Reversible formation of aminals: A new strategy to control the release of bioactive volatiles from dynamic mixtures

Article abstract of DOI:10.1039/c002302g

Dynamic mixtures generated by reversible aminal formation of fragrance aldehydes with N,N′-dibenzyl alkyldiamines in aqueous systems were found to be suitable delivery systems for the controlled release of bioactive volatiles. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c002302g

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Reversible formation of aminals: a new strategy to control the release
of bioactive volatiles from dynamic mixtures
a
a
a
b
a
Guillaume Godin, Barbara Levrand, Alain Trachsel, Jean-Marie Lehn* and Andreas Herrmann*
Received 3rd February 2010, Accepted 26th March 2010
First published as an Advance Article on the web 12th April 2010
DOI: 10.1039/c002302g
Dynamic mixtures generated by reversible aminal formation
0
2 (see Table 1) are commercially available; others, for example
3 and 4, were prepared by reaction of the primary diamine
of fragrance aldehydes with N,N -dibenzyl alkyldiamines in
aqueous systems were found to be suitable delivery systems for
the controlled release of bioactive volatiles.
4
with benzaldehyde and reduction with NaBH . The corres-
ponding five- or six-membered aminals 5–8, serving as
reference compounds for our study, were prepared by precipi-
7
tation from water as described in the literature.
Dynamic combinatorial chemistry (DCC) based on reversible
1
covalent bond formation has recently attracted considerable
To verify the reversibility of the reaction as the general
concept, we first investigated the formation and hydrolysis of
1
aminals 5–8 by H-NMR spectroscopy in buffered aqueous
interest for the identification of biologically or catalytically
2
active small molecule ligands in drug discovery or receptor
3
design and, inspired by these systems, also for the controlled
solution. Finding the ideal solvent mixture in which the com-
pounds and the buffer were entirely soluble turned out to be
release of volatile bioactive compounds (e.g. fragrances) from
4
dynamic mixtures.
,5
8 2
difficult. Mixtures of THF(D )/D O 3 : 1 or 2 : 1 (using a phos-
Successful fragrance delivery increases the long-lastingness of
many volatiles simultaneously. With respect to preformed
profragrances allowing the delivery of single compounds by
phate buffer at pH ca. 8.5) were identified as the best compromise
for the present studies. Measurements were carried out at
equimolar concentrations in both directions, and NMR spectra
were recorded at different time intervals after mixing the com-
pounds to see the evolution of the spectra.w The ratios of diamine
and aminal obtained at equilibration are listed in Table 1. Almost
identical spectra were obtained starting from diamines 1–4 and
an equimolar amount of benzaldehyde or, alternatively, from
pure aminals 5–8. In all cases, equilibration was relatively slow.
Our data show that similar final equilibrium compositions
were obtained in solution for the different diamines tested
(Table 1). Furthermore, the THF content in the solvent and
the buffer concentration seemed to be less important; generally
slightly higher amounts (ca. 5–10%) of aminals 6–8 were
obtained at equilibrium in the solutions with a lower THF
content (Table 1).
4
covalent bond cleavage, dynamic mixtures are obtained in situ
by reversible (temporary) covalent bond formation of com-
pound mixtures with a suitable substrate and thus influence the
4
,5
controlled, slow release of several volatiles at the same time.
Following our previous studies on the controlled release of
6
fragrances by reversible hydrazone formation, we became
interested in investigating alternative reversible reactions as
possible delivery systems of bioactive compounds.
The preparation of a series of aminals (imidazolidines) by
7
reaction of diamines with aldehydes in water has been reported.
Despite the fact that aminal formation is reversible in aqueous
8
systems (Scheme 1), reasonable to good yields of the desired
products were obtained by precipitation of the aminals from the
reaction medium (and thus by removal from the equilibrium) as a
7
consequence of their low water solubility. If these compounds
The use of surfactants is another possibility to solubilise
hydrophobic compounds in an aqueous environment. This is
particularly interesting in view of the targeted application
of aminals as delivery systems for the controlled release of
could be kept in solution, the generation of dynamic mixtures by
reversible reaction of diamines with mixtures of bioactive volatile
carbonyl compounds should be possible and consequently allow
1
0
volatiles. Many commercial, water-based product formu-
lations contain high amounts of surfactants, which should
facilitate the setting up of dynamic mixtures in these appli-
cations. Cationic surfactants, such as quaternised triethanol-
amine esters of fatty acids (TEA-esterquats), are efficiently
deposited onto cotton in aqueous media and thus find use as
9
their controlled release by slow evaporation into the environment.
8
As primary diamines form Schiff bases as side-products,
we focused our study on the use of secondary diamines.
0
Several symmetric N,N -disubstituted diamines such as 1 and
1
1
fabric softening agents.
We thus compared the evaporation of mixtures of fragrance
aldehydes and ketones in the presence and absence of diamines
1
–4 from cotton under more realistic application conditions.
As long as the different carbonyl compounds can be separated
by gas chromatography (GC), the evaporation of each indivi-
dual compound in the mixture can be followed by dynamic
Scheme 1 General mechanism of reversible aminal formation.
a
6
Firmenich SA, Division Recherche et De´veloppement,
Route des Jeunes, B.P. 239, CH-1211 Gene`ve 8, Switzerland.
E-mail: andreas.herrmann@firmenich.com
ISIS, Universite´ de Strasbourg, 8 Alle´e Gaspard Monge, B.P. 70028,
F-67083 Strasbourg Cedex, France. E-mail: lehn@isis.u-strasbg.fr
headspace analysis. In a typical experiment, an equimolar
1
mixture of 18 fragrance aldehydes and ketones (A–R, Fig. 1)
and one equivalent of either one of the diamines 1–4 was
added to an emulsion of a TEA-esterquat in water (fabric
b
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Table 1 Composition of the equilibria obtained for the formation and hydrolysis of aminals 5–8 in buffered THF(D
8
)/D
2
O solutions as
1
determined by H-NMR spectroscopy
Diamine : aminal ratio at equilibrium (%)
Time/d
ca.
Diamine
Aminal
THF(D
8
2
)/D O
Formation
Hydrolysis
3
: 1
22 : 78
10 : 90
10
a
a
3
2
: 1
: 1
19 : 81
13 : 87
11
16
a
a
12 : 88
13 : 87
b
b
3
2
: 1
: 1
52 : 48
18 : 82
20 : 80
33 : 67
11
29
3
2
: 1
: 1
33 : 67
21 : 79
25
26
a
a
22 : 78
20 : 80
a
b
Average values. Equilibrium not yet reached.
softener base, pH ca. 3.1). The sample was left equilibrating
for 5 days to form the dynamic mixture before being diluted
with water (rinsing cycle), which results in an increase of pH of
about 1 unit (pH ca. 4.0–4.2). Then a small cotton sheet was
added to deposit the dynamic mixture of fragrances together
with the surfactant on the fabric surface. The cotton sheet was
wrung out and air-dried overnight. The fragrance concen-
tration in the headspace above the sample was determined
reproducible with respect to the large differences observed by
comparing headspace concentrations measured in the presence
or absence of the diamine (relative concentrations).
Each dynamic mixture represented in Fig. 2a–d can form
up to 18 different aminals which are in equilibrium with the
unreacted diamine and the corresponding carbonyl compound.
Once exposed to air the non-covalently bound aldehydes and
ketones will be removed from the system by evaporation,
which continuously shifts the equilibrium of the dynamic
mixture towards the hydrolysis of the aminal. This results in
a slow release of the carbonyl compounds from the dynamic
mixture, resulting in an increased long-lastingness of fragrance
perception above the cotton sheet.
6
by GC and compared to a reference sample without diamine. z
Fig. 2 summarises the headspace concentrations measured
for the evaporation of volatiles A–R from dry cotton in the
presence (grey bars) or absence (white bars) of either one of
the diamines 1–4. Despite the relatively large variations of the
absolute concentrations observed in some cases (due to the
variation of a series of parameters during drying at ambient air
which cannot easily be controlled), the data were found to be
Interpretation of the data in Fig. 2 indicated that the choice
of the substituents at the N-atoms influences the efficiency of
0
the delivery system. Whereas N,N -dimethyl diamine 1 gave
rise to only a modest long-lastingness of fragrance release
0
(
Fig. 2a), efficient release profiles were obtained with N,N -
dibenzyl diamines 2–4 (Fig. 2b–d) with respect to the reference
samples without diamine. Furthermore, the efficiency of the
formation of aminals depends on the structure of the carbonyl
compound (in general, aldehydes were found to be more
efficiently retained than ketones). This in return suggests that
the compounds for which no increase in headspace concen-
tration was observed are likely to react with the diamine to a
limited extent only. This aspect is to be further investigated.
The combination of conformational and steric (N-substituents)
restriction obtained with diamine 3 gave the best overall results,
with an increase of headspace concentration by a factor of about
40 for aldehydes C and D with respect to the reference without 3.
Fig. 1 Structures of volatile aldehydes and ketones (A–R) used to set
The size of the aminal heterocycle seems to be less important;
up dynamic mixtures of aminals.
comparable headspace data were measured for dynamic mixtures
3
126 | Chem. Commun., 2010, 46, 3125–3127
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mixture of THF (D
8
)/D
2
O 2:1 (pH = 8.6) or 3:1 (pH = 8.4). The
samples (ca. 5.6 x 10 M in aminal or diamine) were agitated (t = 0)
ꢁ
3
1
and analysed by H-NMR spectroscopy (128 scans, delay time 5 s) at
different time intervals until equilibrium was reached. The com-
pound distribution was determined by integration of characteristic,
non-overlapping signals of the diamine and the corresponding
aminal.
z Procedure for the headspace analysis: to 1.80 g of a TEA-esterquat
s
Stepantex , 16.5% by weight in water) were added one of the
(
diamines 1–4 (0.37 mmol), 0.5 mL of the solution containing the
18 fragrance molecules (A–R, each at ca. 0.041 M in ethanol) and
1.5 mL of ethanol. The sample was closed and left equilibrating for
5 d. Then it was dispersed in a beaker with 600 mL of tap water, and a
cotton sheet (ca. 12 ꢂ 12 cm) was added. The sheet was agitated
manually for 3 min, left standing for 2 min and wrung out by hand. It
was then left drying overnight, put into a home-made headspace
sampling cell (160 mL) and exposed to a constant air flow of ca.
ꢁ1
2
00 mL min at 25 1C. The air was filtered through active charcoal
and aspirated through a saturated solution of NaCl. For 135 min the
system was left equilibrating, and then the volatiles were adsorbed
for 15 min onto a Tenax cartridge. The cartridge was thermally
s
desorbed and the trapped volatiles analysed by GC-MS (in the SIM
mode). Similarly, a second sample without diamine was prepared
and analysed under the same conditions. Headspace concentrations
ꢁ1
(
in ng L of air) were obtained by external standard calibration.
1
2
See for example: (a) J.-M. Lehn, Chem.–Eur. J., 1999, 5,
455–2463; (b) S. J. Rowan, S. J. Cantrill, G. R. L. Cousins, J.
K. M. Sanders and J. F. Stoddart, Angew. Chem., Int. Ed., 2002,
1, 898–952; (c) P. T. Corbett, J. Leclaire, L. Vial, K. R. West,
J.-L. Wietor, J. K. M. Sanders and S. Otto, Chem. Rev., 2006, 106,
652–3711; (d) J.-M. Lehn, Chem. Soc. Rev., 2007, 36, 151–160;
e) S. Ladame, Org. Biomol. Chem., 2008, 6, 219–226.
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Drug Discov. Today, 2002, 7, 117–125; (b) O. Ramstrom and
J.-M. Lehn, Nat. Rev. Drug Discovery, 2002, 1, 26–36;
c) O. Ramstrom, T. Bunyapaiboonsri, S. Lohmann and
J.-M. Lehn, Biochim. Biophys. Acta, Gen. Subj., 2002, 1572,
78–186; (d) J. D. Cheeseman, A. D. Corbett, J. D. Gleason and
2
4
3
(
¨
(
¨
1
R. J. Kazlauskas, Chem.–Eur. J., 2005, 11, 1708–1716; (e) K. R. West
and S. Otto, Curr. Drug Discovery Technol., 2005, 2, 123–160.
Fig. 2 Headspace concentrations measured for the evaporation of a
mixture of volatile carbonyl compounds A–R from dry cotton in the
presence (grey bars) or absence (white bars) of diamines (1–4).
3 See for example: (a) S. Otto, Curr. Opin. Drug Discovery Dev.,
2003, 6, 509–520; (b) A. D. Hamilton, D. M. Tagore and
K. I. Sprinz, in Functional Synthetic Receptors, ed. T. Schrader
and A. D. Hamilton, Wiley-VCH, Weinheim, 2005, pp. 299–332;
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Chem., 2007, 277, 267–288; (e) C. D. Meyer, C. S. Joiner and
J. F. Stoddart, Chem. Soc. Rev., 2007, 36, 1705–1723.
set up with diamines 2 (forming five-membered imidazolidine 6)
and 4 (giving rise to six-membered heterocycle 8, Fig. 2c and d).
In conclusion, the reversible formation of aminals by
reaction of diamines with carbonyl compounds allowed the
generation of dynamic mixtures and combinatorial libraries.
The in situ formation of dynamic mixtures not only avoided
4 A. Herrmann, Angew. Chem., Int. Ed., 2007, 46, 5836–5863.
5
6
A. Herrmann, Org. Biomol. Chem., 2009, 7, 3195–3204.
(a) B. Levrand, Y. Ruff, J.-M. Lehn and A. Herrmann, Chem.
Commun., 2006, 2965–2967; (b) B. Levrand, W. Fieber, J.-M. Lehn
and A. Herrmann, Helv. Chim. Acta, 2007, 90, 2281–2314.
1
0
the preparation of preformed profragrances, it also allowed
the slowing down of the evaporation of several fragrance
components in the mixture simultaneously. The fact that the
evaporation of the different carbonyl compounds was not equally
affected even suggests the possibility of setting up a time-
dependent scent spectrum via sequential release of different
fragrances from a mixture of aminals. Furthermore, the present
results might be of general interest in DCC by extension to the
screening of pharmaceutically active compounds or receptors
and to the development of ligands with catalytic activity in
chemical transformations.
7 V. Jurc
ˇ
ı
´
k and R. Wilhelm, Tetrahedron, 2004, 60, 3205–3210.
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8
9
Soc., 1973, 95, 3362–3368; (b) C. Chapuis, A. Gauvreau,
A. Klaebe, A. Lattes and J. J. Peire, Bull. Soc. Chim. Fr., 1973,
977–985; (c) G. P. Tuszynski and R. G. Kallen, J. Am. Chem. Soc.,
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Parts of this publication are the subject of a patent application:
A. Herrmann, G. Godin and J.-M. Lehn (to Firmenich SA,
´
Universite Louis Pasteur and CNRS) WO 2008/093272, 2008;
1
Chem. Abstr., 2008, 149, 252005.
0
0
1
0 Aminals of N,N -dialkyl and N,N -diphenyl diamines have recently
been reported as profragrances: U. Huchel, S. Sauf and T. Gerke
(
1
to Henkel KGaA) DE 10 2005 062 175, 2007; Chem. Abstr., 2007,
47, 101295. In this work the aminal precursors for each com-
Notes and references
w Procedure for the equilibration measurements: phosphate buffer stock
pound to be released were prepared individually; the reversibility
of the system and the possible formation of dynamic mixtures were
not explored.
solutions of Na
compounds used for aminal formation and hydrolysis, respectively,
were dissolved in THF (D ) and added to the buffer to give a final
2 4 2 4 2
HPO and KH PO were prepared in D O. The
8
11 S. Mishra and V. K. Tyagi, J. Oleo Sci., 2007, 56, 269–276.
This journal is ꢀc The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 3125–3127 | 3127