ltd.
Key Words: ammonium salts; tetradecyl bromide; deuterium; surfactants; trimethy-
lamine
Introduction
Resolving structures at buried liquid–liquid interfaces contributes to our
current understanding of many important processes, such as the transport
properties of cell membranes and the stabilisation of emulsions used for drug
delivery. The recent development of a novel, versatile and complementary
approach for probing the structure of adsorbed polymers and surfactants at
oil–water interfaces using neutron reflectometery has made inroads in this
area.1,2 A preliminary investigation of the interface between an aqueous
solution of tetradecyl trimethylammonium bromide (C14TAB) at critical
micelle concentration and hexadecane3 posed several intriguing questions
regarding the nature of the structure at the oil–water interface. In order to
determine adsorbed amounts, the oil and water distributions through the
interface need to be known. However, regardless of the underlying oil and
water distributions, the nature of the amphiphile distribution raises the most
interest. If a single-layer model is used to model the data, the adsorbed amount
is significantly less than that found at the air–solution interface,4 whereas, one
*Correspondence to: J. Eames, Department of Chemistry, University of Hull, Cottingham Road, Kingston
upon Hull, HU6 7RX, UK. E-mail: j.eames@hull.ac.uk
Contract/grant sponsor: Queen Mary, University of London
Contract/grant sponsor: GOSS Scientific Instruments Ltd
Copyright # 2005 John Wiley & Sons, Ltd.
Received 17 October 2005
Revised 6 November 2005
Accepted 12 November 2005

148
S. CHAVDA ET AL.
might have expected the adsorbed amount to be comparable or possibly
greater when both segments of the amphiphile are solvated. Furthermore, to
obtain both a good fit to the data and an adsorbed amount in the primary
adsorbed film that is comparable to that found at the air–solution interface, it
is necessary to include a water-rich secondary adsorbed layer. Inclusion of this
unexpected layer leads to an excellent fit to the data.
In order to resolve the structure of a water-rich secondary adsorbed layer using
neutron reflectometery, isotopic substitution with appropriate deuterium labelling
is essential. This would help to determine the adsorbed amount and to examine
the oil, water and amphiphile distributions through the interface. In this paper,
we report a user friendly and practical route for the synthesis of D-labelled
ammonium salts that can be carried out safely by a non-synthetic chemist.
Results and discussion
With this aim in mind, we chose to synthesize the required unlabelled
ammonium salt, trimethyl tetradecyl ammonium bromide 2,5 by sequential
addition of four equivalents of trimethylamine (b.p. 3–48C) to neat
1-bromotetradecane 1 at 08C under a nitrogen atmosphere. The resulting
solution was stirred for 12 h to give a crude residue of trimethyl tetradecyl
ammonium bromide 2. This was subsequently purified through precipitation,
by addition of acetone, to give the required trimethyl tetradecyl ammonium
bromide 2 as a white powder in 74% yield (Scheme 1). It is interesting to note,
by placing the reaction vessel under a positive pressure of nitrogen (by using a
balloon of nitrogen) considerably reduced the volatility of the trimethylamine
(b.p. 3–48C).
Br
1
Me3N
NMe3
Br
2; 74%
AgSO4
(-AgBr)
NMe3
SO4
NMe3
3; 84%
Scheme 1.
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 147–151

SYNTHESIS OF D-LABELLED TRIMETHYL TETRADECYL AMMONIUM SULPHATE 149
Our attention next turned towards the synthesis of the trimethyl tetradecyl
ammonium sulphate 3 by substituting the bromide counter in the ammonium
bromide 2 with a sulphate counter. This was achieved using a modified route,5
by addition of silver sulphate (0.5 equiv.) to a stirred solution of ammonium
bromide 2 (1 equiv.) in water (Scheme 1). This solution was stirred for 20 min
and the resulting grey precipitate (silver bromide) was removed through
filtration. Acetone was added to the filtrate to assist precipitation of the
remaining silver bromide, which was removed through decanting. The final
traces of silver bromide were removed through double filtration using a
cotton-wool pipette. Evaporation of the colourless acetone–water layer gave,
after sequential addition of dry acetone to remove the final traces of water, the
required trimethyl tetradecyl ammonium sulphate 3 as a white powder in 84%
yield (Scheme 1).
With this information in hand, we next turned our attention towards the
synthesis of the corresponding deuterium-labelled trimethyl tetradecyl
ammonium sulphate 3-d29. We chose to use the commercially available
deuterium-labelled bromotetradecane 1-d29 as our starting precursor (Scheme 2).
Using our previously outlined protocol, the required trimethyl tetradecyl
ammonium bromide 2-d29 and sulphate 3-d29 were economically synthesized
on a small laboratory scale (0.5–2.0 mmol scale) from the corresponding
D2 D2 D2 D2 D2 D2 D2
C
C
C
C
C
C
C
D3C
C
C
C
C
C
C
Br
D2 D2 D2 D2 D2 D2
1
Me3N
D2 D2 D2 D2 D2 D2 D2
Br
NMe3
C
C
C
C
C
C
C
D3C
C
C
C
C
C
C
D2 D2 D2 D2 D2 D2
2; 40%
AgSO4
(-AgBr)
D2 D2 D2 D2 D2 D2 D2
C
C
C
C
C
C
C
D3C
D3C
C
C
C
C
C
C
NMe3
SO4
D2 D2 D2 D2 D2 D2
D2 D2 D2 D2 D2 D2 D2
C
C
C
C
C
C
C
C
C
C
C
C
C
NMe3
D2 D2 D2 D2 D2 D2
3; 95%
Scheme 2.
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 147–151

150
S. CHAVDA ET AL.
bromide 1-d29, in 40 and 57% yields, respectively (Scheme 2). It is interesting
to note, the melting points for these unlabelled and deuterium-labelled
sulphates, 3 and 3-d29 were different, which was presumably due to the changes
within their lattice energies. Our neutron diffraction studies of these samples
will be published in due course.
Experimental
All reactions were carried out under nitrogen using oven-dried glassware.
Proton and carbon NMR spectra were recorded on a Bruker AM 400 Fourier
transform spectrometers using an internal deuterium lock. Chemical shifts are
quoted in parts per million downfield from tetramethylsilane. Carbon NMR
spectra were recorded with broad proton decoupling. Infrared spectra were
recorded on a Shimadzu 8300 FTIR machine. The levels of D-incorporation
were determined by a combination of mass and proton NMR spectra.
Trimethyl tetradecyl ammonium bromide 15
Trimethylamine (0.47 g, 0.65 ml, 7.9 mmol) was added to neat 1-bromotetra-
decane 1 (2 g, 2.15 ml, 7.2 mmol) at 08C and the resulting solution was stirred
for 4 h. Three further portions of trimethylamine (0.47 g, 0.65 ml, 7.9 mmol)
were added to this solution after 4-h intervals. The resulting solution was left to
stir for a further 12 h. The resulting residue was purified by the addition of
acetone to give the ammonium salt 2 (1.8 g, 74%) as white crystalline solid; mpt
>2308C; dH (400 MHz, CDCl3) 3.45 (2 H, m, CH2N), 3.20 (9 H, s, 3 ꢀ CH3),
1.80 (2 H, m, CH2), 1.40 (6 H, br m, 3 ꢀ CH2), 1.32 (18 H, m, 9 ꢀ CH2)
and 0.90 (3 H, t, J ¼ 6:9 Hz, CH3CH2); dC (100 MHz, CDCl3) 66.5 (CH2N),
53.2 (CH3N), 32.1 (CH2), 30.1 (2 ꢀ CH2), 30.0 (CH2), 29.9 (CH2), 29.8 (CH2),
29.6 (CH2), 29.3 (CH2), 26.3 (CH2), 22.9 (CH2), 22.7 (2 ꢀ CH2) and 13.9 (CH3)
(found C17H38N+, 256.2999. C17H38N requires M, 256.2999).
Trimethyl tetradecyl ammonium bromide 2-d29
Using the same method as the ammonium salt 2, trimethylamine (0.47 g,
0.65 ml, 7.9 mmol; four portions of 0.47 g, 0.65 ml, 7.9 mmol) and 1-
bromotetradecane 1-d29 (0.5 g, 1.63 mmol), gave the deuterium-labelled
ammonium salt 2-d29 (0.23 g, 40%) as a white; mpt>2308C; vmax(film)/cmꢁ1
2150–2100 (CD); dH (400 MHz, CDCl3) 3.11 (9 H, s, 3 ꢀ CH3); dC(100 MHz,
CDCl3)y 53.0 (CH3N) (found C17H9D29N+, 285.4817. C17H9D29N requires
M, 258.4819).
y The absence of defined multiplets for CD2 and CD3 groupings (within the 13C NMR spectrum) is
presumably due to a combination of long relaxation times for the associated carbon nuclei, and low
solubility of the parent ammonium salt in deuterochloroform. For additional information see Eames et al.6
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 147–151

SYNTHESIS OF D-LABELLED TRIMETHYL TETRADECYL AMMONIUM SULPHATE 151
Trimethyl tetradecyl ammonium sulphate 35
Silver sulphate (93 mg, 0.29 mmol) was added to a stirred solution of
ammonium salt 2 (0.2 g, 0.59 mmol) in water (3 ml) at room temperature.
The resulting solution was stirred for 30 min to give a cream coloured solution.
The residual silver bromide was filtered off to give a light grey solution.
Acetone (20 ml) was added to assist the precipitation of the remaining silver
bromide, which was removed by decanting into another flask. The remaining
solution was filtered twice through a pipette column packed with cotton wool,
evaporated under reduced pressure by sequential addition of acetone (to aid
removal of the resulting water) to give the ammonium sulphate 3 (0.15 g, 84%)
as a white crystalline solid; mpt 207–2108C; dH (400 MHz, CDCl3) 3.16 (2 H,
m, CH2N), 2.99 (9 H, s, 3 ꢀ CH3), 1.61 (2 H, m, CH2), 1.22 (6 H, br m,
3 ꢀ CH2), 1.16 (18 H, m, 9 ꢀ CH2) and 0.73 (3 H, t, J ¼ 6:8 Hz, CH3CH2); dC
(100 MHz, CDCl3) 66.5 (CH2N), 52.9 (CH3N), 31.9 (CH2), 30.2 (2 ꢀ CH2),
30.0 (CH2), 29.9 (CH2), 29.8 (CH2), 29.7 (CH2), 29.5 (CH2), 26.1 (CH2), 22.9
(CH2), 22.7 (2 ꢀ CH2) and 13.9 (CH3) (found C17H38N+, 256.3002. C17H38N
requires M, 256.2999).
Trimethyl tetradecyl ammonium sulphate 3-d29
Using the same method as the ammonium sulphate 3, silver sulphate (89 mg,
0.28 mmol) and the ammonium salt 2-d29 (0.211 g, 0.57 mmol), gave the
deuteriated ammonium sulphate 3-d29 (0.18 g, 95%) as a white solid; mp ¼
210–2128C; vmax(film)/cmꢁ1 2160–2090 (CD); dH (400 MHz, CDCl3) 3.99 (9 H,
s, 3 ꢀ CH3); dC(100 MHz, CDCl3)6 52.8 (CH3N) (found C17H9D29N+,
285.4817. C17H9D29N requires M, 258.4819).
Acknowledgements
We thank Queen Mary, University of London and GOSS Scientific
Instruments Ltd for their generous financial assistance, and the EPSRC
National Mass Spectrometry Service (Swansea) for accurate mass determina-
tions.
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Copyright # 2005 John Wiley & Sons, Ltd.
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