Synthesis of per-deuterated alkyl amines for the preparation of deuterated organic pyromellitamide gelators

Article abstract of DOI:10.1016/j.tetlet.2013.03.031

A general, direct and scalable synthesis of per-deuterated alkyl amines is reported, together with their incorporation into pyromellitamides, which form self-assembled gels in cyclohexane. The deuterium labelling of these gelators allows the study of the dynamic intermolecular interactions in these materials using solid-state ²H NMR spectroscopy.

Full text of DOI:10.1016/j.tetlet.2013.03.031

Tetrahedron Letters 54 (2013) 2538–2541
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Tetrahedron Letters
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Synthesis of per-deuterated alkyl amines for the preparation of deuterated
organic pyromellitamide gelators
Nageshwar R. Yepuri a, Scott A. Jamieson b, Tamim A. Darwish a, , Aditya Rawal c, James M. Hook c,
⇑
Pall Thordarson b, Peter J. Holden a, Michael James a,b
a National Deuteration Facility, Bragg Institute, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, NSW 2232, Australia
b School of Chemistry, The University of New South Wales, Kensington, NSW 2052, Australia
c NMR Facility, Mark Wainwright Analytical Centre, The University of New South Wales, Kensington, NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A general, direct and scalable synthesis of per-deuterated alkyl amines is reported, together with their
incorporation into pyromellitamides, which form self-assembled gels in cyclohexane. The deuterium
labelling of these gelators allows the study of the dynamic intermolecular interactions in these materials
using solid-state 2H NMR spectroscopy.
Received 21 January 2013
Revised 22 February 2013
Accepted 7 March 2013
Available online 15 March 2013
Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
Keywords:
Self-assembling organogels
Deuterated amines
Supramolecular chemistry
Solid state deuterium NMR
Research into self-assembled gels is a rapidly expanding field
due to their numerous technological,1 biomaterial and medical
applications,2 ranging from targeted drug delivery3 to artificial
muscle fibres,4 and even formation of scaffolds for the regeneration
of spinal cords.5 The design and synthesis of organic molecule
based self-assembling gels has advanced rapidly over the last
two decades.6 Although gelator molecules are readily designed
and assembled, detailed structural analysis of these molecules in
the gel phase remains a significant challenge.
between the gel fibre network and surrounding solvent matrix.
Furthermore, 2H NMR line shapes are sensitive to the rate and
mechanism of the particular re-orientational motion of the C–D
bond. Line shape analysis using appropriate simulation programs
can give important information on the motional behaviour of mol-
ecules in gel matrices.
Simple amide- and urea-based gelators derived from alkyl
amines feature heavily in the literature on self-assembled gels.1,6
Methods to more effectively per-deuterate amines are therefore
of general interest to this research area. We report here the synthe-
sis of per-deuterated alkyl amines which can then be integrated
into the pyromellitamides. We demonstrate the utility of deutera-
tion by solid-state 2H NMR analysis of the resulting compounds
giving us valuable insight into the mobility of the alkyl side chains.
Deuterium-labelled compounds are commonly used for deter-
mination of structure,8 reaction pathways,9 as stable isotope trac-
ers,10 for the synthesis of drug compounds with improved
We have demonstrated that a new family of gelator molecules,
the pyromellitamides 1 and 2 in Figure 1, form organogels in non-
polar solvents such as cyclohexane at ꢀ1% w/w.7 Intermolecular
hydrogen-bonds and
p–p interactions allow these molecules to
assemble into one-dimensional fibres of ꢀ2 nm in diameter.
Pyromellitamides then aggregate into higher-order hierarchical
assemblies and show evidence of forming bundles of twisted heli-
cal fibres (of hundreds of nm) and ultimately a three-dimensional
network resulting in gel formation.7b Techniques such as electron
microscopy and atomic force microscopy, while useful for imaging
these gel structures in the dry state, do not allow the structure of
these pyromellitamide organogels to be quantified in their fully
solvated state. In situ studies of solvated gel structures require
techniques such as NMR and small angle neutron scattering (SANS)
in conjunction with deuterium labelling in order to differentiate
⇑
Corresponding author. Tel.: +61 2 9717 9080; fax: +61 2 9717 3038.
E-mail address: tamim.darwish@ansto.gov.au (T.A. Darwish).
Figure 1. Pyromellitamide gelator.
0040-4039/$ - see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.031

N. R. Yepuri et al. / Tetrahedron Letters 54 (2013) 2538–2541
2539
Scheme 1. Synthesis of deuterated amines 5 and 8 from the corresponding perdeuterated fatty acids 3 and 6.
metabolic stability,11 and to provide enhanced contrast in neutron
scattering studies.12 Deuterium labelled aliphatic alkyl amines can-
not be produced directly by hydrothermal exchange methods using
metal catalysts at high temperature and pressure,13a–c as they lead
to oxidation of the amine groups.
The same protocol was used to produce 6 from n-butanoic acid in
70% yield [98( 2)% deuteration—Supplementary data, Figs. S3 and
S4]. The overall level of deuteration within each of these molecules
was determined using ESI-mass spectrometry for both 3 and 6.
The method for converting the carboxylic acid (i.e., C4 and C6)
into the corresponding amine needs to consider critically the high
volatility of the possible common intermediate compounds that
are usually produced in such reactions (e.g., alcohol, bromides, or
azides). To obtain the targeted per-deuterated amine 5 (Scheme
1a), 3 was treated with excess thionyl chloride in dichloromethane
at 0 °C. After adding a catalytic amount of N,N-dimethylformamide,
the reaction was stirred for 5 h at reflux temperature. Excess thio-
nyl chloride was then distilled off and the residue taken into dry
acetonitrile and cooled to 0 °C. Aqueous ammonia was added
slowly and the mixture stirred for 2 h at room temperature.16
The mixture was partitioned into dichloromethane and upon evap-
oration the residue was purified by flash column chromatography
to give a white solid, n-hexamide-d11 4 in 76% yield. Amide 4 was
then successfully reduced to give 5 using LiAlD4 in tetrahydrofuran
at 70 °C. The amine was then purified by distillation through a
Vigreux column at 100 mbar pressure and 70 °C, giving 5 in 82%
yield. Deuteration levels were found to be retained at 98%
(Supplementary data, Figs. S5–S7).
For the equivalent reaction scheme, the synthesis of per-deuter-
ated 8 from 6 would be complicated by the fact that the boiling
point of the intermediate butyryl chloride is similar to that of thio-
nyl chloride, making the removal of the latter from the reaction
mixture difficult, prior to the conversion into the amide. We there-
fore chose a different approach for this step of the synthesis
(Scheme 1b); using benzoyl chloride as the chlorinating agent in-
stead of thionyl chloride.17 The optimized reaction conditions used
3 mol equiv of benzoyl chloride and 1 mol equiv of 6, heating un-
der refluxing conditions for 30 min, before distilling off the desired
butyryl chloride intermediate. Conversion of this acid chloride into
the n-butylamide-d7 7 (solid, 70% yield) was achieved under the
same conditions described above.
Mixed results have been obtained by those attempting to
deuterate aliphatic amines under more moderate conditions. Only
a few examples of the H/D-exchange of amines using heteroge-
neous catalysts are known.13d In most of these cases, H/D exchange
reactions suffer from only moderate deuterium incorporation.
Depending on the position of the amine along the aliphatic chain
(i.e., 1°, 2° or 3° amine), exchange may occur at alpha, beta and/
or in rare cases, at the gamma positions.13 Desai et al.14 used the
basic nature of the alkyl amine to help deuterate these molecules
at ꢀ120 °C using platinum chloride reduced by NaBH4; however
only the
a
- and b-positions showed significant levels of deutera-
- and
tion.14 For n-butylamine-d4 the deuteration levels of the
a
b-positions were 82% and 21%; while for n-hexylamine-d4 deuter-
ation levels were found to be 62% and 36%, respectively.
Homogeneous transition metal catalysts are more commonly
used to allow for selective H/D exchange of amines.15 Takahashi
et al.15a and Alexakis et al.15b have used Ru-based catalysts to
deuterate selectively the
and b-positions of 2° amines, respectively. Beller and
co-workers15c also demonstrated chemoselective deuteration of
the - and b-positions of tertiary amines using a ruthenium Shvo
catalyst.
Deuterating the hydrocarbon chain of aliphatic amines beyond
their -, b- and -positions becomes impossible using the above
a-positions of 1° and 2° amines, and the
a-
a
a
c
methods with moderate conditions. This is due to the inactive nat-
ure of the carbon sites that are situated away from the amine
group. Moreover, the harsher conditions of the hydrothermal
exchange reactions can lead to oxidation of the amine groups.
Therefore, in order to achieve the complete deuteration of the
hydrocarbon chains of these aliphatic amines, it is necessary to
firstly produce per-deuterated forms of stable precursors (i.e., fatty
acids) before converting them into their respective amine. This Let-
ter reports optimized methods for the production of per-deuter-
Due to the similarity in boiling points between 8 and tetrahy-
drofuran, the reduction of 7 was carried out in diethyl ether at
reflux temperature overnight before distillation through a Vigreux
column at ambient pressure. The required product 8 was obtained
in good yield (82%). It should be noted that the reduction of 7 was
also attempted in diglyme and tetraglyme as high boiling ether
solvents, however the amide was not sufficiently soluble in these
solvents. The deuteration levels of 8 were found to be retained at
97% (Supplementary data, Figs. S8–S10).
ated
5 and 8, and the details of their assembly into the
deuterated pyromellitamide gelators 10 and 11, to demonstrate
their capacity as effective probes in 2H NMR measurements.
The per-deuterated amines 5 and 8 were synthesized using per-
deuterated n-hexanonic acid-d11 3 and n-butanoic acid-d7 6,
respectively, as starting materials (Scheme 1). Starting from n-hex-
anoic acid, 3 was prepared using 10% Pt/C (4% w/w) and D2O under
basic conditions in a Parr reactor at 220 °C for two cycles, each of
3 days. This hydrothermal process gave 3 with 97( 2)% deuterium
exchange and over 75% yield (Supplementary data,Figs. S1 and S2).
The deuterated pyromellitamide gelators 11 and 10 were pre-
pared according to the method of Tong et al.7b In brief, a solution
of benzene-1,2,4,5-tetracarbonyl tetrachloride (9)18 in dry THF

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N. R. Yepuri et al. / Tetrahedron Letters 54 (2013) 2538–2541
Scheme 2. Synthesis of deuterated pyromellitamide gelators 10 and 11.
Figure 3. Solid-state 2H NMR of 10 (left) and 11 (right) at 250 K (lower) and 310 K
(top) as fully solvated gels in cyclohexane. Both gels show sharp isotropic
a
resonance which is superimposed on a small broad resonance. As the gels are frozen
(250 K), a large fraction of the intensity of the isotopic peak is transferred to the
small broad peak due to immobilization of the side chains.
the additional process of freezing the fibre chains, we can then
monitor the chain dynamics during the self-assembly process. Pre-
liminary studies on 10 and 11 focused on a fully-solvated gel when
hot (viscous) and frozen (solid), to monitor changes in the solid
state 2H NMR line shape between these two conditions.
The solid-state 2H NMR spectra in Figure 3, show that at slightly
elevated temperatures (310 K), there is a sharp isotropic peak cen-
tred on a small broad peak. This isotropic peak corresponds to
ꢀ80% and 77% of the total signal for 10 and 11 respectively, indi-
cating that the majority of the side-chains are mobile, save for that
part which is closest to the core. When the temperature is dropped
by 60° to 250 K, the isotropic peak decreases in intensity to ꢀ30%
and ꢀ23% respectively, indicating that only the terminal deuter-
ated methyl groups remain mobile.
Figure 2. FTIR spectra of the protonated 2 (red) and deuterated 11 (blue) tetrahexyl
pyromellitamide gelators.
In conclusion, we have demonstrated that per-deuterated alkyl
amines (ꢀ98% D) can be readily obtained from the corresponding
hydrogenated aliphatic acids in three simple steps with overall
yields of ꢀ50%. Our methodology affords large quantities of amines
and overcomes issues related to amine-oxidation that are associ-
ated with classical methods for H/D exchange of amines under
hydrothermal conditions. This approach allows the synthesis of
deuterated pyromellitamide gelators 10 and 11 possessing per-
deuterated alkyl side chains. Solid-state 2H NMR of these materials
demonstrates the difference in the core–shell structures of the gel
fibres from the two gelators. Our preliminary investigation
demonstrates that both 10 and 11 form self-assembled gels in both
protonated and deuterated cyclohexane at concentrations of ꢁ1%
w/w, similar to the findings in our previous work on the corre-
sponding protonated gelators.7 These compounds are, to our best
knowledge, the first deuterated gelators reported which form
self-assembled gels. Further investigation into the gelation proper-
ties of these compounds is in progress in our laboratory.
was stirred at room temperature for 1 h and then cooled to 0 °C,
followed by slow addition of the appropriate per-deuterated amine
5 or 8 dissolved in a 20:20:1 mixture of THF, dichloromethane and
pyridine at 0 °C for 1 h, and then stirring overnight at room tem-
perature (Scheme 2). Starting from per-deuterated amines 5 and
8, this method gave the deuterated pyromellitamides 11 and 10
in 34% and 26% yields, respectively. High-resolution MS of 10
and 11 indicated ꢀ98% deuteration of the carbon atoms of the
butylamide and hexylamide groups, respectively (Supplementary
data, Figs. S11–S16).
Figure 2 shows the FTIR spectra of the deuterated 11 and pro-
tonated 2 forms of the tetrahexyl pyromellitamide gelator, show-
ing a clear shift in the absorption lines associated with the CH
stretches at ꢀ2900 cmÀ1 and CD stretches at ꢀ2100 and 2200 cm
À1
of the hexylamide pendant groups. The difference between the
CH2 bend (1450 cmÀ1) and CD2 bend (1050 cmÀ1) in 2 and 11,
respectively, is also clearly visible. The corresponding FTIR spectra
for the deuterated 10 and protonated 1 forms of the tetrabutyl
pyromellitamide gelator show similar shifts in the CH/CD stretches
and CH2/CD2 bends (Supplementary data, Fig. S17).
Acknowledgments
The use of deuterium-based solid state NMR provides informa-
tion on the molecular orientation order parameters of the gels,19 as
the molecules are essentially trapped in a semi-crystalline state. By
The authors acknowledge the use of NCRIS-funded National
Deuteration Facility Laboratories for the synthesis of these mole-
cules, as well as the facilities of the Mark Wainwright Analytical

N. R. Yepuri et al. / Tetrahedron Letters 54 (2013) 2538–2541
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Centre of the University of New South Wales. Dr. Greta Moraes and
Ms. Marie Gillon from NDF are acknowledged for their help in the
laboratory. We acknowledge the Australian Research Council for a
Discovery Project Grant (DP09855059) and Future Fellowship
(FT120100101) to P.T. and a scholarship to S.A.J.
Supplementary data
Supplementary data (synthesis, 1H and 2H NMR, IR and MS
spectroscopy characterisation and spectral details) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.03.031.
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