Controlled release of volatile aldehydes and ketones by reversible hydrazone formation - "Classical" profragrances are getting dynamic

Article abstract of DOI:10.1039/b602312f

Dynamic mixtures obtained by reversible covalent acylhydrazone formation of fragrance aldehydes and/or ketones and a hydrazide in water were found to be efficient delivery systems for the controlled release of highly volatile organic molecules. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b602312f

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Controlled release of volatile aldehydes and ketones by reversible
hydrazone formation – ‘‘classical’’ profragrances are getting dynamic
Barbara Levrand,a Yves Ruff,b Jean-Marie Lehn*b and Andreas Herrmann*a
Received (in Cambridge, UK) 15th February 2006, Accepted 20th March 2006
First published as an Advance Article on the web 3rd April 2006
DOI: 10.1039/b602312f
prepared their corresponding acylhydrazones 4–6 by heating
them with a slight excess of benzaldehyde, vanillin or trans-
cinnamaldehyde in ethanol, respectively.10 The products crystal-
lised on cooling to room temperature, and could thus be easily
isolated.11 The choice of the aldehyde was essentially influenced by
the ease of measurement of the kinetic rate constants by UV/Vis
spectroscopy at different pH, so as to allow the analysis of the
reaction mixture at equilibrium.
Dynamic mixtures obtained by reversible covalent acylhydra-
zone formation of fragrance aldehydes and/or ketones and a
hydrazide in water were found to be efficient delivery systems
for the controlled release of highly volatile organic molecules.
For optimal performance, biologically active substances such as
pharmaceuticals, agrochemicals, and also flavours or fragrances
have to be efficiently delivered to their target site and usually
released at a well-defined rate. In the case of fragrances the target
sites are different types of surfaces from which the active
compound then evaporates. Fragrances are very volatile and their
perception is therefore limited in time. Furthermore, many of
them, in particular aldehydes, are unstable and undergo partial
degradation prior to their effective use. To circumvent these
problems, fragrance precursors (so called ‘‘profragrances’’) have
been developed which are cleaved under mild reaction conditions
during application.1,2 These precursors thus have to be reasonably
stable during product storage but relatively labile once deposited
on the target surface such as skin, hair or fabric, in order to release
the active compound.
Kinetic measurements were carried out in buffered solutions of
water/ethanol 2 : 1 at pH 2.47 (phosphate buffer) and 4.48
(citrate buffer), and at a product concentration of ca. 1.7 6
1025 M. UV/Vis spectra were recorded at constant time intervals
between 240 and 450 nm. All reactions were investigated at
equimolar concentrations for both formation and hydrolysis of the
acylhydrazones. Good linear fits of the data points (r2 > 0.99) were
generally obtained by plotting the logarithm of the difference of
absorption at time t + Dt and time t (At + Dt 2 At) against time
(Guggenheim method),12 thus indicating first order kinetics.{
Within the experimental error, the same equilibrium states were
reached either from a mixture of hydrazide and aldehyde or,
alternatively, by hydrolysis of the corresponding acylhydrazone as
illustrated in Fig. 1 for the reaction between 2, cinnamaldehyde
and 5c at pH 2.47.
The successful use of reversible covalent reactions in the
development of dynamic combinatorial libraries,3–5 in particular
for drug discovery,5 prompted us to adapt this concept to the
controlled delivery of fragrances. For our investigations we chose
the reaction of hydrazine derivatives (namely hydrazides) with
aldehydes or ketones which are in an equilibrium with the
corresponding hydrazones via an intermediate hemiaminal in a
two-step mechanism (Scheme 1).6–8 This reaction is pH dependent
and, at neutral pH, the dehydration of the hemiaminal was found
to be the rate-determining step, whereas at lower pH hemiaminal
formation is the slower step.6–8
The data in Table 1 show that at pH 2.47 the rates of formation
and hydrolysis for a given acylhydrazone are very similar, whereas
at pH 4.48 the acylhydrazone formation is generally slightly faster
than its hydrolysis. At pH 2.47 the reactions with cinnamaldehyde
were found to be slower than those with benzaldehyde or vanillin.
This effect was less pronounced at higher pH, and the
equilibrations with benzaldehyde occurred slightly faster than
To screen the potential of reversible hydrazone formation for
controlled fragrance delivery, we used a series of commercially
available hydrazides such as benzhydrazide (1), furoic acid
hydrazide (2) or the Girard-T reagent9 (3) (Scheme 2), and
Scheme 1 Equilibrium for the reversible hydrazone formation.
aFirmenich SA, Division Recherche et De´veloppement, B.P. 239,
CH-1211 Gene`ve 8, Switzerland.
E-mail: andreas.herrmann@firmenich.com
bISIS, Universite´ Louis Pasteur, 8 alle´e Gaspard Monge, B.P. 70028,
F-67083 Strasbourg cedex, France. E-mail: lehn@isis.u-strasbg.fr
Scheme 2 Structures of acylhydrazones 4–6 obtained by reaction of
hydrazides 1–3 with different perfumery aldehydes.
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an emulsion of a TEA-esterquat in water (fabric softener base, pH
ca. 3.1), and left equilibrating for 5 days to form the dynamic
mixture. The sample was then diluted with water (rinsing cycle),
which results in an increase of pH of about 1 unit (pH ca. 4.0–4.2)
and which is expected to slow down the re-equilibration. To
deposit the surfactant together with the hydrazide and the
fragrances on the fabric surface, a small cotton sheet was added
which was agitated manually for 5 min, then wrung out and air-
dried overnight. The fragrance concentration in the headspace
above the sample was determined at constant time intervals and
compared to a reference sample without hydrazide 3, which was
prepared and analysed under the same conditions.{
The data in Fig. 2 show that the presence of 3 has a significant
effect on the evaporation of the fragrance aldehydes and ketones
of the mixture. At the end of the experiment (after 7.5 h) the
presence of 3 increased the amount of (Z)-4-dodecenal measured
in the headspace by a factor of about 1.4, and that of 10-
undecenal, 4-phenyl-2-butanone, (¡)-3-phenylbutanal and (+)-
citronellal by a factor of 4.6, 5.6, 7.6 and 8.8, respectively. In the
case of acetophenone the headspace concentration was even found
to be 20.5 times higher than for the reference sample without 3. In
terms of olfactory features this means that the time release
spectrum, and therefore the olfactory perception, are significantly
different for the mixtures of the parent fragrance compounds and
for the mixture of the dynamic release derivatives. In general,
fragrances with vapour pressures above ca. 2 Pa were found to give
rise to much higher headspace concentrations than less volatile
compounds.15
Fig. 1 Equilibrium reached for the reaction of equimolar amounts of
hydrazide 2 with cinnamaldehyde (decrease in absorption at 270 nm and
increase at 320 nm) and for the hydrolysis of the corresponding
acylhydrazone 5c (increase at 270 nm and decrease at 320 nm) at pH 2.47.
those with the other two aldehydes at pH 4.48. As expected, the
pH has a much stronger effect on the reaction rates than the
structure of the aldehydes or hydrazides. The rate constants for
acylhydrazone formation or hydrolysis increased by a factor of
10 to 60 when the pH was decreased by 2 units. This should make
this delivery system especially interesting for practical applications
which involve a change in pH.
The present results show that dynamic mixtures prepared in situ
by mixing (perfumery) aldehydes and/or ketones with a hydrazine
derivative in water are efficient delivery systems for the controlled
release of biologically active compounds. Acylhydrazones are
particularly attractive as this functional group incorporates both a
peptide bond and a reversible imine unit.16 The dynamic mixtures
can easily be deposited on various substrates. Once exposed to a
surface in contact with air, the fragrances are removed from the
mixture by evaporation, and consequently shift the equilibrium
towards the free hydrazine derivative. The gradual hydrolysis of
the hydrazones results in a long-lasting fragrance release whose
effect is particularly strong for highly volatile odorants. The
concept of reversible covalent hydrazone formation to modulate
the evaporation of volatile organic molecules from various
substrates may find general use in other areas such as the
pharmaceutical or agrochemical industry.
We then investigated the kinetics of evaporation of different
fragrance aldehydes and ketones in a dynamic mixture with an
acylhydrazone from a surface by dynamic headspace analysis13
under more realistic application conditions. Cationic surfactants,
such as quaternised triethanolamine esters of fatty acids (TEA-
esterquats), are known to be efficiently deposited onto cotton in
aqueous media and thus find use as fabric softening agents.14 With
its quaternary ammonium function, hydrazide 3 seemed to be a
promising candidate to facilitate the deposition of the dynamic
mixture onto the target surface, and was therefore selected to
initiate the study of these fragrance delivery systems.
In a simple experiment, a mixture of six fragrance aldehydes and
ketones (4-phenyl-2-butanone, (R)-3,7-dimethyl-6-octenal ((+)-
citronellal), (¡)-3-phenylbutanal, acetophenone, (Z)-4-dodecenal
and 10-undecenal) and an equimolar amount of 3 were added to
Table 1 Observed pseudo-first order kinetic rate constants and half-life times to reach the equilibrium for the formation and hydrolysis of
acylhydrazones 4–6 at pH 2.47 and 4.48. All data are average values of at least two measurements, with standard deviations ,0.09 6 1024
pH 2.47
acylhydrazone kobs 6 104 [s21
pH 4.48
pH 2.47
t1/2 [h] acylhydrazone kobs 6 104 [s21
pH 4.48
Formation of
Hydrolysis of
]
t1/2 [h] kobs 6 104 [s21
]
]
t1/2 [h] kobs 6 104 [s21
]
t1/2 [h]
4a
4b
4c
5a
5b
5c
6a
6b
a
9.93
8.35a
3.34
6.10
6.44b
2.57
5.53c
5.54
b
0.19
0.23
0.58
0.32
0.30
0.75
0.35
0.35
0.41
0.24
0.31
0.29
0.13
0.23
0.15
0.11d
4.7
8.0
6.2
6.6
14.8
8.4
12.8
17.5
4a
4b
4c
5a
5b
5c
6a
6b
10.82
10.79
3.29
6.43
6.61
2.01
5.98
4.94
0.18
0.18
0.59
0.30
0.29
0.96
0.32
0.39
0.30
0.18
0.14
0.18
0.11
0.08
0.11
0.09
6.4
10.7
13.8
10.7
17.5
24.1
17.5
21.4
¡0.61, r2 . 0.98. ¡0.16. Observation of a baseline drift in the UV/Vis spectrum, r2 . 0.99. Average r2 . 0.96.
c
d
2966 | Chem. Commun., 2006, 2965–2967
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Fig. 2 Comparison of the headspace concentrations (in ng/l of air) measured for the evaporation of a mixture of fragrance aldehydes and ketones on a
dry cotton sheet in the presence (—$—) or absence (—#—) of hydrazide 3.
3 For some reviews see: J.-M. Lehn, Chem.–Eur. J., 1999, 5, 2455;
We thank Maude Gaillard for assistance in the preparation of
G. R. L. Cousins, S.-A. Poulsen and J. K. M. Sanders, Curr. Opin.
some of the compounds, Dr Jean-Yves de Saint-Laumer for the
Chem. Biol., 2000, 4, 270; S. J. Rowan, S. J. Cantrill, G. R. L. Cousins,
calculation of vapour pressures and Dr Roger Snowden for
constructive comments on the manuscript.
J. K. M. Sanders and J. F. Stoddard, Angew. Chem., Int. Ed., 2002, 41,
898; S. Otto, R. L. E. Furlan and J. K. M. Sanders, Curr. Opin. Chem.
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11, 1708.
Notes and references
{ Procedure for the kinetic measurements: phosphate and citrate buffer
stock solutions (0.15 M, I = 0.1) were prepared in water/ethanol 4 : 1. All
UV/Vis measurements were carried out in quartz cuvettes (1 cm) by adding
0.4 ml of hydrazine derivative and aldehyde or the corresponding
hydrazone. UV/Vis spectra were recorded at constant time intervals
between 240 and 450 nm (every 5 or 10 min at pH 2.47, and every 30 or
60 min at pH 4.48, respectively). The rate constants were determined from
the change of absorption measured at 290 nm (benzaldehyde) or 320 nm
(cinnamaldehyde and vanillin), with Dt = 1 or 2 h (pH 2.47) or Dt = 7.5 or
15 h (pH 4.48).
{ Procedure for the headspace analysis: to 1.80 g of a TEA-esterquat
(Stepantex1, 16.5% by weight in water) were added 1 ml of ethanol
containing the six fragrance molecules (each at 0.041 M), and 1 ml of 3
(0.248 M) in water (or 1 ml of pure water, reference). 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 6 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.
200 ml/min at 25 uC. The air was filtered through active charcoal and
aspirated through a saturated solution of NaCl. During 15 min the system
was left equilibrating, then the volatiles were adsorbed during 15 min onto
a clean Tenax1 cartridge. The sampling was repeated every hour (8 times).
The cartridges were desorbed thermally and analysed by GC-FID.
Headspace concentrations (in ng/l of air) were obtained by external
standard calibration.
4 For recent work see: B. Shi and M. F. Greaney, Chem. Commun., 2005,
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double bond, and as syn isomers (4 and 5) or as a mixture of anti and
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15 For the compounds used in this work the following vapour pressures
were calculated with the EPIwin v 3.10 program (US Environmental
Protection Agency, 2000): 2.4 Pa ((Z)-4-dodecenal), 8.7 Pa (4-phenyl-2-
butanone), 8.7 Pa (10-undecenal), 11.4 Pa ((¡)-3-phenylbutanal),
37.3 Pa ((+)-citronellal) and 43.5 Pa (acetophenone).
1 A. Herrmann, The Spectrum (Bowling Green), 2004, 17(2), 10.
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Chem. Commun., 2006, 2965–2967 | 2967